Gene Expression and Polymorphisms of DNA Repair Enzymes: Cancer Susceptibility and Response to Chemotherapy

comprehensive revie w Gene Expression and Polymorphisms of DNA Repair Enzymes: Cancer Susceptibility and Response to Chemotherapy Carlos Camps,1,2* Rafael Sirera,1,2* Vega Iranzo,1 Miquel Tarón,3 Rafael Rosell3 Abstract Platinum compounds play a central role in cancer chemotherapy. Although treatment is limited by side effects, they continue to have widespread application. One of the main aims of clinical or translational research in cancer is the search for genetic factors that could foresee treatment outcomes, in biologic activity and toxic effects. This genetic analysis might allow selection of patients who will have the greatest benefit from chemotherapy. Furthermore, a better knowledge of the underlying molecular profile of the host and the tumor will facilitate screening for lung cancer susceptibility and tailoring of chemotherapy in individual patients, chosing those most likely to respond, adjusting doses more precisely in order to reduce less adverse effects, and establishing safety profiles based on individual genetic analyses. Herein, we discuss current knowledge regarding gene expression and polymorphisms of DNA repair enzymes in regard to cancer susceptibility and response to chemotherapy. Clinical Lung Cancer, Vol. 8, No. 6, 369-375, 2007

Key words: Cisplatin, Single nucleotide polymorphisms, Squamous cell carcinoma

Introduction

The major mechanisms for cisplatin resistance1 are as follows: inactivation of cisplatin by glutathione or other sulphur-containing molecules; increased repair rate of cisplatin adducts; reduced cisplatin accumulation in the cell; and increased tolerance of cisplatin adducts and failure of apoptotic pathways induced by DNA damage.

Cisplatin and carboplatin play a central role in cancer chemotherapy and have been used widespread for many years; however, the treatment is limited by side effects, including nephrotoxicity, emetogenesis, and neurotoxicity. The efforts made to understand the mechanisms by which cells process platinum salts provide important insights for designing more efficient platinum agent–based drugs. Platinum derivatives form intrastrand or interstrand adducts on DNA, distorting the structure of the DNA duplex, and these structures are recognized by DNA repair mechanisms, mainly the mismatch repair proteins and some damage-recognition proteins. *Contributed equally to this work 1Servicio

de Oncología Médica, Hospital General Universitario, Valencia de Oncología Molecular, Fundación Investigación, Hospital General Universitario, Valencia 3Institut Català d’Oncología, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain 2Laboratorio

Submitted: Mar 12, 2007; Revised: May 8, 2007; Accepted: May 8, 2007 Address for correspondence: Carlos Camps, MD, Servicio de Oncología Médica, Hospital General Universitario de Valencia, Av. Tres Cruces s/n; 46014 Valencia, Spain Fax: 34-961972151; e-mail: [email protected]

DNA Repair Mechanisms Cellular DNA is subjected to continual attack by reactive species inside cells and by environmental agents (Table 1). The most important endogenous agents able to produce genetic damage are the presence of reactive oxygen species, alkylating agents, abundance of hydrolysis reactions, or mistakes during the process of DNA replication. The main exogenous factors that can distort the DNA helix are the ultraviolet light; ionizing radiations; certain toxins or chemical agents such as inhaled cigarette smoke or polycyclic aromatic compounds; the administration of chemotherapy or radiation therapy (RT); and other still incompletely defined dietary factors. However, these toxic and mutagenic consequences are minimized by different pathways of DNA repair. Although these metabolic pathways remain incompletely defined, > 130 proteins of human DNA repair genes have already been characterized. DNA damage that is incompletely repaired is typically recognized by the

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DNA Polymorphisms and Cancer Table 1 Different Kinds of DNA Damage

DNA Repair Gene Polymorphisms

DNA Damaging Agents

Examples

Endogenous

Reactive oxygen species Alkylating agents Hydrolysis Erroneous or unmatched base pairing

Exogenous

Ultraviolet light Ionizing radiation Toxins Chemical agents (inhaled cigarette smoke or polycyclic aromatic compounds) Chemotherapy Radiation therapy Incomplete defined dietary factors

biologic cell machinery, and programmed cell death or apoptosis is induced. However, in certain circumstances, failure to recognize DNA damage will produce anomalous growth of the cell and even lead to carcinogenesis. Because of the importance of this cell process or checkpoint that allows maintaining DNA integrity in the cell and preventing neoplasic transformation, DNA repair genes have been proposed as critical to cancer susceptibility2 as well as understanding of the cellular aging process.3 Furthermore, therapeutic modulation of DNA repair might lead to clinical applications including improved outcomes from chemotherapy and RT. The main biologic function of DNA repair enzymes is to monitor DNA strands and, if damage is present, to correct nucleotide residues. DNA exposure to carcinogens, mutagens, or even cytotoxic compounds can alter genomic information. Human DNA repair enzymes involve gene products that are functionally linked to the recognition and/or repair of damaged DNA, many of which are homologous to DNA repair mechanisms in other organisms. The major mechanisms for DNA damage repair, which are summarized in Table 2, are as follows: direct repair of alkyl adducts; repair of base damage and single strand breaks by base excision repair; repair of double strand breaks by homologous recombination or by nonhomologous end joining; repair of bulky DNA adducts by nucleotide excision repair; and repair of mismatches and insertion/deletion loops by DNA mismatch repair.4 There are outstanding reviews about DNA repair mechanism,3-8 but the main aim of this revision is to link DNA damage detection and repair with lung cancer susceptibility and treatment efficacy. The search for new enzymes involved in DNA repair still continues. Surely, new genes will be discovered in the near future, and maybe addition repair mechanisms will be identified and characterized. For example, several classes of DNA damage exist that have not been extensively investigated, such as the repair of lipid peroxidation or that caused by reactive metabolites and catabolites. A multitude of genetic polymorphisms in DNA repair genes have been identified. Although many of them have been correlated with modifications of enzyme activity and biologic function, much work has to be done to identify the biologic implications of other subtle changes in amino acid sequences. Included in this category are not only variations in genetics, but also some epigenetic modifications as well. DNA repair polymorphisms have been analyzed in the context of efficacy and toxicity.9

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Cancer is a multistep and multifactorial disease. Understanding the interaction between environmental factors and individual genetic characteristics can delineate individuals at risk for cancer development,10 as in cancer syndromes resulting from inherited defects in DNA repair genes, such as skin cancer caused by sunlight exposure.5 Subsequently, it was then demonstrated that impairment in DNA repair mechanisms increases genomic instability and tumorigenesis.11 This approach has also been linked to the study of DNA repair gene polymorphisms and how DNA repair capacity (DRC) influences the development of cancer.12 Many epidemiologic studies have focused on single nucleotide polymorphism (SNPs) of genes involved in DNA repair pathways.4,13 Table 3 shows the allele frequency of some common SNPs in DNA repair enzymes. For example, genetic polymorphisms in mutY homologue, a base excision repair protein, have been associated with individual cancer susceptibility.14 Additional evidence has come from MMR-defective tumors with incremental genomic instability and, hence, tumorogenic potential.15 Impaired DRC has been associated with increased risk of developing lung cancer,16 as discussed herein. In this regard, several DNA repair enzyme polymorphisms have been shown to exert a modulating effect on DRC.17 Susceptibility to Lung Cancer. A large number of investigations have linked polymorphisms of DRC genes with susceptibility to lung cancer, as detailed herein. The OGG1 (8-oxoguanine DNA glycosylase) protein has the ability to suppress mutagenesis induced by 8-hydroxyguanine, an oxidatively damaged promutagenic base. The activity of OGG1 has been associated with development of lung cancer,18 as described by an extensive epidemiologic study analyzing the influence of OGG1 polymorphisms on lung cancer risk by Le Marchand et al. They discovered a risk increase in the group with Cys/Cys versus Ser/Ser genotype.19 In addition, XPD-312Asp and XPD-751Lys polymorphisms are more frequent in patients with non–small-cell lung cancer (NSCLC), indicating an attenuation of DNA repair ability.20 Cheng et al demonstrated that individuals with reduced expression levels of ERCC5 and ERCC6 might be at higher risk of developing lung cancer.21 Carriers of the polymorphic XRCC1 399Gln allele might be at greater risk for lung cancer induced by tobacco or just by the process of aging.22 Conversely, the presence of the XRCC1 R194W genotype decreases the risk of developing lung cancer,23 whereas other polymorphisms of the same gene like Arg194Trp and Arg399Gln do not confer a significant risk for head and neck carcinogenesis.24 In the Chinese population, the genotype XRCC1 Trp194Trp and the 751Lys allele of XPD might be risk genotypes for lung cancer.25 XPD variant alleles in exon 10 have been associated with reduced repair of aromatic DNA adducts and an increased lung cancer risk even among never-smokers.26 Genetic variation in XRCC1, XRCC3, and NBS1 influence lung cancer susceptibility among women.27 The XPA A23G polymorphism might increase the susceptibility for lung cancer.28 In younger individuals, a POLI gene SNP, Thr706Ala, was associated with the risk of lung adenocarcinoma and squamous cell carcinoma (SCC).29

Carlos Camps et al Table 2 DNA Repair Pathways DNA Repair Pathways

Mechanism

Main Enzymes

Direct DNA Repair

Direct reversal of damage. Removes methyl or alkyl groups from O6 position of guanine.

MGMT

Base Excision Repair

Excises and replaces damaged bases mainly caused by endogenous oxidative and hydrolytic decay of DNA or deamination. Process initiated by DNA-glycosylases and requires DNA nick-joining by DNA ligases.

OGG1, MYH, APE1, LIG3, XRCC1

Removes bulky adducts caused by environmental factors. DNA damage affects both strands and comprises from 2 to 30 nucleotides. This unwinds the helix and suffers base excision and replacement with normal DNA.

XPC, XPA, ERCC1, ERCC3 (XPB), ERCC2 (XPD), ERCC5 (XPG), CSA, CSB

Process that recognizes DNA mismatches created by replication errors, nonhomologous recombination, or damage to 1 DNA base and corrects the error.

MSH2, MSH3, MSH6, MLH1, MLH3

Repaired by homologous or nonhomologous recombination pathways.

RAD51 family, XRCC2, XRCC3, BRCA1, BRCA2

Nucleotide Excision Repair Mismatch Repair DNA Double-Strand Breaks

However, in fact, the magnitude of the associations between the XRCC1 and ERCC2 polymorphisms and lung cancer risk depends greatly on the cumulative number of smoked cigarettes.30 A polymorphism in XRCC1 (Arg399Gln) might modify the risk of lung cancer attributable to cigarette smoking exposure.31 In this regard, it has been observed that cumulative cigarette smoking increases the risk of ERCC2 Asp312Asn polymorphisms and lung cancer.32 Also, XPC variants might contribute to the risk of lung cancer in the Chinese population and might modulate the risk of lung cancer associated with smoking.33 On the other hand, the polymorphism of XRCC1 at codon 399 might be a genetic determinant of SCC of the lung in nonsmokers.34 The polymorphism in ERCC1 C8092A might modify the associations between cumulative cigarette smoking and lung cancer risk.35 Susceptibility to Other Cancers. Similarly, a large body of literature supports a link between polymorphisms in DNA repair genes and cancer susceptibility in a number of additional tumor types, as reviewed herein. Common DNA repair gene polymorphisms have been reported to alter the risk of SCC of the head and neck (SCCHN).36 Sturgis et al conducted a case-control study of 203 patients with SCCHN and 424 control subjects and found that a polymorphic XRCC1 DNA repair gene contributed to the development of SCCHN.37 An association of the XRCC1 polymorphism with susceptibility for SCCHN has also been reported in the Korean population.38 Other polymorphisms in ERCC1 (C8092A) and/or in XPD (G23591A) can contribute to the risk of SCCHN.36 Polymorphisms in XRCC1 (R194W) or OGG1 (S326C) have been demonstrated to increase the risk of developing prostate and esophageal cancer in white people2 or in Japanese people.39 In addition, 2 copies of the allele XPD with the codon 312 Asn allele might increase prostate cancer risk, and this effect is enhanced by the XRCC codon 399 Gln allele in its recessive state.40 Furthermore, the XPC (Lys939Gln) polymorphism might be a risk factor for prostate cancer.39 The influence of OGG1 polymorphisms and prostate cancer risk was analyzed by Xu et al, and a risk increase was reported in the group with Cys/Cys versus Ser/Ser genotype.41 One polymorphism in exon 23 of the XPD gene leading to an amino acid substitution (Lys751Gln) and 1 silent in exon

6 might contribute to the risk of basal cell carcinoma development.42 Additionally, certain XPD haplotypes might modulate risk of leukemia and bladder cancer.43 Also, the OGG1 (Cys326Cys) genotype was found to be more frequent among patients with bladder cancer and has been proposed as a useful prognostic genetic marker for bladder cancer in the clinical setting.44 Conversely, a polymorphism in codon 241 of XRCC3 or in codon 399 of XRCC1 had a protective effect against bladder cancer, mainly among heavy-smokers.45 Yu et al have suggested that the XRCC1 (Gln399Gln) genotype might contribute to the risk of esophageal SCC and that this could even modify the risk associated with smoking.46 Other polymorphisms in XRCC1 (R194W) and OGG1 (S326C) demonstrated an augmentation of the risk of developing esophageal SCC.2,47 There is also evidence that an XRCC1 genotype at codon 399 might influence breast cancer risk; however, interpretation of these results is limited by incomplete knowledge regarding the biologic function of XRCC1.48 Also, smokers with a polymorphism in the XPD gene might face an increased risk of breast cancer.49 Healey and colleages evaluated different SNPs that could be implicated in breast cancer development and found that a BRCA2 polymorphism (N372H) increased the risk,50 as did the XRCC1 R194W polymorphism.9 The family of genes RAD51, which includes, among others, XRCC2 and XRCC3, have a crucial role in this pathway and in breast cancer susceptibility.51 It is known that 9% of patients with endometrial cancer carry a variant allele in MLH1 and MSH2; those individuals with the MSH2 rs2303428 C allele or the MSH2 rs2059520 G allele were at risk of developing endometrial cancer compared with controls.52 Genetic polymorphisms are not the only contributors to the development of cancer. Epigenetic changes in the promoter region of DNA repair genes might impair gene expression and, therefore, the amount of the bioactive protein and its repair capacity. The presence of aberrant hypermethylation is associated with loss of MGMT protein, and this epigenetic inactivation of MGMT plays an important role in neoplasia, up to 40% in gliomas and colorectal carcinomas and 25% in NSCLC and head and neck carcinomas.53 In fact, defects in DNA repair might be responsible for the genesis of mutations in key genes in cancer cells, leading to G to A transitions.54 In this regard,

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DNA Polymorphisms and Cancer Table 3 Single Nucleotide Polymorphisms in DNA Repair Genes Repair Pathway BER

NER

DSBR

Gene

Location in DNA

SNPs Allele Frequency

Frequency in Controls

OGG1

3p26.2/601982

S326C 1245 cAg

0.22-0.45

XRCC1

19q13.2/194360

R194W 26304 cAt

0.06-0.35

ERCC1

19q13.2-13.3/126380

19007 gAa

0.45

XPC

3p25/278720

1457-1461 deletion

0.33

XPD

19q13.2-13.3/278730

22451cAa

0.4-0.45

XPF

16p13.3-13.13/278760

5´UTR 2063 tAa

0.31

BRCA2

13q12.3/600185

N372H 1342 aAc

0.22-0.29

XRCC3

14q32.3/600675

T214M 18067 cAt

0.23-0.38

Abbreviations: BER = base excision repair; DSBR = DNA double-strand breaks; NER = nucleotide excision repair

Esteller et al and Wolf et al independently suggested that tumors with MGMT hypermethylation have a new mutator phenotype characterized by the generation of transition point mutations in genes involved in carcinogenesis, such as p53 and K-ras.55,56

DNA Repair Genes and Response to Treatment in Lung Cancer Cisplatin is a key agent in almost every chemotherapy schedule, alone or in combinations. Substantial evidence indicates that DRC influences response to cisplatin-based regimens. Cisplatin’s mode of action is through formation of mono- or bifunctional DNA adducts in position N7 of adenine or guanine. These adducts can form interstrand bridges between 2 DNA strands, modifying the 3-dimensional structure and abrogating its biologic function, strongly inhibiting DNA replication.1,55,57 It has been demonstrated in NSCLC cell lines that elevated DRC causes cisplatin resistance.58 In 27 patients with locally advanced NSCLC treated with cisplatin-based therapy, patients with low cisplatin–DNA-adduct staining had lower survival rates compared with patients with high levels of platinum DNA adducts.59 In another cohort of 86 patients with cisplatin-treated NSCLC, the group with higher DRC had a median survival of 8.9 months versus 15.8 months for those in the bottom quartile. Furthermore, patients in the top quartile were at twice the risk of death as those in the lowest quartile.60 DNA Repair Gene Polymorphisms Influence Therapeutic Response and Survival. DRC and, therefore, the clearance of DNA adducts formed by cisplatin compounds is a determinant mechanism for drug resistance. In this regard, individual variations in genes involved in genomic repair can influence drug response.61 Several XRCC1 polymorphisms appear to be associated with an adverse RT effect.62 In multivariate analysis, only the combined XPD and XRCC1 genotypes were independently associated with cancer-specific survival in patients with muscleinvasive bladder cancer treated with chemoradiation therapy.63 Furthermore, SNPs in DNA repair enzymes have a predominant role in chemotherapy toxicity as, for example, the evidence that C8092A and codon 118 polymorphism in the ERCC1 gene

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is associated with a more than doubled risk of gastrointestinal toxicity among patients with platinum-treated NSCLC.64 In fact, it has been shown that ERCC1 C8092A impairs the stability of the messenger RNA (mRNA) transcript and could be the primary reason for decreased DRC.65 Recently, SNPs in XPD and XRCC1 were evaluated in 103 patients with advanced NSCLC treated with chemotherapy with platinum doublets. It was observed that allelic variants of XPD Asp312Asn and XRCC1 Arg399Gln presented lower rates of survival independent of performance status or chemotherapeutic schedule. The authors concluded that these SNPs were important prognostic factors and also predictors of response to therapy in NSCLC.66 In the same context, a study done by Camps and coworkers in 39 patients with metastatic NSCLC treated with cisplatin/gemcitabine showed a trend toward better survival in the subgroup of patients with XPD Asp312Asn and Asn312Asn SNPs when compared with the subgroup with Asp312Asp.67 Several SNPs in ERCC1, an enzyme of the nucleotide excision repair pathway, have been correlated with better survival in patients with NSCLC treated with platinum combinations. Data from Zhou et al in 128 patients revealed a median survival of 22.3 months for ERRCC1 C8092C versus 13.4 months in the subgroups with ERCC1 C8092A and A8092A.68 XRCC3 is a key protein in the homologous recombination pathway; a polymorphism at codon 241 (Thr to Met) has been associated with adduct levels in peripheral blood leukocytes in healthy individuals. Subjects carrying Met241Met presented higher levels of DNA adducts in an independent fashion of cigarette smoking habits,69 which implicates inefficient DNA repair activity and could be translated into a stronger sensibility to platinum-based treatments for cancer. Recently, in 135 patients with locally advanced or metastasic NSCLC treated with gemcitabine/cisplatin, the SLCG (Spanish Lung Cancer Group) analyzed the association of survival with 14 SNPs in 13 different genes involved in different pathways of DNA repair. The authors found that XRCC3 241 SNP was the only DNA repair SNP predicting survival and that patients exhibiting XRCC3 241 MetMet had higher levels of DNA adducts and better survival when treated with gemcitabine/cisplatin.70 Preliminary results of another study of the SLCG in patients with advanced NSCLC evaluated the relationship of different chemotherapeutic schedules with age and SNPs of XRCC3. The results showed a statistical benefit in survival for the younger patients and carriers of a homozygous XRCC3 241 MetMet treated with gemcitabine/cisplatin, whose median survival was not reached versus 8.4 months for patients treated with docetaxel/cisplatin. By contrast, this difference could not be observed for older patients even if they were carriers of homozygous XRCC3 241 MetMet, maybe because of increased DNA repair activity and, hence, clearance of cisplatin adducts. Differences were not significant in patients treated with other chemotherapeutic regimens (docetaxel/cisplatin and docetaxel/gemcitabine), perhaps because of the cytotoxic synergism between gemcitabine and cisplatin.71 In another study with 92 patients with potentially resectable pancreatic adenocarcinoma, Li et al reported a strong combined effect of the 4 genotypes in overall survival.72 Patients with

Carlos Camps et al RecQ1 A159C, RAD54L C157T, XRCC1 R194W, and ATM T77C SNPs had a mean survival time of 62.1 months, and those with 1, 2, or * 3 alleles had poorer survival times.

Gene Expression of DNA Repair Genes Only ERCC1 mRNA levels have been analyzed extensively in lung cancer or other cancers as an independent predictive factor for survival or response to therapy in patients treated by platinum agent–based therapy.73 It has been reported that the activation of oncogenes such as H-Ras might induce ERCC1 expression, which indeed activates DRC and can be involved in the protection of the cells against platinum agent–based anticancer agents.74 For example, Bellmunt et al demonstrated on multivariate analysis with pretreatment prognostic factors that ERCC1 is associated with survival in bladder cancer.75 In patients with completely resected NSCLC, another report showed that ERCC1-negative tumors appeared to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors did not.76 It appears that overexpression of ERCC1 correlates with poor survival in patients with gemcitabine/cisplatin–treated NSCLC, and based on this knowledge, the SLCG is performing a customized ERCC1-based chemotherapy trial. Patients are randomized to the control arm of cisplatin/docetaxel or to the experimental arm, in which docetaxel is combined with cisplatin or gemcitabine according to ERCC1 levels. Preliminary findings showed that a subset of gemcitabine/cisplatin–treated patients with low ERCC1 and RRM1 mRNA levels had a significantly longer survival.77 Another potentially important tool for use as a predictive biomarker is BRCA1 expression,78 because loss of BRCA1 function is associated with sensitivity to DNA-damaging chemotherapy and might also be associated with resistance to spindle poisons.79 Therefore, mRNA levels of BRCA1 could be assessed for predicting differential chemosensitivity and tailoring chemotherapy in lung cancer. In contrast, Wachters et al in tumor biopsy samples from patients with NSCLC found that immunohistochemical staining of ERCC1, hRad51, and BRCA1 was not predictive for tumor response and survival after chemotherapy.80 Thus, these findings suggest that, although expression levels of DNA repair mechanisms are appealing determinants for customizing cisplatin-based chemotherapy,81 validation of ERCC1 or other enzymes as predictive biomarkers must occur through prospective clinical trials.82,83 A recent report by Zheng et al showed that, in patients with early-stage NSCLC, the expression levels of RRMM1 and ERCC1 were significantly associated with disease-free and overall survival after surgical treatment.84 Promoter Hypermethylation of DNA Repair Genes. Analysis of hypermethylation in DNA repair genes and demonstration of sensitivity for the cytotoxic effects of alkylating drugs raises the possibility of pharmacoepigenomic impact. For example, MGMT hypermethylated tumors are more sensitive to alkylating agents,85-87 and this information could be useful as a predictor of responsiveness to alkylating chemotherapy.88 Of importance, serum DNA and peripheral blood lymphocytes are easily obtainable sources for analysis of these genetic and epigenetic changes.89,90

Conclusion DRC is genetically determined, and different levels of expression of these genes, mainly attributable to SNPs of enzymes such as ERCC1, XPD, or XRCC3, modulate lung cancer susceptibility or the response to different chemotherapeutic regimens, mainly based on agents that promote the formation of DNA adduct–like platinum salts. A better knowledge of these DNA repair mechanisms and elucidation of different polymorphisms in the genes involved in these metabolic pathways, in the future, will allow us to be able to screen for lung cancer susceptibility and to tailor chemotherapy, choose the most responsive patients, adjust the dose more precisely, and establish safety profiles based on individual genetic analysis. By assessing DNA repair enzymes, mRNA, SNPs, promoter hypermethylation status, DRC, or the level of cisplatin adducts, we can obtain a complete genetic profile, which can be used in real translational research and will help move the field forward in terms of risk stratification and therapy selection.

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