Pancreatic cancer genetics

Pancreatic cancer genetics

IAP/APA Meeting Pancreatology 2001;1:571–575 Pancreatic Cancer Genetics E. Efthimiou T. Crnogorac-Jurcevic N.R. Lemoine ICRF Molecular Oncology Unit,...

70KB Sizes 19 Downloads 259 Views

IAP/APA Meeting Pancreatology 2001;1:571–575

Pancreatic Cancer Genetics E. Efthimiou T. Crnogorac-Jurcevic N.R. Lemoine ICRF Molecular Oncology Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK

Key Words Pancreatic cancer W Cancer genes W Inherited predisposition

Abstract Cancer is a multi-stage process resulting from accumulation of genetic changes in the somatic DNA of normal cells. Although in the majority of cases the changes occur only in the cancer cells there is a small proportion of cancers where a germline mutation confers an increased risk for cancer. Cancer susceptibility genes have effects that range from high to low penetrance with a corresponding high to lower likelihood for cancer in the carriers. Pancreatic cancer-prone families have been identified and some of the germline mutations responsible elucidated. Germline mutations in the BRCA2, CDKN2A/ p16, hMSH2, hMLH1, hPMS1, hPMS2, LKB1/STK1, and PRSS1 genes have been associated with increased risk for pancreatic cancer. The concept of screening high-risk groups for pancreatic cancer is emerging, preferably in specialised centres with a multidisciplinary team approach. Copyright © 2001 S. Karger AG, Basel and IAP

Based on a lecture at the combined meeting of the International Association of Pancreatology and the American Pancreatic Association, Chicago, 2000.

ABC

© 2001 S. Karger AG, Basel and IAP 1424–3903/01/0016–0571$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/pan

Cancer Susceptibility Genes

The process of transformation of a normal into a malignant cell is a step-wise process during which the cell progressively accumulates genetic changes. Whilst the vast majority of cancers arise as a result of sporadic mutations in somatic DNA there is evidence that certain mutations inherited in the germline account for the hereditary cancer syndromes which comprise about 1% of all cancers [1]. Study of the inherited cancer syndromes has provided insights into the pathogenesis of inherited and sporadic cancer. Mutations in the so called ‘inherited cancer genes’ exhibit a variable degree of prevalence and penetrance and often affect the same genes as in sporadic cases. The likelihood of these gene mutations causing cancer is also influenced by other genes (modifier genes) as well as environmental and dietary factors. This explains why not all mutation carriers develop cancer. Polymorphisms in modifier gene alleles seem to influence an individual’s risk of developing cancer. All the genes that contribute to an increased risk for cancer are termed ‘cancer susceptibility genes’. Inherited cancer genes represent a subgroup of the cancer susceptibility genes [1]. The effects of the cancer susceptibility genes in cancer pathogenesis range from high-penetrance genes with a high risk for cancer development as well as medium- and low-penetrance genes with lesser likelihood for cancer development. Cancer susceptibility genes with a high penetrance have a low prevalence in the general population (less than 0.5%). As a

Prof. N.R. Lemoine ICRF Molecular Oncology Unit, Department of Cancer Medicine Imperial College School of Medicine, Hammersmith Campus London W12 0NN (UK) Tel. +44 208 383 3975, Fax +44 208 383 3258, E-Mail [email protected]

result of the high penetrance for the particular mutation, cancer risk is high (80–100% of the mutation carriers develop cancer). Demand for genetic testing for these genes is high and a limited service to screen for germline mutations in families with strong history of cancer is available in major centres around the world. Cancers linked to germline mutations with high penetrance include colorectal cancer and mutations in the APC gene and hMSH2, hMLH1, hPMS1, hPMS2 genes, breast/ ovarian cancer and BRCA1 and BRCA2 gene, malignant melanoma and the CDKN2A gene and childhood and breast cancers with TP53 gene mutations. Mutations in the medium-penetrance cancer susceptibility genes occur in about 2% of the general population and are likely to be associated with small familial clusters (typically 2–4 cases). As a result of the medium penetrance a family history of cancer (particularly in small families) may not be obvious. In cases where a family history is evident, a pressing need for genetic testing is developing. Finally, cancer susceptibility genes with a low penetrance are more common in the general population and the majority of carriers will remain unaffected. The risk of cancer in these cases is mildly elevated (1- to 2-fold). It is likely that the low-penetrance genes cause cancer by modulating certain environmental exposures in the affected individuals [2].

Pancreatic Cancer-Prone Families

Pancreatic cancer ranks fifth amongst the leading causes of death from cancer in men and women in Europe and North America. Despite the recent advances in our understanding of the molecular changes accompanying pancreatic cancer, the prognosis has not changed significantly. Chemotherapy and radiotherapy have proven rather ineffective in providing control of the disease [3]. The only hope for prolongation in survival is surgical resection. Unfortunately, the vast majority of tumours (over 80%) are discovered late when curative resection is not an option. Evidence about the increased risk of pancreatic cancer amongst relatives of patients with pancreatic cancer comes from a variety of studies. Ghadirian et al. [4] found that 7.8% of patients with pancreatic cancer reported a positive family history for the disease compared with 0.6% reported by matched controls. Fernandez et al. [5] found a significant association between a family history for pancreatic cancer and the risk of developing pancreat-

572

Pancreatology 2001;1:571–575

ic cancer (odds ratio = 2.8, 95% confidence intervals 1.3– 6.3). The same study suggested a genetic component in 3% of the newly diagnosed pancreatic cancers. Two recent studies, one population-based and the other derived from the National Familial Pancreas Tumour Registry, showed an odds ratio for pancreatic cancer approximating 3.5 in first- and second-degree relatives when there are two or more affected members in a family [6, 7]. There are several studies in the literature supporting the view that some cases of pancreatic cancer exhibit a definite familial clustering and it is estimated that 5–10% of cases are due to hereditary factors [8–15]. The challenge is to identify these families and investigate the presence of possible germline mutations that could account for the increased predisposition for pancreatic cancer in these families. The first step in this process is to set selection criteria that identify individuals with an increased risk for pancreatic cancer. In a pancreatic cancer surveillance program set up at the University of Washington the following criteria are used: (1) an individual with two or more first-degree relatives with pancreatic adenocarcinoma, or (2) an individual with one first-degree relative who developed pancreatic adenocarcinoma at a young age (younger than 50 years), or (3) an individual with two or more second-degree relatives with pancreatic adenocarcinoma, one of whom developed the cancer at an early age [16, 17]. Pancreatic cancer-prone families exist as two distinct groups: families where the inherited predisposition to pancreatic cancer is a part of a known inherited cancer syndrome and families where pancreatic cancer is the only type of cancer these families develop. In the first group belong families with germline mutations in the BRCA2, CDKN2A/p16, LKB1/STK1 and hMSH2, hMLH1, hPMS1, hPMS2 genes. In the second group belong families with hereditary pancreatitis and a unique family described by Evans et al. [10].

BRCA2 Mutations

BRCA2 germline mutation carriers have a 25% lifetime risk for breast cancer [18]. As well as the increased breast cancer risk published data support an increased risk for pancreatic cancer in these families. Tonin et al. [19] found in a study of 220 Jewish families affected by breast cancer that a positive family history for pancreatic cancer was a strong predictor of the presence of BRCA2 mutations in these families (odds ratio = 6.1; p = 0.03).

Efthimiou/Crnogorac-Jurcevic/Lemoine

Thorlacius et al. [20] investigated 21 Icelandic families with male and female breast cancer and found 11 cases of pancreatic cancer in the 16 mutation-positive families (all with a 999del5 mutation in the BRCA2 gene) whilst there were no cases of pancreatic cancer in the mutation-negative families. Phelan et al. [21] studied 49 site-specific breast cancer families and found 4 cases of pancreatic cancer in the 8 BRCA2 mutation-positive families. In the 41 BRCA2 mutation-negative families there were 5 cases of pancreatic cancer (RR = 7.2, p = 0.03). The age at onset for the 4 pancreatic cancer cases in mutation-positive families was significantly lower than in the mutation-negative families. Goggins et al. [22] detected germline BRCA2 mutations in 7.3% of sporadic pancreatic cancers, whilst Ozcelik et al. [23] identified two germline BRCA2 mutations (4.9%) in 42 cases of pancreatic cancer without family history. The same group investigated 39 Jewish patients with pancreatic cancer for germline BRCA2 mutations and found 4 mutations (10%). The risk of acquiring pancreatic cancer by the age of 75 years in carriers of the BRCA2 mutation was estimated at 7% in contrast with the 0.85% for the general population. Lal et al. [24] investigated the frequency of germline BRCA1 and BRCA2 mutations in 102 patients with histologically confirmed pancreatic adenocarcinoma. Mutation analysis was performed in 38 high-risk for germline mutations patients and 5 germline mutations (3 BRCA2, 1 BRCA1, 1 p16) were shown. BRCA2 germline mutation carriers appear to have a 10-fold higher risk of developing pancreatic cancer than the general population [17]. Families that exhibit clustering of pancreatic and breast cancer may warrant screening for BRCA2 mutations [7].

Early reports in literature suggested a susceptibility to systemic cancers, in addition to melanoma, in families with FAMMM [25]. Bergman et al. [26] in a study of 9 Dutch families with FAMMM found an increased frequency of systemic cancer, particularly of the gastrointestinal tract. For pancreatic cancer, the ratio of observed to expected frequencies was 13.4. Goldstein et al. [27] found a 22-fold increased risk of pancreatic cancer in FAMMM families with CDKN2A germline mutations, indicating that this subset of FAMMM families has a higher than expected risk for pancreatic cancer (7 observed versus 0.32 expected). Similar associations between CDKN2A germline mutation and pancreatic cancer in FAMMM families have been reported by other investigators [13, 28]. Borg et al. [29] showed CDKN2A germline mutations in 19% of 52 malignant melanoma families. In this study the families with germline CDKN2A mutation also had a higher frequency of pancreatic cancer (6 cases observed versus 0.16 expected; p ! 0.0001). FAMMM kindreds have an increased risk of pancreatic cancer, however not all the FAMMM families are prone to pancreatic cancer development. Goldstein et al. [30] showed similar mutations in the CDKN2A gene in FAMMM families with and without pancreatic cancer, indicating that other factors may also be involved in the development of pancreatic cancer. Melanoma-prone families exhibit an earlier than expected age of onset for malignant melanoma (by two decades), whilst the pancreatic cancers in these families appear at the same late age as in the sporadic form of the disease (typically the seventh decade) [30].

hMSH2, hMLH1, hPMS1, hPMS2 Mutations

CDKN2A/p16 Mutations

The FAMMM syndrome is an autosomal, dominantly inherited syndrome characterised by multiple atypical (dysplastic) nevi, familial clustering of cutaneous malignant melanoma and increased incidence of extracutaneous cancers. Two genes have been implicated in the pathogenesis of malignant melanoma. The first is the CDKN2A/p16 gene which encodes a protein (p16) that controls a checkpoint at the G1 stage of cell cycle. The second gene involved in the pathogenesis of malignant melanoma is the CDK4 gene, a proto-oncogene located at chromosome 12q13. Mutation of this gene has been noted so far in three melanoma-prone families.

Hereditary non-polyposis colorectal carcinoma (HNPCC) is an autosomal, dominantly transmitted syndrome. The affected families have an increased risk of developing colorectal, endometrial, ovarian and breast cancers, transitional carcinoma of the ureter and renal pelvis, as well as pancreatic carcinoma. Mutations in one of the DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2) are considered to be the cause of this syndrome. These genes encode proteins responsible for correcting small DNA errors arising during replication. Inactivation by mutation leads to accumulation of replication errors in the DNA and a phenotype called MSI+ or ‘microsatellite instability’. Goggins et al. [31] have shown the presence of MSI+ in about 3.7% of pancreatic cancers.

Pancreatic Cancer Genetics

Pancreatology 2001;1:571–575

573

The tumours were characterised by pushing borders, poor differentiation and syncytial growth pattern and a wildtype KRAS gene and this subgroup of patients was associated with better prognosis despite having a poorly differentiated histological phenotype. The observation of this characteristic phenotype combined with wild-type KRAS should raise the suspicion of an MSI+ phenotype and the possibility of colonic carcinomas in the affected patient and family. The exact risk of pancreatic cancer in HNPCC kindreds remains unknown [17].

LKB1/ STK11 Mutations

The Peutz-Jeghers syndrome is an autosomal dominant condition characterised by multiple hamartomatous polyps of the gastrointestinal tract and the presence of pigmented lesions (melanin deposits) in the lips, oral mucosa and digits of the affected individuals. Mutation in the LKB1/ STK11 gene which maps to 19p13 is considered to be the cause of the syndrome. LKB1/ STK11 gene encodes a serine/threonine kinase with an as yet undefined role [32–34]. Approximately 50% of PJS patients have been shown to develop some form of cancer [35–37]. The LKB1/STK1 gene has been shown to be inactivated in 4% of sporadic pancreatic cancer suggesting a possible role in tumour suppression [38]. From 53 PJS patients reported in 4 independent studies, 11% developed pancreatic adenocarcinoma [38]. The exact risk of pancreatic cancer in PJS patients is unknown [17].

PRSS1 Mutations

Hereditary pancreatitis is an autosomal-dominant disorder characterised by recurrent attacks of abdominal pain and acute pancreatitis that start in childhood and lead to the development of chronic pancreatitis by the teenage years. A mutation in the cationic trypsinogen gene PRSS1 has been linked with hereditary pancreatitis. The cumulative lifetime risk of pancreatic cancer in a patient with hereditary pancreatitis has been estimated to be 40% by the age of 70, with smokers having a substantially higher risk of cancer than non-smokers [39]. The risk of developing pancreatic cancer is substantially higher than the estimated cumulative risk in chronic nonhereditary pancreatitis, which is around 4% 20 years after the diagnosis of chronic pancreatitis [40].

574

Pancreatology 2001;1:571–575

Seattle Family X

Evans et al. [10] have reported an interesting family characterised by an autosomal, dominantly transmitted propensity for pancreatic ductal adenocarcinoma. The members of this family develop diabetes and exocrine pancreatic insufficiency prior to the onset of cancer. Interestingly, the members of the family develop pancreatic cancer at an earlier age in each generation (a phenomenon called anticipation). No germline mutation in any candidate gene has yet been identified and some consider this family to represent some form of hereditary pancreatitis. Another possible explanation is that in some of the pancreatic cancer families pancreatic cancer may be the result of exposure to a common, so far unidentified carcinogenic factor.

Future Challenges

It is believed that the study of families with an increased susceptibility to pancreatic cancer will provide insight into the pathogenesis of both inherited and sporadic pancreatic cancer. The definition of the groups with an increased susceptibility for this cancer will help to establish pilot screening programmes for early detection of the disease in high-risk groups. There are important issues to be considered before application of large scale screening programs for cancer susceptibility genes. Genetic counselling for individuals and their families is crucial, and the ethical and medicolegal sequelae should be explored in detail. Screening programs for pancreatic cancer will be expensive, as the diagnostic techniques are sophisticated and likely to be available in specialist centres with multidisciplinary teams including pancreatic surgeons, gastroenterologists, molecular pathologists and cancer geneticists.

Efthimiou/Crnogorac-Jurcevic/Lemoine

References 1 Fearon ER: Human cancer syndromes: Clues to the origin and nature of cancer. Science 1997;278:1043–1050. 2 Shields PG, Harris CC: Cancer risk and lowpenetrance susceptibility genes in gene-environment interactions. J Clin Oncol 2000;18: 2309–2315. 3 Schnall SF, Macdonald JS: Chemotherapy of adenocarcinoma of the pancreas. Semin Oncol 1996;23:220–228. 4 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;10:183–196. 5 Fernandez E, La Vecchia C, D’Avanzo B, Negri E, Franceschi S: Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev 1994;3: 209–212. 6 Silverman DT, Schiffman M, Everhart J, Goldstein A, Lillemoe KD, Swanson GM, et al: Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Br J Cancer 1999;80:1830– 1837. 7 Hruban RH, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, Falatko F, et al: Familial pancreatic cancer. Ann Oncol 1999; 10(suppl 4):69–73. 8 Danes BS, Lynch HAT: A familial aggregation of pancreatic cancer: An in vitro study. JAMA 1982;247:2798–2802. 9 Ehrenthal D, Haeger L, Griffin T, Compton C: Familial pancreatic adenocarcinoma in three generations. A case report and a review of the literature. Cancer 1987;59:1661–1664. 10 Evans JP, Burke W, Chen R, Bennett RL, Schmidt RA, Dellinger EP, et al: Familial pancreatic adenocarcinoma: Association with diabetes and early molecular diagnosis. J Med Genet 1995;32:330–335. 11 Lynch HT, Fitzsimmons ML, Smyrk TC, Lanspa SJ, Watson P, McClellan J, et al: Familial pancreatic cancer: Clinicopathologic study of 18 nuclear families. Am J Gastroenterol 1990; 85:54–60. 12 Lynch HT, Fusaro L, Lynch JF: Familial pancreatic cancer: A family study. Pancreas 1992; 7:511–515. 13 Whelan AJ, Bartsch D, Goodfellow PJ: Brief report: A familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med 1995;333:975–977. 14 Levin B: An overview of preventive strategies for pancreatic cancer. Ann Oncol 1999; 10(suppl 4):193–196. 15 Lynch HT, Smyrk T, Kern SE, Hruban RH, Lightdale CJ, Lemon SJ, et al: Familial pancreatic cancer: A review. Semin Oncol 1996;23: 251–275.

Pancreatic Cancer Genetics

16 Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB: Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med 1999;131:247–255. 17 Brentnall TA: Cancer surveillance of patients from familial pancreatic cancer kindreds. Med Clin North Am 2000;84:707–718. 18 Roa BB, Boyd AA, Volcik K, Richards CS: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 1996;14:185–187. 19 Tonin P, Weber B, Offit K, Couch F, Rebbeck TR, Neuhausen S, et al: Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 1996;2: 1179–1183. 20 Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, et al: A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 1996;13:117– 119. 21 Phelan CM, Lancaster JM, Tonin P, Gumbs C, Cochran C, Carter R, et al: Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996;13:120–122. 22 Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, et al: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996;56:5360–5364. 23 Ozcelik H, Schmocker B, Di Nicola N, Shi XH, Langer B, Moore M, et al: Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 1997;16:17– 18. 24 Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, et al: Inherited predisposition to pancreatic adenocarcinoma: Role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res 2000;60:409–416. 25 Lynch HT, Fusaro RM, Kimberling WJ, Lynch JF, Danes BS: Familial atypical multiple molemelanoma (FAMMM) syndrome: Segregation analysis. J Med Genet 1983;20:342–344. 26 Bergman W, Watson P, de Jong J, Lynch HT, Fusaro RM: Systemic cancer and the FAMMM syndrome. Br J Cancer 1990;61:932–936. 27 Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, et al: Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 1995;333:970–974. 28 Lal G, Liu L, Hogg D, Lassam NJ, Redston MS, Gallinger S: Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. Genes Chromosomes Cancer 2000;27:358–361. 29 Borg A, Sandberg T, Nilsson K, Johannsson O, Klinker M, Masback A, et al: High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2000; 92:1260–1266.

30 Goldstein AM, Struewing JP, Chidambaram A, Fraser MC, Tucker MA: Genotype-phenotype relationships in US melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst 2000;92:1006–1010. 31 Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, et al: Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology: Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 1998; 152:1501–1507. 32 Hemminki A, Tomlinson I, Markie D, Jarvinen H, Sistonen P, Bjorkqvist AM, et al: Localization of a susceptibility locus for PeutzJeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat Genet 1997;15:87–90. 33 Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, et al: A serine/ threonine kinase gene defective in PeutzJeghers syndrome. Nature 1998;391:184–187. 34 Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, et al: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 1998;18:38–43. 35 Hizawa K, Iida M, Matsumoto T, Kohrogi N, Kinoshita H, Yao T, et al: Cancer in PeutzJeghers syndrome. Cancer 1993;72:2777– 2781. 36 Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittelsohn AM, Booker SV, et al: Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987;316:1511– 1514. 37 Boardman LA, Thibodeau SN, Schaid DJ, Lindor NM, McDonnell SK, Burgart LJ, et al: Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med 1998;128:896–899. 38 Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, et al: Germline and somatic mutations of the STK11/LKB1 PeutzJeghers gene in pancreatic and biliary cancers. Am J Pathol 1999;154:1835–1840. 39 Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK Jr, Perrault J, et al: Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997;89:442– 446. 40 Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, et al: Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993;328:1433–1437.

Pancreatology 2001;1:571–575

575