- Email: [email protected]
Genetic predisposition for pancreatic cancer
CHAPTER 8
Genetic predisposition for pancreatic cancer Irina Nakashidze1, a, Sarfraz Ahmad2, a 1
Departments of Biology and Clinical Medicine, Faculty of Natural Sciences and Health Care, Batumi Shota Rustaveli State University, Batumi, Georgia; 2Department of Gynecologic Oncology, AdventHealth Cancer Institute, FSU and UCF Colleges of Medicine, Orlando, FL, United States
Abstract Pancreatic cancer (PC) is widely prevalent in the world and is the fourth leading cause of cancer-related deaths. Most patients with PC present with advanced or metastatic disease. Despite advances in the development of radiological techniques and chemotherapeutic drugs, PC still has a poor prognosis. There are several risk factors for PC, among the most prominent of which are cigarette smoking, a high body mass index particularly during early adulthood, and diabetes mellitus. It is suggested that genetic susceptibility and predisposition for PC is a crucial factor. To investigate the single nucleotide polymorphisms, it is important to have a better understanding of the molecular biology and predictive tests for PC. Therefore, it is crucial to identify positive predictive factors because genetics have a prominent role in PC development. In this chapter, we discuss the association between the polymorphism of some candidate genes and PC. Taken together, the genetic polymorphism of contributed genes in PC suggests that genetic susceptibility and predisposition might be involved in the development of PC. Notably, different genetic variants may act together and alter susceptibility to PC. It is hoped that genetic signatures coupled with available standards of care (better-matched therapies) may provide a more personalized approach to managing patients with PC.
Keywords: Clinical outcomes; Gene mutation; Genetic predisposition; Genetic susceptibility; Genetic variants; Pancreatic cancer; Predictive markers; Single nucleotide polymorphism.
List of abbreviations ABO A system of four basic types of blood (A, AB, B, and O) APC Advanced pancreatic cancer FPC Familial pancreatic cancer GSTT1 Glutathione S-transferase q1 a
All authors have diligently contributed to the conception, literature search, data interpretation, and manuscript writing, and have approved the final draft for publication.
G.P. Nagaraju, S. Ahmad (eds.) Theranostic Approach for Pancreatic Cancer ISBN 978-0-12-819457-7 https://doi.org/10.1016/B978-0-12-819457-7.00008-6
Copyright © 2019 Elsevier Inc. All rights reserved.
153
154
Theranostic Approach for Pancreatic Cancer
GSTM1 Glutathione S-transferase Mu1 GWAS Genome-wide association studies MTHFR Methylenetetrahydrofolate reductase PC Pancreatic cancer PALB2 Partner and localizer of BRCA2 PDAC Pancreatic ductal adenocarcinoma SNP Single nucleotide polymorphism TGF-b Transforming growth factor-b VD Vitamin D VDR Vitamin D receptor
Introduction/background Pancreatic cancer (PC) is widely prevalent in the world and is the fourth leading cause of cancer-related deaths [1]. In addition, PC has among the highest mortality rates from cancer in the world, with an estimated 45,750 deaths in 2019 alone in the United States [2]. There are several risk factors for PC, the most prominent of which are cigarette smoking, a high body mass index particularly during early adulthood, and diabetes mellitus [3e6]. Previous studies suggested that genetic and environmental factors contribute to the progression and development of PC susceptibility [7,8]. Several genetic and genome instabilities and alterations are revealed in PC. Genetic alteration such as point mutations, amplifications, deletions, translocations, frameshifts, substitution, and inversions significantly increase the risk for PC; they are found in about 97% of patients with PC [9]. Based on an analysis of multiple genes, it is suggested that the genetic susceptibility and predisposition for PC is a crucial factor. Alterations in methylation of enzymes, genes, and oncogenes (e.g., Diamond-Blackfan anemia repairing genes) and within the genes responsible for cell cycle processes are major risk factors for PC [10]. Despite this, the etiology of PC remains unclear.
Single nucleotide polymorphisms and pancreatic cancer To investigate single nucleotide polymorphisms (SNP), it is important to have a better understanding of molecular biology and predictive assessments for PC. Therefore, it is crucial to identify positive predictive factors because the contribution of epigenetics has a prominent role(s) in PC development [11,12]. Genomic analysis confirmed several ongoing events involved in pancreatic tumorigenesis, among which mutations in the following genes have been implicated: KRAS, TP53, SMAD4, and CDKN2A [13]. It is well-known that mutated KRAS genes contribute significantly to the
Genetic predisposition for pancreatic cancer
155
development of PC, particularly in pancreatic ductal adenocarcinoma (PDAC) [14]. There is positive association between the polymorphism of some candidate genes and PC. Notably, SMAD4 gene mutations have a positive correlation with worse prognosis and outcomes of PC [15]. Hori and colleagues [16] showed that polymorphisms in TP53 codon 72 and MDM2 SNP 309 might be useful for studying the molecular diagnosis of PDAC. The KRAS gene has a crucial role(s) in PDAC and may represent a key target for disease treatment. Frequencies of genetic and epigenetic alterations are high in pancreatic adenocarcinoma. Based on the investigation, KRAS mutation (in codon 12) occurs in PC. It is suggested that KRAS mutation is involved in initiating PDAC; notably, it is found at about 95% in the preneoplastic stages of pancreatic intraepithelial neoplasia [17]. Based on the study of 2249 patients with PC (including tissue detection studies), Tao et al. [18] argued that mutations in K-ras genes are associated with a relatively poorer prognosis in patients with PC. A study by Boeck and colleagues [19] showed that KRAS codon 12 was mutated in 121 of 173 patients (70%). According to this study [19], KRAS wild-type patients improved during second-line chemotherapy (hazard ratio ¼ 1.68; p ¼ .005), which suggests that KRAS may be a useful prognostic and predictive biomarker in PC [19]. The study also suggested that KRAS mutation was detected in 96% of patients with PC. Thus, it is evident that K-ras mutation is useful for the treatment of PC and may be a reliable prognostic factor. Using the Sanger sequencing system, the exonic regions of the following crucial genes were noted: KRAS, TP53 (p53), CDKN2A (p16), SMAD4, ZIP4, and PDX-1 in two cell lines of mouse PC cells and healthy syngeneic mouse pancreas. With the reference mouse genome sequence, it was suggested that SMAD4 homozygote G to T mutation in the first position of codon 174 (GAA) mutation was present in both cell lines [20]. Notably, the SNP in KRAS gene (TAT to TAC at codon 32) was in the syngeneic mouse (from normal pancreas DNA) and both tumoral cells. According to this study [20], there was no mutation or SNP in CDKN2A (p16), TP53 (p53), ZIP4, or PDX-1 genes in both cell lines. Therefore, it was presumed that in the absence of mutations in KRAS, TP53, and CDKN2A genes, which were considered significant genes in PC development, SMAD4 may have a central role in mouse PC [20]. According to another study [21], mutations in the genes with unknown functions were mostly detected at a trinucleotide repeat containing 18,
156
Theranostic Approach for Pancreatic Cancer
locus 728,190, poliovirus receptor-related immunoglobulin domain, SH3-domain binding protein 2, transmembrane protein 168, DEAD box protein 60, and NHL repeat containing 2. The same study confirmed the tumoral heterogeneity of PDAC and identified known mutations in the genes involved in the RAS signaling, the p53 pathway, and transforming growth factor-b (TGF-b) signaling, including SMAD4 and SMAD3 mutations, which suggests that RAS gene mutation is involved in the allelic imbalance in human tumors. About 75% of the PDAC patients carry the mutation in TP53. At the later stages of the disease, an ongoing missense mutation in TP53 and SMAD4 tumor suppressor genes occurs. Within the PC, Smad4 has a close association with the metastatic disease. As about the Smad4 functions, it is considered to be downstream for the TGF-b signaling network [22]. Clinical evidence suggests that TP53 (the tumor suppressor gene) has prominent roles in several conditions. Research showed that mutation in the TP53 gene is common for PC; nearly 70% is mutated [23]. Thus, TP53 could be used as a biomarker for PC prognosis and treatment [24]. Several P53 gene mutations are found in tumors [25], which affects PDAC. Studies also showed that patients with low TP53 mRNA expression have a worse prognosis [26]. It is well-established that adenomatous polyposis coli (APC) genes are essential during the malignant transformation of gastrointestinal cells. The study conducted by Shamai et al. [27] showed that genetic variants of APC (I1307K and E1317Q) and four different SNPs in the CD24 gene (C170T [rs52812045], TG1527del [rs3838646], A1626G [rs1058881], and A1056G [rs1058818]) are involved in the process. The authors argued that these gene SNPs of APC and CD24 genes may contribute to PC development [27]. Genetics polymorphisms of SLC22A3 gene showed that the SNPs rs2504938, rs9364554, and rs2457571 had a significant impact on the risk for PC [28]. rs7758229 is associated with distant metastases of PC. According to that study, rs512077 and rs2504956 correlated well with the survival of PC. The common variation in the SLC22A3 gene is unlikely to contribute significantly to PC risk. Remarkably, rs2504938 SNP in SLC22A3 was significantly associated with an unfavorable prognosis for patients with PC [28]. A hospital-based, case-control study of white Czech-origin people (500 individuals among the 235 cases and 265 controls), involving SOD2, SOD3, NQO1, and NQO2 polymorphisms, revealed the association for
Genetic predisposition for pancreatic cancer
157
PC risk [29]. Lifestyle factors (such as smoking and alcohol, and coffee or tea consumption) did not modify the effect on the studied gene polymorphisms [29]. In a study of a German population, investigation of NR5A2 SNPs showed an association between the rs12029406_T allele and shorter survival [30]. Furthermore, based on Japanese subjects in a case-control study, rs3790843 and rs3790844 of NR5A2 gene were associated with PC [31]. A study with Chinese patients revealed that interleukin (IL)-6-634 CG þ GG genotype was associated with a relatively shorter duration of survival compared with the CC genotype (p ¼ .023). It is therefore plausible that carriers of IL-6-634 CG þ GG genotype may have increased susceptibility toward decreased survival for PC [32].
BRCA1/2 gene polymorphism and pancreatic cancer BRCA1 belongs to the tumor suppressor gene located on chromosome 17q21. BRCA1/2 belongs to autosomal dominant genes and has incomplete penetrance [33]. The mutation in BRCA1/2 genes is a common mutation in familial breast and ovarian cancers in the Ashkenazi Jewish population [34]. BRCA1 and BRCA2 tumor suppressor genes also have prominent roles in the DNA repair processes. Therefore, mutations in BRCA1/2 genes are associated with tumorigenesis of PC. BRCA1 and BRCA2 mutations are predisposed to a higher rate of lifetime risk among the female-specific cancers (e.g., breast, ovarian) [35] and are known to have several mechanisms, but correlations between the BRCA1/2 polymorphisms and PC prognosis is relatively less known. A family history of PC has been observed to predict the presence of a BRCA2 mutation, and PC is more frequent in breast cancer families with BRCA2 mutations than in families without the mutation [36]. Investigators showed that in families with PC, BRCA2 mutations are more likely. Female carriers of BRCA1/2 mutations who have a high risk for breast and ovarian tumors also tend to develop PC. Somatic mutations and germline genetic variants on BRCA1/2 have been found to be associated with tumorigenesis of PC. Also, PC frequency is relatively high within breast cancer families (carrier) of the BRCA2 mutation compared with families with absence of BRACA2 gene mutations. Murphy and colleagues [37] indicated that BRCA2 mutation increases the risk for PDAC; the mutation is common in up to 17% of familial pancreatic cancer (FPC) kindreds.
158
Theranostic Approach for Pancreatic Cancer
The development of PC risk increases about 10 times in carriers of BRCA2 gene mutations [38]. The sporadic mutation gene is a protein that subsequently contributes to tumorigenesis [39]. Zhu and colleagues [40] genotyped the Chinese population’s three tag missense variants on BRCA1/2 among 603 sporadic PC patients and revealed that rs1799966 on BRCA1 was associated with a poor prognosis for patients with PC who had locally advanced-stage disease.
PALB2 gene polymorphism and pancreatic cancer Studies showed that mutations in the partner and localizer of BRCA2 (PALB2) gene are at an increased risk for breast and PC. The PALB2 protein binds with BRCA2 protein, stabilizing it in the nucleus [41]. In a study, carriers of BRCA2 mutations from 180 families showed high risks for PC [42]. A study by Slater et al. [43] involving 81 familial PC patients, based on the sequencing of 13 exons of the PALB2 gene, identified three truncating PALB2 mutations (3.7%) (in different stop codons: R414X, 5089delAG, and 3116delA). Notably, these three families also had a history of breast cancer. Another study [44] confirmed that PALB2 mutations tend to increase the risk for FPC; the PC risk prevalence was 3.1% based on the sequenced PALB2 gene within 96 patients with FPC. The study concluded that PALB2 mutations are involved in FPC. Klein et al. [45] argued that PC has characteristic genetic components that are also based on other factors, including family history, which increases the tendency and risks for PC [46,47]. A study revealed that mutation of the PALB2 gene is about 2%, based on unselected Czech PDAC [48]. Stratford et al. [49] showed that a six-gene signature might be used for better staging of patients with PDAC and may result in useful treatment decisions for surgery or management of the disease. These observations also suggest that these genes may be useful potential biomarkers for the disease [49].
Vitamin D receptor gene polymorphism and pancreatic cancer As a member of the nuclear receptor protein family, vitamin D (VD) receptor (VDR) is widely distributed and found in several human cell types. VD has a prominent role in several pathophysiologic processes in the human body. It contributes to maintenance of the serum calcium level by adjusting the calcium-phosphorus balance in the blood. It also has a crucial role in cell-cycle regulation [50] by inhibiting cell proliferation [51] and
Genetic predisposition for pancreatic cancer
159
facilitating cell differentiation [52], angiogenesis [53], aging, cellular proliferation, differentiation, and T cellemediated immune responses [54]. It is well-known that VDR gene contributes in VD signaling (acting as a kind of hormone for protective effects against several cancers). Based on an epidemiological investigation, it has become clear that dietary VD as well as sunlight exposure may be characterized as protective agents against PC [55]. The VDR gene is associated with the development of different types of tumors, including PC, but the exact mechanism of this protective effect (association) is unclear. Studies have also revealed that VD deficiency is highly prevalent among patients with a new diagnosis of advanced PC [56]. Previous studies suggested that there is lower PC risk with proxy markers of higher VD status. Epidemiological and clinical investigations support the ideas that VD has a protective function against PC [57] and that VDR prevents tumorigenesis. VDR is believed to prevent tumorigenesis in three significant ways. First, activated VDR could upregulate the activity of cycle-dependent kinase inhibitors such as p21waf1, p27kip1, and E-cadherin [58], which impede cellecell proliferation at G0/G1 stagnation of the cell cycle [59]. Second, VD via the VDR could inhibit tumorigenesis and tumor cell proliferation by regulating such signaling pathways as b-catenin, nuclear factor-kb, and Hedgehog signaling pathways [60,61]. Third, the VDR can also induce tumor cell apoptosis by downregulating the Bcl-2 gene [62]. In a detailed study, Li and colleagues [63] investigated the association between VD receptor gene rs2228570 and rs1544410 polymorphisms and PC. The authors evaluated 643 patients (258 PC and 385 control cases), the analysis was performed to study the relation between the noted gene polymorphisms and some pathological differentiation, and the tumor, node, metastasis classification of PC. Based on this study [63], in rs2228570, the T loci and genotypes with T allele may increase the risk for PC. For the rs1544410, the G loci and genotypes AG þ GG also tend to decrease the onset risk for PC development [63]. The study was based on the North Chinese population, which suggested that FokI and BsmI polymorphisms have a higher risk for PC development. Importantly, the FF genotype showed noticeable differences between PC patients and control subjects (p ¼ .009). Also, distribution of FF and Ff/ff frequency was significant (p ¼ .002). This investigation revealed that genotypes ffbb and Ffbb have an increased risk for PC (11.66- and 6.42-fold, respectively) [64]. A study showed that VDRs are expressed in pancreatic tumor stroma and mediate stromal reprogramming to suppress pancreatitis and PC [65].
160
Theranostic Approach for Pancreatic Cancer
Ciesli nska et al. [66] showed that polymorphism Taq-1 in the VDR may have a prominent role in the development of acute pancreatitis. The study was based on the Caucasian population and revealed that the CYP24A1 rs2585428 SNP tended to decrease the risk for PC [66]. Furthermore, based on multiple studies (including the clinical and genetic characteristics), genetic variation in the VDR may become a useful and novel target for PC investigation, diagnostics, and drug treatment, improving the outcomes of chemotherapy [67].
ABO system gene polymorphism and pancreatic cancer Several investigations have shown an association between ABO system genes and the risk for PC. According to genome-wide association studies (GWAS), there is an association between ABO gene polymorphisms and PC risk [68]. A population-based case-control study and metaanalysis indicated that ABO blood group A has an increased risk for PC in Western populations [69]. According to a GWAS study, ABO alleles are associated with an increased risk for PC. ABO glycosyltransferase can alter oligosaccharides on cell surface glycoproteins. Variations in the ABO gene have an important role in different enzyme activities [70]. It is known that ABO glycosyltransferase is located within the first intron of the ABO gene, which encodes ABO glycosyltransferase [71]. Studies have also shown an association between blood group antigens and cancers, including PC [72]. The first GWAS for PC was found to have common risk variants that map to the first intron of the ABO gene on chromosome 9q34.2; these findings revealed that there was a lower risk among individuals with blood group O compared with those with blood group A or B [69]. According to the second GWAS for PC, three loci (on chromosomes 13q22.1, 1q32.1, and 5p15.33) were found associated with PC susceptibility [73]. Based on these studies, the SNP variation at rs505922 tends to develop PC [71,73]. Amundadottir et al. [71] showed that rs505922 SNP within the ABO gene is associated with PC across all ethnic groups, and for SNP rs505922 heterozygous, the odds ratios (OR) were 1.20 and 1.44, respectively. In addition, based on a metaanalysis, Duan et al. [74] revealed that there is a noticeable association between SNP variation rs505922 and cancer susceptibility to PC. Accordingly, the ABO gene rs505922 C > T polymorphism showed a strong association with PC, and the risk of allele BC^ carriers had an OR of 1.35 for PC [74].
Genetic predisposition for pancreatic cancer
161
A study conducted by Xu et al. [75] revealed that carriers of the C allele of rs505922 tended to develop cancer (adjusted OR ¼ 1.42; 95% confidence interval [CI], 1.02e1.98) compared with TT carriers. Based on that investigation, haplotype analysis showed that the haplotype CTTC was associated with an increased risk for PDAC (adjusted OR ¼ 1.46; 95% CI, 1.12e1.91) compared with haplotype TGGT. The study confirmed that there was an association between the ABO SNP and PDAC risk in the Chinese population [75]. Using rs8176719 as a marker for the O allele, and rs8176746 and rs8176747 for the B allele, based on a case-control study (using 185 PC and 1465 control cases), Nakao and colleagues [76] revealed that the PC risk increased with any non-O allele (p ¼ .012). Notably, the AO and BB genotypes had significantly increased ORs of 1.67 (CI, 1.08e2.57) and 3.28 (CI, 1.38e7.80), respectively. Based on this case-control study, in the Japanese population, there is a significant association between the ABO blood group and PC risk [76]. Studies on the large two independent population, using the ABO system, showed a correlation with risk for PC development [77]. Based on the metaanalysis, a significant association was noted between rs505922 C > T polymorphism on the ABO gene and PC risk [74]. Based on a population-based, case-controlled study and in a metaanalysis, Risch and colleagues [69] showed that carriers of A had a higher tendency to develop PC. Also, Greer et al. [61] revealed that the A group had characteristics that increased the risk for PC, and O decreased the risk for this disease [61]. Thus, it is reaffirmed that genetic polymorphisms affect genetic instability and have prominent role(s) in PC development.
XRCC2/XRCC3 gene polymorphism and pancreatic cancer The XRCC2 gene, located at 7q36.1, is involved in the development of several cancers. As about the XRCC3 gene, located at chromosome 14q32.3, have a tendency for some cancers such as lung and gastric cancers, including PC [78,79]. Talar-Wojnarowska et al. [80] showed that there is no association between the XRCC2 and XRCC3 polymorphisms and PC. The authors showed that in smokers, carriers of XRCC2 Arg188Arg mutations have a high risk for PC compared with subjects who never smoked. Variations in the XRCC2 polymorphism may have some roles in susceptibility to PC, especially when there is significant exposure to cigarette carcinogens [81]. Studies also showed a risk-modifying effect of
162
Theranostic Approach for Pancreatic Cancer
the XRCC2 Arg188His polymorphism among smokers with PC [82]. However, the evidence did not suggest that the analyzed XRCC2 and XRCC3 polymorphisms were directly associated with PC risk, and correlations between the XRCC2 and XRCC3 polymorphisms and the clinical data of PC patients could be ascertained. The XRCC2 and XRCC3 genes have an essential role in maintaining genomic stability, as evidenced by an investigation of genetic polymorphisms in DNA repair that alter the protein functions and eventually increases genetic alterations in the genome [82]. The Arg188His polymorphism within XRCC2, tend to develop PC [83]. As noted earlier, Talar-Wojnarowska et al. [80] revealed that XRCC2 and XRCC3 polymorphisms were not directly associated with PC risk. Interestingly, the XRCC2 Arg188His polymorphism was shown to have an association with smoking-related PC [81]. Thus, these studies confirm that mutation of XRCC2 and XRCC3 gene polymorphism is an ambiguous phenomenon.
MTHFR gene single nucleotide polymorphism and pancreatic cancer It is well-known that methylenetetrahydrofolate reductase (MTHFR) has a vital role in folate metabolism. Studies support the idea that the gene polymorphism contributes to PC risk. Research confirmed that the C667T polymorphism affects the risk for PC [84e86]. Investigations revealed that the frequencies of MTHFR 667CC, 667CT, and 667 TT genotypes were 49.5%, 38.6%, and 11.9% among cases compared with controls (48.5%, 45.0%, and 6.5%, respectively) [84]. Notably, carriers of the 667 TT genotype have two times the increased risk for PC compared with carriers of CC/CT genotypes (OR¼ 2.14; 95% CI, 1.14e4.0). Also, a positive correlation was revealed among the 677 TT genotype, heavy cigarette smoking or heavy alcohol consumption, and PC risk [84]. Another study reported that carriers of MTHFR 677CT (OR ¼ 2.60; 95% CI, 1.61e4.29; p ¼ .0005) or 677 TT (OR ¼ 5.12; 95% CI, 2.94e9.10; p < .0001) genotypes have an increased risk for PC compared with the MTHFR CC genotype. In that study, the MTHFR C677T polymorphism and smoking or drinking tended to increase the risk for PC [85]. A metaanalysis by Tu et al. [86] indicated that there was no association between MTHFR polymorphisms (C667T and A1298C) and PC risk.
Genetic predisposition for pancreatic cancer
163
GSTM1 and GSTT1 gene single nucleotide polymorphisms in pancreatic cancer Glutathione S-transferase q1 (GSTT1) and glutathione S-transferase Mu1 (GSTM1) gene polymorphisms are involving in the development of several tumors, including PC; however, the results are confusing. A metaanalysis [87] showed that the null genotype of GSTT1 is associated with an increased risk for PC (OR ¼ 1.61; 95% CI, 1.06e2.44; POR ¼ .025, respectively). However, the association with the GSTT1 gene polymorphism was reported to be significant higher in Asians (OR ¼ 02.58; 95% CI, 1.67e3.98; POR < .001). According to that study, GSTM1 did not have an association with PC risk [87]. Yamada and colleagues [88] indicated that in the Japanese population, there was no association between the GSTM1 and GSTT1 deletion polymorphisms and the development of risk for PC. Another study [89] on the three GST genes confirmed that PC risk could be for older individuals (aged > 62 year) who were carriers of the GSTP1*C (105Val-114Val) genotype and had a reduced risk compared to with younger patients who did not carry the *C genotype. The same study confirmed that patients carrying the GSTP1*C genotype had significantly prolonged survival compared with those with the non-*C genotype (multivariate hazard ratio, 0.45; 95% CI, 0.22e0.94) [89].
Steroid hormone receptor polymorphism and pancreatic cancer Investigations showed that sex steroid hormones also participate in the development of PC (including studies in male and female rats) [90e92]. Based on some select studies, hormones reflect the promotion and progression stages of carcinogenesis, especially in promoting or inhibiting carcinogenesis [90]. According to investigations, women who used menopausal hormone therapy had a reduced risk for PC [91]. Konduri et al. [92] demonstrated that estrogen and its metabolites inhibited PC cell growth in in vitro studies. Androgen receptor (NR3C4) and estrogen receptors-a and -b (NR3A1 and NR3A2) belong to the steroid receptor subfamily (NR3), which regulates several physiological processes. Among them is the development of some types of malignancies [93,94].
164
Theranostic Approach for Pancreatic Cancer
Mitochondrial gene polymorphism and pancreatic cancer Mitochondria vitally participate in several cellular processes, and mitochondrial DNA mutation increases the risk for PC development [95]. An investigation revealed an association between the mitochondrial gene polymorphism and PC survival [96]. Studies found 24 somatic mutations within mitochondrial DNA and demonstrated that metabolic changes are consistent with mitochondrial dysfunction, including reduced oxygen consumption and increased glycolysis [97,98].
Conclusions Early diagnosis of PC has remained problematic. The development and progression of the disease are caused by complex factors such as genetics and the environment, which are difficult to identify and are decisive factors. It is clear that PC is a polygenic disease, because there are several known genes with high-risk susceptibility alleles. Genetic polymorphisms have important roles in the risk for PC, as demonstrated by a number of investigations. SNPs are useful as a molecular marker for understanding the genetic predisposition for PC. Molecular markers are the most fundamental part for assessing the genetic peculiarities of PC, but despite considerable interest in best prognostic biomarkers for early detection, diagnosis and treatment of the disease remains challenging. The genetic polymorphism of contributing genes in PC suggests that genetic susceptibility and predisposition are likely involved in the development of PC. Different genetic variants may act together and alter susceptibility to PC. Finally, geneegene and genee environmental interactions may also alter contributions to PC development in humans.
References [1] Siegel R, Naishadham D, Jemal ACA. Cancer statistics. Cancer J Clin 2013;63(1):11e30. [2] Society AC. Cancer facts & figures 2019. Atlanta: American Cancer Society; 2019. [3] Iodice S, Gandini S, Maisonneuve P, Lowenfel AB. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbeck’s Arch Surg 2008;393(4):535e45. [4] Li D, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. J AMA 2009;301(24):2553e62. [5] Vrieling A, et al. Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European prospective investigation into cancer and nutrition. Int J Cancer 2010;126(10):2394e403.
Genetic predisposition for pancreatic cancer
165
[6] Eijgenraam P, et al. Diabetes type II, other medical conditions and pancreatic cancer risk: a prospective study in the Netherlands. Br J Cancer 2013;109(11):2924e32. [7] Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer 2002;2(12):897e909. [8] Hocevar, et al. Contribution of environment and genetics to pancreatic cancer susceptibility. PLoS One 2014;9(3):e90052. https://doi.org/10.1371/ journal.pone.0090052. [9] Cicenas J, Kvederaviciute K, Meskinyte I, Meskinyte-Kausiliene E, Skeberdyte A, Cicenas J. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 mutations in pancreatic cancer. Cancers 2017;9(5):42. https://doi.org/10.3390/cancers9050042. [10] Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog 2012;51(1):14e24. [11] Kwon HM, Kang EJ, Kang K, Kim SD, Yang K, Yi JM. Combinatorial effects of an epigenetic inhibitor and ionizing radiation contribute to targeted elimination of pancreatic cancer stem cell. Oncotarget 2017;8(51):89005e20. https://doi.org/ 10.18632/oncotarget.21642. [12] Nguyen AH, et al. Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts. Oncotarget 2017;8(12):19074e88. https://doi.org/10.18632/oncotarget.13572. [13] Bailey P, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016;531(7592):47e52. [14] Garcia MN, et al. IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation. J Clin Investig 2014;124(11):4709e22. [15] Blackford A, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 2009;15(14):4674e9. https://doi.org/10.1158/ 1078-0432.CCR-09-0227. [16] Hori Y, et al. Impact of TP53 codon 72 and MDM2 SNP 309 polymorphisms in pancreatic ductal adenocarcinoma. PLoS One 2015;10(3):e0118829, https://doi.org/ 10.1371/journal.pone.0118829. [17] Kanda M, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012;142(4):730e3. e9. [18] Tao LY, Zhang LF, Xiu DR, Yuan CH, Ma ZL, Jiang B. Prognostic significance of Kras mutations in pancreatic cancer: a meta-analysis. World J Surg Oncol 2016;14:146. https://doi.org/10.1186/s12957-016-0888-3. [19] Boeck S, Jung A, Laubender RP, et al. KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. J Gastroenterol April 2013;48(4):544e8. https://doi.org/10.1007/ s00535-013-0767-4. Epub 2013 Feb 23. [20] Wang Y, et al. Genomic sequencing of key genes in mouse pancreatic cancer cells. Curr Mol Med 2012;12(3):331e41. [21] Di Marco M, et al. Characterization of pancreatic ductal adenocarcinoma using whole transcriptome sequencing and copy number analysis by single-nucleotide polymorphism array. Mol Med Rep 2015;12(5):479e7484, https://doi.org/10.3892/mmr. 2015.4344. [22] Malkoski SP, Wang XJ. Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett 2012;586(14):1984e92. [23] Hwang RF, Gordon EM, Anderson WF, Parekh D. Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene. Surgery 1998;124(2):143e50. https://doi.org/10.1016/S0039-6060(98) 70114-X.
166
Theranostic Approach for Pancreatic Cancer
[24] Grochola LF, Taubert H, Greither T, Bhanot U, Udelnow A, Würl P. Elevated transcript levels from the MDM2 P1 promoter and low p53 transcript levels are associated with poor prognosis in human pancreatic ductal adenocarcinoma. Pancreas 2011;40(2):265e70. [25] Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev 2012;26(12):1268e86. [26] Xiang JF, et al. Mutant p53 determines pancreatic cancer poor prognosis to pancreatectomy through upregulation of cavin-1 in patients with preoperative serum CA199 1,000 U/mL. Sci Rep 2016;6:25115. https://doi.org/10.1038/srep25115. [27] Shamai S, et al. CD24 and APC genetic polymorphisms in pancreatic cancers as potential biomarkers for clinical outcome. PLoS One 2015;10(9):e0134469. https:// doi.org/10.1371/journal.pone.0134469. [28] Mohelnikova-Duchonova B, et al. SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival. Sci Rep 2017;7:43812. https:// doi.org/10.1038/srep43812. [29] Mohelnikova-Duchonova B, Marsakova L, Vrana D, Holcatova I, Ryska M, Smerhovsky Z, Slamova A, Schejbalova M, Soucek P. Superoxide dismutase and nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase polymorphisms and pancreatic cancer risk. Pancreas 2011;40(1):72e8. https://doi.org/10.1097/ MPA.0b013e3181f74ad7. [30] Rizzato C, et al. Pancreatic cancer susceptibility loci and their role in survival. PLoS One 2011;6(11):e27921. https://doi.org/10.1371/journal.pone.0027921. [31] Ueno M, et al. Genome-wide association study-identified SNPs (rs3790844, rs3790843) in the NR5A2 gene and risk of pancreatic cancer in Japanese. Sci Rep 2015;5:17018. https://doi.org/10.1038/srep17018. [32] Zhang D, Zhou Y, Wu L, Wang S, Zheng H, Yu B, Li J. Association of IL-6 gene polymorphisms with cachexia susceptibility and survival time of patients with pancreatic cancer. Ann Clin Lab Sci 2008;38(2):113e9. [33] Thull DL, Vogel VG. Recognition and management of hereditary breast cancer syndromes. Oncologist 2004;9(1):13e24. [34] Ghadirian P, Liu G, Gallinger S, Schmocker B, Paradis AJ, Lal G, Brunet JS, Foulkes WD, Narod SA. Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. Int J Cancer 2002;97(6):807e10. [35] Apostolou P, Fostira F. Hereditary breast cancer: the era of new susceptibility genes. BioMed Res Int 2013:747318. https://doi.org/10.1155/2013/747318. [36] Phelan CM, et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996;13:120e2. [37] Murphy KM, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 2002a;62(13):3789e93. [38] Brentnall TA. Cancer surveillance of patients from familial pancreatic cancer kindreds (Review). Med Clin N Am 2000;84(3):707e18. [39] Stadler ZK, et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer 2012;118(2):493e9. https:// doi.org/10.1002/cncr.26191. [40] Zhu Y, et al. BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population. Oncotarget 2017;8(22):36033e9. [41] Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog 2011;51(1):14e24. https://doi.org/10.1002/mc.20855. [42] Couch FJ, et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomark Prev 2007;16(2):342e6.
Genetic predisposition for pancreatic cancer
167
[43] Slater EP, Langer P, Niemczyk E, Strauch K, Butler J, Habbe N, Neoptolemos JP, Greenhalf W, Bartsch DK. PALB2 mutations in European familial pancreatic cancer families. Clin Genet 2010;78(5):490e4. [44] Jones S, et al. APExomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009;324(5924):217. [45] Klein AP, Hruban RH, Brune KA, Petersen GM, Goggins M. Familial pancreatic cancer. Cancer J 2001;7(4):266e73. [46] Jacobs EJ, et al. Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Int J Cancer 2010;127(6):1421e8. [47] Ghadirian P, Boyle P, Simard A, Baillargeon J, Maisonneuve P, Perret C. Reported family aggregation of pancreatic cancer within a population-based case-control study in the Francophone community in Montreal, Canada. Int J Pancreatol 1991;10:183e96. [48] Borecka M, et al. Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic. Cancer Genet 2016;209(5):199e204. [49] Stratford JK, et al. A six-gene signature predicts survival of patients with localized Phelan CM, pancreatic ductal adenocarcinoma. PLoS Med 2010;7(7):e1000307. [50] Chiang KC, et al. MART-10, a novel vitamin D analog, inhibits head and neck squamous carcinoma cells growth through cell cycle arrest at G0/G1 with upregulation of p21 and p27 and downregulation of telomerase. J Steroid Biochem Mol Biol 2013;138:427e34. [51] Jehan F, d’Alesio A, Garabedian M. Exons and functional regions of the human vitamin D receptor gene around and within the main 1a promoter are well conserved among mammals. J Steroid Biochem Mol Biol 2007;103(3e5):361e7. 13. [52] Miyamoto K, et al. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol 1997;11(8):1165e79. [53] Greer J,B, Brand RE. New developments in pancreatic cancer. Curr Gastroenterol Rep 2011;13:131e9. [54] Mathieu C, van Etten E, Decallonne B, Guilietti A, Gysemans C, Bouillon R, Overbergh L. Vitamin D and 1,25-dihydroxyvitamin D3 as modulators in the immune system. (Review). J Steroid Biochem Mol Biol 2004;89e90(1e5):449e52. [55] Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 2013;144(6):1252e61. https://doi.org/10.1053/j.gastro.2013. 01.068. [56] van Loon K, et al. 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). J Natl Cancer Inst 2014;106(8). https://doi.org/10.1093/jnci/dju185. p. pii: dju185. [57] Vogt DP. Pancreatic cancer: a current overview. Curr Surg 2000;57(3):214e20. [58] Verlinden L, et al. Two novel 14-Epianalogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res 2000;60(10):2673e9. [59] Campbell MJ, et al. Inhibition of proliferation of prostate cancer cells by a 19-norhexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. J Mol Endocrinol 1997;19(1):15e27. [60] Jiang YJ, et al. 1alpha,25(OH)2- dihydroxyvitamin D3/VDR protects the skin from UVB-induced tumor formation by interacting with the beta-catenin pathway. J Steroid Biochem Mol Biol 2013;136:229e32. [61] Greer JB, et al. Significant association between ABO blood group and pancreatic cancer. World J Gastroenterol 2010;16(44):5588e91. [62] Rosli SN, et al. 1alpha,25OH2D3 downregulates HBp17/FGFBP-1 expression via NF-kappaB pathway. J Steroid Biochem Mol Biol 2013;136:98e101.
168
Theranostic Approach for Pancreatic Cancer
[63] Li L, et al. Role of vitamin D receptor gene polymorphisms in pancreatic cancer: a caseecontrol study in China. Tumor Biol 2015;36(4):4707e14, https://doi.org/10. 1007/s13277-015-3119-6. [64] Li L, Wu B, Yang L, Yin G, Wei W, Sui S, Liu J. Association of vitamin D receptor gene polymorphisms with pancreatic cancer: a pilot study in a North China population. Oncol Lett 2013;5(5):1731e5. [65] Sherman MH, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014;159(1):80e93. [66] Ciesli nska A, Kostyra E, Fiedorowicz E, Snarska J, Kordulewska N, Kiper K, Savelkoul H. Single nucleotide polymorphisms in the vitamin D receptor gene (VDR) may have an impact on acute pancreatitis (AP) development: a prospective study in populations of AP patients and alcohol-abuse controls. Int J Mol Sci 2018;19(7):1919. https://doi.org/10.3390/ijms19071919. [67] Innocenti F, et al. The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: genomic analysis and experimental validation. PLoS One 2018;13(8):e0202272, https://doi.org/10.1371/journal.pone.0202272. [68] Itzkowitz SH, et al. Cancer associated alterations of blood group antigen expression in the human pancreas. J Natl Cancer Inst 1987;79(3):425e34. [69] Risch HA, Lu L, Wang J, Zhang W, Ni Q, Gao YT, Yu H. ABO blood group and risk of pancreatic cancer: a study in Shanghai and meta-analysis. Am J Epidemiol 2013;177(12):1326e37. [70] Reid ME, Mohandas N. Red blood cell blood group antigens: structure and function. Semin Hematol 2004;41:93e117. https://doi.org/10.1053/j.seminhematol. 2004.01.001. [71] Amundadottir L, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41(9):986e90. [72] Annese V, Minervini M, Gabbrielli A, Gambassi G, Manna R. ABO blood groups and cancer of the pancreas. Int J Pancreatol 1990;6(2):81e8. [73] Petersen GM, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 2010;42(3):224e8. [74] Duan YF, Zhu F, Li XD, An Y, Zhang H, Zhou Y, Zhang X, Jiang Y. Association between ABO gene polymorphism (rs505922) and cancer risk: a meta-analysis. Tumour Biol 2015;36(7):5081e7. https://doi.org/10.1007/s13277-015-3159-y. [75] Xu HL, et al. Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population. Chin J Cancer 2014;33(2):68e73. https://doi.org/10.5732/cjc.013.10060. [76] Nakao M, et al. ABO blood group alleles and the risk of pancreatic cancer in a Japanese population. Cancer Sci 2011;102(5):1076e80. https://doi.org/10.1111/j.13497006.2011.01907.x. [77] Wolpin BM, et al. ABO blood group and the risk of pancreatic cancer. J Natl Cancer Inst 2009;101(6):424e31. [78] Qin XP, Zhou Y, Chen Y, Li NN, Wu XT. XRCC3 Thr241Met polymorphism and gastric cancer susceptibility: a meta-analysis. Clin Res Hepatol Gastroenterol 2014;38(2):226e34. https://doi.org/10.1016/j.clinre.2013.10.011. [79] Nissar S, Sameer AS, Lone TA, Chowdri NA, Rasool R. XRCC3 Thr241Met gene polymorphism and risk of colorectal cancer in Kashmir, A case control study. Asian Pac J Cancer Prev 2014;15(22):9621e5. https://doi.org/10.7314/APJCP.2014. 15.22.9621.
Genetic predisposition for pancreatic cancer
169
[80] Talar-Wojnarowska R, G3ąsiorowska A, Olakowski M, Dranka-Bojarowska D, Lampe P, Smolarz B, Małecka-Panas E. Analysis of XRCC2and XRCC3 gene polymorphisms in pancreatic cancer. Biomed Rep 2015;4(2):236e40. [81] Jiao L, Hassan MM, Bondy ML, et al. XRCC2 and XRCC3 gene polymorphism and risk of pancreatic cancer. Am J Gastroenterol 2008;103(2):360e7. [82] Tambini CE, Spink KG, Ross CJ, Hill MA, Thacker J. The importance of XRCC2 in RAD51-related DNA damage repair. DNA Repair (Amst) 2010;9(5):517e25. [83] He Y, Zhang Y, Jin C, Deng X, Wei M, Wu Q, Yang T, Zhou Y, Wang Z. Impact of XRCC2 Arg188His polymorphism on cancer susceptibility, A meta-analysis. PLoS One 2014;9(3):e91202. https://doi.org/10.1371/journal.pone.0091202. [84] Li D. 5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer. Cancer Epidemiol Biomark Prev 2005;14(6):1470e6. https:// doi.org/10.1158/1055-9965.epi-04-0894. [85] Wang L, et al. Genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase and risk of pancreatic cancer. Clin Gastroenterol Hepatol 2005;3(8):743e51. [86] Tu YL, Wang SB, Tan, et al. MTHFR gene polymorphisms are not involved in pancreatic cancer risk: a meta-analysis. Asian Pac J Cancer Prev 2012;13(9):4627e30. [87] Fan Y, Zhang W, Shi C-Y, Cai D-F. Associations of GSTM1 and GSTT1 polymorphisms with pancreatic cancer risk. Tumor Biol 2012;34(2):705e12. https:// doi.org/10.1007/s13277-012-0598-6. [88] Yamada I, et al. Lack of associations between genetic polymorphisms in GSTM1, GSTT1 and GSTP1 and pancreatic cancer risk: a multi-institutional case-control study in Japan. Asian Pac J Cancer Prev 2014;15(1):391e5. [89] Jiao L, et al. Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer. Cancer 2007;109(5):840e8. https://doi.org/10.1002/cncr.22468. [90] Longnecker DS, Sumi C. Effects of sex steroid hormones on pancreatic cancer in the rat. Int J Pancreatol 1990;7(1e3):159e65, https://doi.org/10.1007/BF02924233. [91] Sadr-Azodi O, Konings P, Brusselaers N. Menopausal hormone therapy and pancreatic cancer risk in women: a population-based matched cohort study. United European Gastroenterol J 2017;5(8):1123e8. [92] Konduri S, Schwarz RE. Estrogen receptor beta/alpha ratio predicts response of pancreatic cancer cells to estrogens and phytoestrogens. J Surg Res 2007;140(1):55e66. [93] Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS, Chatterjee B. Androgen receptor: structural domains and functional dynamics after ligand-receptor interaction. Ann N Y Acad Sci 2001;949:44e57. [94] Culig Z, Klocker H, Bartsch G, Hobisch A. Androgen receptors in prostate cancer. Endocr Relat Cancer 2002;9:155e70. [95] Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 2005;39:359e407. [96] Halfdanarson TR, et al. Mitochondrial genetic polymorphisms do not predict survival in patients with pancreatic cancer. Cancer Epidemiol Biomark Prev 2008;17:2512e3. https://doi.org/10.1158/1055-9965.EPI-08-0460. [97] Wang L, et al. Mitochondrial genetic polymorphisms and pancreatic cancer. Cancer Epidemiol Biomark Prev 2007;16(7):1455e9. 1158/1055-9965.EPI-07-0119. [98] Hardie RA, et al. Mitochondrial mutations and metabolic adaptation in pancreatic cancer. Cancer Metabol 2017;5:2. https://doi.org/10.1186/s40170-017-0164-1.
Genetic predisposition for pancreatic cancer Irina Nakashidze1, a, Sarfraz Ahmad2, a 1
Departments of Biology and Clinical Medicine, Faculty of Natural Sciences and Health Care, Batumi Shota Rustaveli State University, Batumi, Georgia; 2Department of Gynecologic Oncology, AdventHealth Cancer Institute, FSU and UCF Colleges of Medicine, Orlando, FL, United States
Abstract Pancreatic cancer (PC) is widely prevalent in the world and is the fourth leading cause of cancer-related deaths. Most patients with PC present with advanced or metastatic disease. Despite advances in the development of radiological techniques and chemotherapeutic drugs, PC still has a poor prognosis. There are several risk factors for PC, among the most prominent of which are cigarette smoking, a high body mass index particularly during early adulthood, and diabetes mellitus. It is suggested that genetic susceptibility and predisposition for PC is a crucial factor. To investigate the single nucleotide polymorphisms, it is important to have a better understanding of the molecular biology and predictive tests for PC. Therefore, it is crucial to identify positive predictive factors because genetics have a prominent role in PC development. In this chapter, we discuss the association between the polymorphism of some candidate genes and PC. Taken together, the genetic polymorphism of contributed genes in PC suggests that genetic susceptibility and predisposition might be involved in the development of PC. Notably, different genetic variants may act together and alter susceptibility to PC. It is hoped that genetic signatures coupled with available standards of care (better-matched therapies) may provide a more personalized approach to managing patients with PC.
Keywords: Clinical outcomes; Gene mutation; Genetic predisposition; Genetic susceptibility; Genetic variants; Pancreatic cancer; Predictive markers; Single nucleotide polymorphism.
List of abbreviations ABO A system of four basic types of blood (A, AB, B, and O) APC Advanced pancreatic cancer FPC Familial pancreatic cancer GSTT1 Glutathione S-transferase q1 a
All authors have diligently contributed to the conception, literature search, data interpretation, and manuscript writing, and have approved the final draft for publication.
G.P. Nagaraju, S. Ahmad (eds.) Theranostic Approach for Pancreatic Cancer ISBN 978-0-12-819457-7 https://doi.org/10.1016/B978-0-12-819457-7.00008-6
Copyright © 2019 Elsevier Inc. All rights reserved.
153
154
Theranostic Approach for Pancreatic Cancer
GSTM1 Glutathione S-transferase Mu1 GWAS Genome-wide association studies MTHFR Methylenetetrahydrofolate reductase PC Pancreatic cancer PALB2 Partner and localizer of BRCA2 PDAC Pancreatic ductal adenocarcinoma SNP Single nucleotide polymorphism TGF-b Transforming growth factor-b VD Vitamin D VDR Vitamin D receptor
Introduction/background Pancreatic cancer (PC) is widely prevalent in the world and is the fourth leading cause of cancer-related deaths [1]. In addition, PC has among the highest mortality rates from cancer in the world, with an estimated 45,750 deaths in 2019 alone in the United States [2]. There are several risk factors for PC, the most prominent of which are cigarette smoking, a high body mass index particularly during early adulthood, and diabetes mellitus [3e6]. Previous studies suggested that genetic and environmental factors contribute to the progression and development of PC susceptibility [7,8]. Several genetic and genome instabilities and alterations are revealed in PC. Genetic alteration such as point mutations, amplifications, deletions, translocations, frameshifts, substitution, and inversions significantly increase the risk for PC; they are found in about 97% of patients with PC [9]. Based on an analysis of multiple genes, it is suggested that the genetic susceptibility and predisposition for PC is a crucial factor. Alterations in methylation of enzymes, genes, and oncogenes (e.g., Diamond-Blackfan anemia repairing genes) and within the genes responsible for cell cycle processes are major risk factors for PC [10]. Despite this, the etiology of PC remains unclear.
Single nucleotide polymorphisms and pancreatic cancer To investigate single nucleotide polymorphisms (SNP), it is important to have a better understanding of molecular biology and predictive assessments for PC. Therefore, it is crucial to identify positive predictive factors because the contribution of epigenetics has a prominent role(s) in PC development [11,12]. Genomic analysis confirmed several ongoing events involved in pancreatic tumorigenesis, among which mutations in the following genes have been implicated: KRAS, TP53, SMAD4, and CDKN2A [13]. It is well-known that mutated KRAS genes contribute significantly to the
Genetic predisposition for pancreatic cancer
155
development of PC, particularly in pancreatic ductal adenocarcinoma (PDAC) [14]. There is positive association between the polymorphism of some candidate genes and PC. Notably, SMAD4 gene mutations have a positive correlation with worse prognosis and outcomes of PC [15]. Hori and colleagues [16] showed that polymorphisms in TP53 codon 72 and MDM2 SNP 309 might be useful for studying the molecular diagnosis of PDAC. The KRAS gene has a crucial role(s) in PDAC and may represent a key target for disease treatment. Frequencies of genetic and epigenetic alterations are high in pancreatic adenocarcinoma. Based on the investigation, KRAS mutation (in codon 12) occurs in PC. It is suggested that KRAS mutation is involved in initiating PDAC; notably, it is found at about 95% in the preneoplastic stages of pancreatic intraepithelial neoplasia [17]. Based on the study of 2249 patients with PC (including tissue detection studies), Tao et al. [18] argued that mutations in K-ras genes are associated with a relatively poorer prognosis in patients with PC. A study by Boeck and colleagues [19] showed that KRAS codon 12 was mutated in 121 of 173 patients (70%). According to this study [19], KRAS wild-type patients improved during second-line chemotherapy (hazard ratio ¼ 1.68; p ¼ .005), which suggests that KRAS may be a useful prognostic and predictive biomarker in PC [19]. The study also suggested that KRAS mutation was detected in 96% of patients with PC. Thus, it is evident that K-ras mutation is useful for the treatment of PC and may be a reliable prognostic factor. Using the Sanger sequencing system, the exonic regions of the following crucial genes were noted: KRAS, TP53 (p53), CDKN2A (p16), SMAD4, ZIP4, and PDX-1 in two cell lines of mouse PC cells and healthy syngeneic mouse pancreas. With the reference mouse genome sequence, it was suggested that SMAD4 homozygote G to T mutation in the first position of codon 174 (GAA) mutation was present in both cell lines [20]. Notably, the SNP in KRAS gene (TAT to TAC at codon 32) was in the syngeneic mouse (from normal pancreas DNA) and both tumoral cells. According to this study [20], there was no mutation or SNP in CDKN2A (p16), TP53 (p53), ZIP4, or PDX-1 genes in both cell lines. Therefore, it was presumed that in the absence of mutations in KRAS, TP53, and CDKN2A genes, which were considered significant genes in PC development, SMAD4 may have a central role in mouse PC [20]. According to another study [21], mutations in the genes with unknown functions were mostly detected at a trinucleotide repeat containing 18,
156
Theranostic Approach for Pancreatic Cancer
locus 728,190, poliovirus receptor-related immunoglobulin domain, SH3-domain binding protein 2, transmembrane protein 168, DEAD box protein 60, and NHL repeat containing 2. The same study confirmed the tumoral heterogeneity of PDAC and identified known mutations in the genes involved in the RAS signaling, the p53 pathway, and transforming growth factor-b (TGF-b) signaling, including SMAD4 and SMAD3 mutations, which suggests that RAS gene mutation is involved in the allelic imbalance in human tumors. About 75% of the PDAC patients carry the mutation in TP53. At the later stages of the disease, an ongoing missense mutation in TP53 and SMAD4 tumor suppressor genes occurs. Within the PC, Smad4 has a close association with the metastatic disease. As about the Smad4 functions, it is considered to be downstream for the TGF-b signaling network [22]. Clinical evidence suggests that TP53 (the tumor suppressor gene) has prominent roles in several conditions. Research showed that mutation in the TP53 gene is common for PC; nearly 70% is mutated [23]. Thus, TP53 could be used as a biomarker for PC prognosis and treatment [24]. Several P53 gene mutations are found in tumors [25], which affects PDAC. Studies also showed that patients with low TP53 mRNA expression have a worse prognosis [26]. It is well-established that adenomatous polyposis coli (APC) genes are essential during the malignant transformation of gastrointestinal cells. The study conducted by Shamai et al. [27] showed that genetic variants of APC (I1307K and E1317Q) and four different SNPs in the CD24 gene (C170T [rs52812045], TG1527del [rs3838646], A1626G [rs1058881], and A1056G [rs1058818]) are involved in the process. The authors argued that these gene SNPs of APC and CD24 genes may contribute to PC development [27]. Genetics polymorphisms of SLC22A3 gene showed that the SNPs rs2504938, rs9364554, and rs2457571 had a significant impact on the risk for PC [28]. rs7758229 is associated with distant metastases of PC. According to that study, rs512077 and rs2504956 correlated well with the survival of PC. The common variation in the SLC22A3 gene is unlikely to contribute significantly to PC risk. Remarkably, rs2504938 SNP in SLC22A3 was significantly associated with an unfavorable prognosis for patients with PC [28]. A hospital-based, case-control study of white Czech-origin people (500 individuals among the 235 cases and 265 controls), involving SOD2, SOD3, NQO1, and NQO2 polymorphisms, revealed the association for
Genetic predisposition for pancreatic cancer
157
PC risk [29]. Lifestyle factors (such as smoking and alcohol, and coffee or tea consumption) did not modify the effect on the studied gene polymorphisms [29]. In a study of a German population, investigation of NR5A2 SNPs showed an association between the rs12029406_T allele and shorter survival [30]. Furthermore, based on Japanese subjects in a case-control study, rs3790843 and rs3790844 of NR5A2 gene were associated with PC [31]. A study with Chinese patients revealed that interleukin (IL)-6-634 CG þ GG genotype was associated with a relatively shorter duration of survival compared with the CC genotype (p ¼ .023). It is therefore plausible that carriers of IL-6-634 CG þ GG genotype may have increased susceptibility toward decreased survival for PC [32].
BRCA1/2 gene polymorphism and pancreatic cancer BRCA1 belongs to the tumor suppressor gene located on chromosome 17q21. BRCA1/2 belongs to autosomal dominant genes and has incomplete penetrance [33]. The mutation in BRCA1/2 genes is a common mutation in familial breast and ovarian cancers in the Ashkenazi Jewish population [34]. BRCA1 and BRCA2 tumor suppressor genes also have prominent roles in the DNA repair processes. Therefore, mutations in BRCA1/2 genes are associated with tumorigenesis of PC. BRCA1 and BRCA2 mutations are predisposed to a higher rate of lifetime risk among the female-specific cancers (e.g., breast, ovarian) [35] and are known to have several mechanisms, but correlations between the BRCA1/2 polymorphisms and PC prognosis is relatively less known. A family history of PC has been observed to predict the presence of a BRCA2 mutation, and PC is more frequent in breast cancer families with BRCA2 mutations than in families without the mutation [36]. Investigators showed that in families with PC, BRCA2 mutations are more likely. Female carriers of BRCA1/2 mutations who have a high risk for breast and ovarian tumors also tend to develop PC. Somatic mutations and germline genetic variants on BRCA1/2 have been found to be associated with tumorigenesis of PC. Also, PC frequency is relatively high within breast cancer families (carrier) of the BRCA2 mutation compared with families with absence of BRACA2 gene mutations. Murphy and colleagues [37] indicated that BRCA2 mutation increases the risk for PDAC; the mutation is common in up to 17% of familial pancreatic cancer (FPC) kindreds.
158
Theranostic Approach for Pancreatic Cancer
The development of PC risk increases about 10 times in carriers of BRCA2 gene mutations [38]. The sporadic mutation gene is a protein that subsequently contributes to tumorigenesis [39]. Zhu and colleagues [40] genotyped the Chinese population’s three tag missense variants on BRCA1/2 among 603 sporadic PC patients and revealed that rs1799966 on BRCA1 was associated with a poor prognosis for patients with PC who had locally advanced-stage disease.
PALB2 gene polymorphism and pancreatic cancer Studies showed that mutations in the partner and localizer of BRCA2 (PALB2) gene are at an increased risk for breast and PC. The PALB2 protein binds with BRCA2 protein, stabilizing it in the nucleus [41]. In a study, carriers of BRCA2 mutations from 180 families showed high risks for PC [42]. A study by Slater et al. [43] involving 81 familial PC patients, based on the sequencing of 13 exons of the PALB2 gene, identified three truncating PALB2 mutations (3.7%) (in different stop codons: R414X, 5089delAG, and 3116delA). Notably, these three families also had a history of breast cancer. Another study [44] confirmed that PALB2 mutations tend to increase the risk for FPC; the PC risk prevalence was 3.1% based on the sequenced PALB2 gene within 96 patients with FPC. The study concluded that PALB2 mutations are involved in FPC. Klein et al. [45] argued that PC has characteristic genetic components that are also based on other factors, including family history, which increases the tendency and risks for PC [46,47]. A study revealed that mutation of the PALB2 gene is about 2%, based on unselected Czech PDAC [48]. Stratford et al. [49] showed that a six-gene signature might be used for better staging of patients with PDAC and may result in useful treatment decisions for surgery or management of the disease. These observations also suggest that these genes may be useful potential biomarkers for the disease [49].
Vitamin D receptor gene polymorphism and pancreatic cancer As a member of the nuclear receptor protein family, vitamin D (VD) receptor (VDR) is widely distributed and found in several human cell types. VD has a prominent role in several pathophysiologic processes in the human body. It contributes to maintenance of the serum calcium level by adjusting the calcium-phosphorus balance in the blood. It also has a crucial role in cell-cycle regulation [50] by inhibiting cell proliferation [51] and
Genetic predisposition for pancreatic cancer
159
facilitating cell differentiation [52], angiogenesis [53], aging, cellular proliferation, differentiation, and T cellemediated immune responses [54]. It is well-known that VDR gene contributes in VD signaling (acting as a kind of hormone for protective effects against several cancers). Based on an epidemiological investigation, it has become clear that dietary VD as well as sunlight exposure may be characterized as protective agents against PC [55]. The VDR gene is associated with the development of different types of tumors, including PC, but the exact mechanism of this protective effect (association) is unclear. Studies have also revealed that VD deficiency is highly prevalent among patients with a new diagnosis of advanced PC [56]. Previous studies suggested that there is lower PC risk with proxy markers of higher VD status. Epidemiological and clinical investigations support the ideas that VD has a protective function against PC [57] and that VDR prevents tumorigenesis. VDR is believed to prevent tumorigenesis in three significant ways. First, activated VDR could upregulate the activity of cycle-dependent kinase inhibitors such as p21waf1, p27kip1, and E-cadherin [58], which impede cellecell proliferation at G0/G1 stagnation of the cell cycle [59]. Second, VD via the VDR could inhibit tumorigenesis and tumor cell proliferation by regulating such signaling pathways as b-catenin, nuclear factor-kb, and Hedgehog signaling pathways [60,61]. Third, the VDR can also induce tumor cell apoptosis by downregulating the Bcl-2 gene [62]. In a detailed study, Li and colleagues [63] investigated the association between VD receptor gene rs2228570 and rs1544410 polymorphisms and PC. The authors evaluated 643 patients (258 PC and 385 control cases), the analysis was performed to study the relation between the noted gene polymorphisms and some pathological differentiation, and the tumor, node, metastasis classification of PC. Based on this study [63], in rs2228570, the T loci and genotypes with T allele may increase the risk for PC. For the rs1544410, the G loci and genotypes AG þ GG also tend to decrease the onset risk for PC development [63]. The study was based on the North Chinese population, which suggested that FokI and BsmI polymorphisms have a higher risk for PC development. Importantly, the FF genotype showed noticeable differences between PC patients and control subjects (p ¼ .009). Also, distribution of FF and Ff/ff frequency was significant (p ¼ .002). This investigation revealed that genotypes ffbb and Ffbb have an increased risk for PC (11.66- and 6.42-fold, respectively) [64]. A study showed that VDRs are expressed in pancreatic tumor stroma and mediate stromal reprogramming to suppress pancreatitis and PC [65].
160
Theranostic Approach for Pancreatic Cancer
Ciesli nska et al. [66] showed that polymorphism Taq-1 in the VDR may have a prominent role in the development of acute pancreatitis. The study was based on the Caucasian population and revealed that the CYP24A1 rs2585428 SNP tended to decrease the risk for PC [66]. Furthermore, based on multiple studies (including the clinical and genetic characteristics), genetic variation in the VDR may become a useful and novel target for PC investigation, diagnostics, and drug treatment, improving the outcomes of chemotherapy [67].
ABO system gene polymorphism and pancreatic cancer Several investigations have shown an association between ABO system genes and the risk for PC. According to genome-wide association studies (GWAS), there is an association between ABO gene polymorphisms and PC risk [68]. A population-based case-control study and metaanalysis indicated that ABO blood group A has an increased risk for PC in Western populations [69]. According to a GWAS study, ABO alleles are associated with an increased risk for PC. ABO glycosyltransferase can alter oligosaccharides on cell surface glycoproteins. Variations in the ABO gene have an important role in different enzyme activities [70]. It is known that ABO glycosyltransferase is located within the first intron of the ABO gene, which encodes ABO glycosyltransferase [71]. Studies have also shown an association between blood group antigens and cancers, including PC [72]. The first GWAS for PC was found to have common risk variants that map to the first intron of the ABO gene on chromosome 9q34.2; these findings revealed that there was a lower risk among individuals with blood group O compared with those with blood group A or B [69]. According to the second GWAS for PC, three loci (on chromosomes 13q22.1, 1q32.1, and 5p15.33) were found associated with PC susceptibility [73]. Based on these studies, the SNP variation at rs505922 tends to develop PC [71,73]. Amundadottir et al. [71] showed that rs505922 SNP within the ABO gene is associated with PC across all ethnic groups, and for SNP rs505922 heterozygous, the odds ratios (OR) were 1.20 and 1.44, respectively. In addition, based on a metaanalysis, Duan et al. [74] revealed that there is a noticeable association between SNP variation rs505922 and cancer susceptibility to PC. Accordingly, the ABO gene rs505922 C > T polymorphism showed a strong association with PC, and the risk of allele BC^ carriers had an OR of 1.35 for PC [74].
Genetic predisposition for pancreatic cancer
161
A study conducted by Xu et al. [75] revealed that carriers of the C allele of rs505922 tended to develop cancer (adjusted OR ¼ 1.42; 95% confidence interval [CI], 1.02e1.98) compared with TT carriers. Based on that investigation, haplotype analysis showed that the haplotype CTTC was associated with an increased risk for PDAC (adjusted OR ¼ 1.46; 95% CI, 1.12e1.91) compared with haplotype TGGT. The study confirmed that there was an association between the ABO SNP and PDAC risk in the Chinese population [75]. Using rs8176719 as a marker for the O allele, and rs8176746 and rs8176747 for the B allele, based on a case-control study (using 185 PC and 1465 control cases), Nakao and colleagues [76] revealed that the PC risk increased with any non-O allele (p ¼ .012). Notably, the AO and BB genotypes had significantly increased ORs of 1.67 (CI, 1.08e2.57) and 3.28 (CI, 1.38e7.80), respectively. Based on this case-control study, in the Japanese population, there is a significant association between the ABO blood group and PC risk [76]. Studies on the large two independent population, using the ABO system, showed a correlation with risk for PC development [77]. Based on the metaanalysis, a significant association was noted between rs505922 C > T polymorphism on the ABO gene and PC risk [74]. Based on a population-based, case-controlled study and in a metaanalysis, Risch and colleagues [69] showed that carriers of A had a higher tendency to develop PC. Also, Greer et al. [61] revealed that the A group had characteristics that increased the risk for PC, and O decreased the risk for this disease [61]. Thus, it is reaffirmed that genetic polymorphisms affect genetic instability and have prominent role(s) in PC development.
XRCC2/XRCC3 gene polymorphism and pancreatic cancer The XRCC2 gene, located at 7q36.1, is involved in the development of several cancers. As about the XRCC3 gene, located at chromosome 14q32.3, have a tendency for some cancers such as lung and gastric cancers, including PC [78,79]. Talar-Wojnarowska et al. [80] showed that there is no association between the XRCC2 and XRCC3 polymorphisms and PC. The authors showed that in smokers, carriers of XRCC2 Arg188Arg mutations have a high risk for PC compared with subjects who never smoked. Variations in the XRCC2 polymorphism may have some roles in susceptibility to PC, especially when there is significant exposure to cigarette carcinogens [81]. Studies also showed a risk-modifying effect of
162
Theranostic Approach for Pancreatic Cancer
the XRCC2 Arg188His polymorphism among smokers with PC [82]. However, the evidence did not suggest that the analyzed XRCC2 and XRCC3 polymorphisms were directly associated with PC risk, and correlations between the XRCC2 and XRCC3 polymorphisms and the clinical data of PC patients could be ascertained. The XRCC2 and XRCC3 genes have an essential role in maintaining genomic stability, as evidenced by an investigation of genetic polymorphisms in DNA repair that alter the protein functions and eventually increases genetic alterations in the genome [82]. The Arg188His polymorphism within XRCC2, tend to develop PC [83]. As noted earlier, Talar-Wojnarowska et al. [80] revealed that XRCC2 and XRCC3 polymorphisms were not directly associated with PC risk. Interestingly, the XRCC2 Arg188His polymorphism was shown to have an association with smoking-related PC [81]. Thus, these studies confirm that mutation of XRCC2 and XRCC3 gene polymorphism is an ambiguous phenomenon.
MTHFR gene single nucleotide polymorphism and pancreatic cancer It is well-known that methylenetetrahydrofolate reductase (MTHFR) has a vital role in folate metabolism. Studies support the idea that the gene polymorphism contributes to PC risk. Research confirmed that the C667T polymorphism affects the risk for PC [84e86]. Investigations revealed that the frequencies of MTHFR 667CC, 667CT, and 667 TT genotypes were 49.5%, 38.6%, and 11.9% among cases compared with controls (48.5%, 45.0%, and 6.5%, respectively) [84]. Notably, carriers of the 667 TT genotype have two times the increased risk for PC compared with carriers of CC/CT genotypes (OR¼ 2.14; 95% CI, 1.14e4.0). Also, a positive correlation was revealed among the 677 TT genotype, heavy cigarette smoking or heavy alcohol consumption, and PC risk [84]. Another study reported that carriers of MTHFR 677CT (OR ¼ 2.60; 95% CI, 1.61e4.29; p ¼ .0005) or 677 TT (OR ¼ 5.12; 95% CI, 2.94e9.10; p < .0001) genotypes have an increased risk for PC compared with the MTHFR CC genotype. In that study, the MTHFR C677T polymorphism and smoking or drinking tended to increase the risk for PC [85]. A metaanalysis by Tu et al. [86] indicated that there was no association between MTHFR polymorphisms (C667T and A1298C) and PC risk.
Genetic predisposition for pancreatic cancer
163
GSTM1 and GSTT1 gene single nucleotide polymorphisms in pancreatic cancer Glutathione S-transferase q1 (GSTT1) and glutathione S-transferase Mu1 (GSTM1) gene polymorphisms are involving in the development of several tumors, including PC; however, the results are confusing. A metaanalysis [87] showed that the null genotype of GSTT1 is associated with an increased risk for PC (OR ¼ 1.61; 95% CI, 1.06e2.44; POR ¼ .025, respectively). However, the association with the GSTT1 gene polymorphism was reported to be significant higher in Asians (OR ¼ 02.58; 95% CI, 1.67e3.98; POR < .001). According to that study, GSTM1 did not have an association with PC risk [87]. Yamada and colleagues [88] indicated that in the Japanese population, there was no association between the GSTM1 and GSTT1 deletion polymorphisms and the development of risk for PC. Another study [89] on the three GST genes confirmed that PC risk could be for older individuals (aged > 62 year) who were carriers of the GSTP1*C (105Val-114Val) genotype and had a reduced risk compared to with younger patients who did not carry the *C genotype. The same study confirmed that patients carrying the GSTP1*C genotype had significantly prolonged survival compared with those with the non-*C genotype (multivariate hazard ratio, 0.45; 95% CI, 0.22e0.94) [89].
Steroid hormone receptor polymorphism and pancreatic cancer Investigations showed that sex steroid hormones also participate in the development of PC (including studies in male and female rats) [90e92]. Based on some select studies, hormones reflect the promotion and progression stages of carcinogenesis, especially in promoting or inhibiting carcinogenesis [90]. According to investigations, women who used menopausal hormone therapy had a reduced risk for PC [91]. Konduri et al. [92] demonstrated that estrogen and its metabolites inhibited PC cell growth in in vitro studies. Androgen receptor (NR3C4) and estrogen receptors-a and -b (NR3A1 and NR3A2) belong to the steroid receptor subfamily (NR3), which regulates several physiological processes. Among them is the development of some types of malignancies [93,94].
164
Theranostic Approach for Pancreatic Cancer
Mitochondrial gene polymorphism and pancreatic cancer Mitochondria vitally participate in several cellular processes, and mitochondrial DNA mutation increases the risk for PC development [95]. An investigation revealed an association between the mitochondrial gene polymorphism and PC survival [96]. Studies found 24 somatic mutations within mitochondrial DNA and demonstrated that metabolic changes are consistent with mitochondrial dysfunction, including reduced oxygen consumption and increased glycolysis [97,98].
Conclusions Early diagnosis of PC has remained problematic. The development and progression of the disease are caused by complex factors such as genetics and the environment, which are difficult to identify and are decisive factors. It is clear that PC is a polygenic disease, because there are several known genes with high-risk susceptibility alleles. Genetic polymorphisms have important roles in the risk for PC, as demonstrated by a number of investigations. SNPs are useful as a molecular marker for understanding the genetic predisposition for PC. Molecular markers are the most fundamental part for assessing the genetic peculiarities of PC, but despite considerable interest in best prognostic biomarkers for early detection, diagnosis and treatment of the disease remains challenging. The genetic polymorphism of contributing genes in PC suggests that genetic susceptibility and predisposition are likely involved in the development of PC. Different genetic variants may act together and alter susceptibility to PC. Finally, geneegene and genee environmental interactions may also alter contributions to PC development in humans.
References [1] Siegel R, Naishadham D, Jemal ACA. Cancer statistics. Cancer J Clin 2013;63(1):11e30. [2] Society AC. Cancer facts & figures 2019. Atlanta: American Cancer Society; 2019. [3] Iodice S, Gandini S, Maisonneuve P, Lowenfel AB. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbeck’s Arch Surg 2008;393(4):535e45. [4] Li D, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. J AMA 2009;301(24):2553e62. [5] Vrieling A, et al. Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European prospective investigation into cancer and nutrition. Int J Cancer 2010;126(10):2394e403.
Genetic predisposition for pancreatic cancer
165
[6] Eijgenraam P, et al. Diabetes type II, other medical conditions and pancreatic cancer risk: a prospective study in the Netherlands. Br J Cancer 2013;109(11):2924e32. [7] Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer 2002;2(12):897e909. [8] Hocevar, et al. Contribution of environment and genetics to pancreatic cancer susceptibility. PLoS One 2014;9(3):e90052. https://doi.org/10.1371/ journal.pone.0090052. [9] Cicenas J, Kvederaviciute K, Meskinyte I, Meskinyte-Kausiliene E, Skeberdyte A, Cicenas J. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 mutations in pancreatic cancer. Cancers 2017;9(5):42. https://doi.org/10.3390/cancers9050042. [10] Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog 2012;51(1):14e24. [11] Kwon HM, Kang EJ, Kang K, Kim SD, Yang K, Yi JM. Combinatorial effects of an epigenetic inhibitor and ionizing radiation contribute to targeted elimination of pancreatic cancer stem cell. Oncotarget 2017;8(51):89005e20. https://doi.org/ 10.18632/oncotarget.21642. [12] Nguyen AH, et al. Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts. Oncotarget 2017;8(12):19074e88. https://doi.org/10.18632/oncotarget.13572. [13] Bailey P, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016;531(7592):47e52. [14] Garcia MN, et al. IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation. J Clin Investig 2014;124(11):4709e22. [15] Blackford A, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 2009;15(14):4674e9. https://doi.org/10.1158/ 1078-0432.CCR-09-0227. [16] Hori Y, et al. Impact of TP53 codon 72 and MDM2 SNP 309 polymorphisms in pancreatic ductal adenocarcinoma. PLoS One 2015;10(3):e0118829, https://doi.org/ 10.1371/journal.pone.0118829. [17] Kanda M, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012;142(4):730e3. e9. [18] Tao LY, Zhang LF, Xiu DR, Yuan CH, Ma ZL, Jiang B. Prognostic significance of Kras mutations in pancreatic cancer: a meta-analysis. World J Surg Oncol 2016;14:146. https://doi.org/10.1186/s12957-016-0888-3. [19] Boeck S, Jung A, Laubender RP, et al. KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. J Gastroenterol April 2013;48(4):544e8. https://doi.org/10.1007/ s00535-013-0767-4. Epub 2013 Feb 23. [20] Wang Y, et al. Genomic sequencing of key genes in mouse pancreatic cancer cells. Curr Mol Med 2012;12(3):331e41. [21] Di Marco M, et al. Characterization of pancreatic ductal adenocarcinoma using whole transcriptome sequencing and copy number analysis by single-nucleotide polymorphism array. Mol Med Rep 2015;12(5):479e7484, https://doi.org/10.3892/mmr. 2015.4344. [22] Malkoski SP, Wang XJ. Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett 2012;586(14):1984e92. [23] Hwang RF, Gordon EM, Anderson WF, Parekh D. Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene. Surgery 1998;124(2):143e50. https://doi.org/10.1016/S0039-6060(98) 70114-X.
166
Theranostic Approach for Pancreatic Cancer
[24] Grochola LF, Taubert H, Greither T, Bhanot U, Udelnow A, Würl P. Elevated transcript levels from the MDM2 P1 promoter and low p53 transcript levels are associated with poor prognosis in human pancreatic ductal adenocarcinoma. Pancreas 2011;40(2):265e70. [25] Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev 2012;26(12):1268e86. [26] Xiang JF, et al. Mutant p53 determines pancreatic cancer poor prognosis to pancreatectomy through upregulation of cavin-1 in patients with preoperative serum CA199 1,000 U/mL. Sci Rep 2016;6:25115. https://doi.org/10.1038/srep25115. [27] Shamai S, et al. CD24 and APC genetic polymorphisms in pancreatic cancers as potential biomarkers for clinical outcome. PLoS One 2015;10(9):e0134469. https:// doi.org/10.1371/journal.pone.0134469. [28] Mohelnikova-Duchonova B, et al. SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival. Sci Rep 2017;7:43812. https:// doi.org/10.1038/srep43812. [29] Mohelnikova-Duchonova B, Marsakova L, Vrana D, Holcatova I, Ryska M, Smerhovsky Z, Slamova A, Schejbalova M, Soucek P. Superoxide dismutase and nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase polymorphisms and pancreatic cancer risk. Pancreas 2011;40(1):72e8. https://doi.org/10.1097/ MPA.0b013e3181f74ad7. [30] Rizzato C, et al. Pancreatic cancer susceptibility loci and their role in survival. PLoS One 2011;6(11):e27921. https://doi.org/10.1371/journal.pone.0027921. [31] Ueno M, et al. Genome-wide association study-identified SNPs (rs3790844, rs3790843) in the NR5A2 gene and risk of pancreatic cancer in Japanese. Sci Rep 2015;5:17018. https://doi.org/10.1038/srep17018. [32] Zhang D, Zhou Y, Wu L, Wang S, Zheng H, Yu B, Li J. Association of IL-6 gene polymorphisms with cachexia susceptibility and survival time of patients with pancreatic cancer. Ann Clin Lab Sci 2008;38(2):113e9. [33] Thull DL, Vogel VG. Recognition and management of hereditary breast cancer syndromes. Oncologist 2004;9(1):13e24. [34] Ghadirian P, Liu G, Gallinger S, Schmocker B, Paradis AJ, Lal G, Brunet JS, Foulkes WD, Narod SA. Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. Int J Cancer 2002;97(6):807e10. [35] Apostolou P, Fostira F. Hereditary breast cancer: the era of new susceptibility genes. BioMed Res Int 2013:747318. https://doi.org/10.1155/2013/747318. [36] Phelan CM, et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996;13:120e2. [37] Murphy KM, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 2002a;62(13):3789e93. [38] Brentnall TA. Cancer surveillance of patients from familial pancreatic cancer kindreds (Review). Med Clin N Am 2000;84(3):707e18. [39] Stadler ZK, et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer 2012;118(2):493e9. https:// doi.org/10.1002/cncr.26191. [40] Zhu Y, et al. BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population. Oncotarget 2017;8(22):36033e9. [41] Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog 2011;51(1):14e24. https://doi.org/10.1002/mc.20855. [42] Couch FJ, et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomark Prev 2007;16(2):342e6.
Genetic predisposition for pancreatic cancer
167
[43] Slater EP, Langer P, Niemczyk E, Strauch K, Butler J, Habbe N, Neoptolemos JP, Greenhalf W, Bartsch DK. PALB2 mutations in European familial pancreatic cancer families. Clin Genet 2010;78(5):490e4. [44] Jones S, et al. APExomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009;324(5924):217. [45] Klein AP, Hruban RH, Brune KA, Petersen GM, Goggins M. Familial pancreatic cancer. Cancer J 2001;7(4):266e73. [46] Jacobs EJ, et al. Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Int J Cancer 2010;127(6):1421e8. [47] Ghadirian P, Boyle P, Simard A, Baillargeon J, Maisonneuve P, Perret C. Reported family aggregation of pancreatic cancer within a population-based case-control study in the Francophone community in Montreal, Canada. Int J Pancreatol 1991;10:183e96. [48] Borecka M, et al. Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic. Cancer Genet 2016;209(5):199e204. [49] Stratford JK, et al. A six-gene signature predicts survival of patients with localized Phelan CM, pancreatic ductal adenocarcinoma. PLoS Med 2010;7(7):e1000307. [50] Chiang KC, et al. MART-10, a novel vitamin D analog, inhibits head and neck squamous carcinoma cells growth through cell cycle arrest at G0/G1 with upregulation of p21 and p27 and downregulation of telomerase. J Steroid Biochem Mol Biol 2013;138:427e34. [51] Jehan F, d’Alesio A, Garabedian M. Exons and functional regions of the human vitamin D receptor gene around and within the main 1a promoter are well conserved among mammals. J Steroid Biochem Mol Biol 2007;103(3e5):361e7. 13. [52] Miyamoto K, et al. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol 1997;11(8):1165e79. [53] Greer J,B, Brand RE. New developments in pancreatic cancer. Curr Gastroenterol Rep 2011;13:131e9. [54] Mathieu C, van Etten E, Decallonne B, Guilietti A, Gysemans C, Bouillon R, Overbergh L. Vitamin D and 1,25-dihydroxyvitamin D3 as modulators in the immune system. (Review). J Steroid Biochem Mol Biol 2004;89e90(1e5):449e52. [55] Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 2013;144(6):1252e61. https://doi.org/10.1053/j.gastro.2013. 01.068. [56] van Loon K, et al. 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). J Natl Cancer Inst 2014;106(8). https://doi.org/10.1093/jnci/dju185. p. pii: dju185. [57] Vogt DP. Pancreatic cancer: a current overview. Curr Surg 2000;57(3):214e20. [58] Verlinden L, et al. Two novel 14-Epianalogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res 2000;60(10):2673e9. [59] Campbell MJ, et al. Inhibition of proliferation of prostate cancer cells by a 19-norhexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. J Mol Endocrinol 1997;19(1):15e27. [60] Jiang YJ, et al. 1alpha,25(OH)2- dihydroxyvitamin D3/VDR protects the skin from UVB-induced tumor formation by interacting with the beta-catenin pathway. J Steroid Biochem Mol Biol 2013;136:229e32. [61] Greer JB, et al. Significant association between ABO blood group and pancreatic cancer. World J Gastroenterol 2010;16(44):5588e91. [62] Rosli SN, et al. 1alpha,25OH2D3 downregulates HBp17/FGFBP-1 expression via NF-kappaB pathway. J Steroid Biochem Mol Biol 2013;136:98e101.
168
Theranostic Approach for Pancreatic Cancer
[63] Li L, et al. Role of vitamin D receptor gene polymorphisms in pancreatic cancer: a caseecontrol study in China. Tumor Biol 2015;36(4):4707e14, https://doi.org/10. 1007/s13277-015-3119-6. [64] Li L, Wu B, Yang L, Yin G, Wei W, Sui S, Liu J. Association of vitamin D receptor gene polymorphisms with pancreatic cancer: a pilot study in a North China population. Oncol Lett 2013;5(5):1731e5. [65] Sherman MH, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014;159(1):80e93. [66] Ciesli nska A, Kostyra E, Fiedorowicz E, Snarska J, Kordulewska N, Kiper K, Savelkoul H. Single nucleotide polymorphisms in the vitamin D receptor gene (VDR) may have an impact on acute pancreatitis (AP) development: a prospective study in populations of AP patients and alcohol-abuse controls. Int J Mol Sci 2018;19(7):1919. https://doi.org/10.3390/ijms19071919. [67] Innocenti F, et al. The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: genomic analysis and experimental validation. PLoS One 2018;13(8):e0202272, https://doi.org/10.1371/journal.pone.0202272. [68] Itzkowitz SH, et al. Cancer associated alterations of blood group antigen expression in the human pancreas. J Natl Cancer Inst 1987;79(3):425e34. [69] Risch HA, Lu L, Wang J, Zhang W, Ni Q, Gao YT, Yu H. ABO blood group and risk of pancreatic cancer: a study in Shanghai and meta-analysis. Am J Epidemiol 2013;177(12):1326e37. [70] Reid ME, Mohandas N. Red blood cell blood group antigens: structure and function. Semin Hematol 2004;41:93e117. https://doi.org/10.1053/j.seminhematol. 2004.01.001. [71] Amundadottir L, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41(9):986e90. [72] Annese V, Minervini M, Gabbrielli A, Gambassi G, Manna R. ABO blood groups and cancer of the pancreas. Int J Pancreatol 1990;6(2):81e8. [73] Petersen GM, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 2010;42(3):224e8. [74] Duan YF, Zhu F, Li XD, An Y, Zhang H, Zhou Y, Zhang X, Jiang Y. Association between ABO gene polymorphism (rs505922) and cancer risk: a meta-analysis. Tumour Biol 2015;36(7):5081e7. https://doi.org/10.1007/s13277-015-3159-y. [75] Xu HL, et al. Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population. Chin J Cancer 2014;33(2):68e73. https://doi.org/10.5732/cjc.013.10060. [76] Nakao M, et al. ABO blood group alleles and the risk of pancreatic cancer in a Japanese population. Cancer Sci 2011;102(5):1076e80. https://doi.org/10.1111/j.13497006.2011.01907.x. [77] Wolpin BM, et al. ABO blood group and the risk of pancreatic cancer. J Natl Cancer Inst 2009;101(6):424e31. [78] Qin XP, Zhou Y, Chen Y, Li NN, Wu XT. XRCC3 Thr241Met polymorphism and gastric cancer susceptibility: a meta-analysis. Clin Res Hepatol Gastroenterol 2014;38(2):226e34. https://doi.org/10.1016/j.clinre.2013.10.011. [79] Nissar S, Sameer AS, Lone TA, Chowdri NA, Rasool R. XRCC3 Thr241Met gene polymorphism and risk of colorectal cancer in Kashmir, A case control study. Asian Pac J Cancer Prev 2014;15(22):9621e5. https://doi.org/10.7314/APJCP.2014. 15.22.9621.
Genetic predisposition for pancreatic cancer
169
[80] Talar-Wojnarowska R, G3ąsiorowska A, Olakowski M, Dranka-Bojarowska D, Lampe P, Smolarz B, Małecka-Panas E. Analysis of XRCC2and XRCC3 gene polymorphisms in pancreatic cancer. Biomed Rep 2015;4(2):236e40. [81] Jiao L, Hassan MM, Bondy ML, et al. XRCC2 and XRCC3 gene polymorphism and risk of pancreatic cancer. Am J Gastroenterol 2008;103(2):360e7. [82] Tambini CE, Spink KG, Ross CJ, Hill MA, Thacker J. The importance of XRCC2 in RAD51-related DNA damage repair. DNA Repair (Amst) 2010;9(5):517e25. [83] He Y, Zhang Y, Jin C, Deng X, Wei M, Wu Q, Yang T, Zhou Y, Wang Z. Impact of XRCC2 Arg188His polymorphism on cancer susceptibility, A meta-analysis. PLoS One 2014;9(3):e91202. https://doi.org/10.1371/journal.pone.0091202. [84] Li D. 5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer. Cancer Epidemiol Biomark Prev 2005;14(6):1470e6. https:// doi.org/10.1158/1055-9965.epi-04-0894. [85] Wang L, et al. Genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase and risk of pancreatic cancer. Clin Gastroenterol Hepatol 2005;3(8):743e51. [86] Tu YL, Wang SB, Tan, et al. MTHFR gene polymorphisms are not involved in pancreatic cancer risk: a meta-analysis. Asian Pac J Cancer Prev 2012;13(9):4627e30. [87] Fan Y, Zhang W, Shi C-Y, Cai D-F. Associations of GSTM1 and GSTT1 polymorphisms with pancreatic cancer risk. Tumor Biol 2012;34(2):705e12. https:// doi.org/10.1007/s13277-012-0598-6. [88] Yamada I, et al. Lack of associations between genetic polymorphisms in GSTM1, GSTT1 and GSTP1 and pancreatic cancer risk: a multi-institutional case-control study in Japan. Asian Pac J Cancer Prev 2014;15(1):391e5. [89] Jiao L, et al. Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer. Cancer 2007;109(5):840e8. https://doi.org/10.1002/cncr.22468. [90] Longnecker DS, Sumi C. Effects of sex steroid hormones on pancreatic cancer in the rat. Int J Pancreatol 1990;7(1e3):159e65, https://doi.org/10.1007/BF02924233. [91] Sadr-Azodi O, Konings P, Brusselaers N. Menopausal hormone therapy and pancreatic cancer risk in women: a population-based matched cohort study. United European Gastroenterol J 2017;5(8):1123e8. [92] Konduri S, Schwarz RE. Estrogen receptor beta/alpha ratio predicts response of pancreatic cancer cells to estrogens and phytoestrogens. J Surg Res 2007;140(1):55e66. [93] Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS, Chatterjee B. Androgen receptor: structural domains and functional dynamics after ligand-receptor interaction. Ann N Y Acad Sci 2001;949:44e57. [94] Culig Z, Klocker H, Bartsch G, Hobisch A. Androgen receptors in prostate cancer. Endocr Relat Cancer 2002;9:155e70. [95] Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 2005;39:359e407. [96] Halfdanarson TR, et al. Mitochondrial genetic polymorphisms do not predict survival in patients with pancreatic cancer. Cancer Epidemiol Biomark Prev 2008;17:2512e3. https://doi.org/10.1158/1055-9965.EPI-08-0460. [97] Wang L, et al. Mitochondrial genetic polymorphisms and pancreatic cancer. Cancer Epidemiol Biomark Prev 2007;16(7):1455e9. 1158/1055-9965.EPI-07-0119. [98] Hardie RA, et al. Mitochondrial mutations and metabolic adaptation in pancreatic cancer. Cancer Metabol 2017;5:2. https://doi.org/10.1186/s40170-017-0164-1.