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The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel

The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic... British Journal of Cancer (2001) 84(4), 478–481 © 2001 Cancer Research Campaign http://www.bjcancer.com doi: 10.1054/ bjoc.2000.1605, available online at http://www.idealibrary.com on The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel 1 1,3 1 1 2 1 3 A Figer , L Irmin, R Geva, D Flex , J Sulkes, A Sulkes and E Friedman 1 2 3 Institute of Oncology and the Epidemiology Unit, Rabin Medical Center (Belinson Campus), Petach Tikva; the Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, 52621, and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Summary Inherited predisposition occurs in 5–10% of all gastrointestinal (GI) cancer patients, but with the exception of colorectal cancer (CRC), the genes involved in conferring genetic susceptibility remain largely unknown. Indirect evidence indicates that germline mutations in BRCA2 might be associated with an increased risk for various GI malignancies. A single mutation (6174delT) occurs in the BRCA2 gene in high-risk breast ovarian cancer families of Jewish Ashkenazi origin, in about 1% of the general Ashkenazi population, and rarely in non- Ashkenazi Jews. In order to assess the contribution of this germline mutation to non-CRC GI cancer in Jewish Israeli patients, we tested 70 unselected, consecutive Jewish Ashkenazi patients with gastrointestinal malignancies for this mutation by PCR amplification and modified restriction enzyme digests. Patients’ age range was 38–90 years (mean 65.8±11.8 years). The most common malignancies were gastric cancer (n = 35) and exocrine pancreatic cancer (n = 23). Overall, 6 mutation carriers were detected: 3/23 (13%) of the patients with pancreatic cancer, 2/35 (5.7%) of patients with gastric cancer and 1/4 (25%) of patients with bile duct cancer. The 8.6% mutation carrier rate among patients is a rate significantly higher than that of the general Ashkenazi population (1.16% P = 0.0002). We conclude that the rate of the predominant Jewish BRCA2 mutation in patients with gastric and pancreatic cancer significantly differ from that of the general population of the same ethnic origin. Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information. © 2001 Cancer Research Campaign http://www.bjcancer.com Keywords: BRCA 2; Jewish founder mutation; non-colon cancer; inherited predisposition to cancer Gastrointestinal malignancies other than colorectal cancer (CRC) degree relatives (Ghadirian et al, 1991; Lynch et al, 1992). These are common. In Israel in 1995, gastric cancer was diagnosed in observations suggest an inherited predisposition to these cancer 572 Jewish individuals, pancreatic cancer in 368, 140 were diag- types in a subset of patients, but the genes that underlie this genetic nosed with primary liver or biliary tract cancer, and 110 had susceptibility remain largely unknown. Clustering of ovarian and oesophageal cancer (Israel Cancer Registry, 1998). Furthermore, gastric cancer (Easton et al, 1996) and breast/ovarian and exocrine the mortality rate from gastric and pancreatic cancer is high: in pancreatic cancer (Tulinius et al, 1992) have been reported, Israel the age stratified rate (ASR) for gastric cancer mortality is suggesting a role for BRCA2 gene mutations in pancreatic cancer 10.9/100 000 in Jewish men and 5.6/100 000 in Jewish women, predisposition (Phelan et al, 1996). Furthermore, a large study compared with an ASR for morbidity of 14.2/100 000 and 7.7/ encompassing more than 3000 BRCA2 mutation carriers and their 100 000, respectively (Israel Cancer Registry, 1998). This high first-degree relatives, estimated the relative risk (RR) for devel- mortality rate stems in part from the paucity of early symptoms oping cancers other than breast/ovarian: for pancreatic cancer the and hence the advanced stage at which these neoplasms are RR was 3.51, for gallbladder and bile duct cancer – 4.97 and for usually diagnosed. Thus, identifying individuals at high risk for stomach cancer – 2.59 (BCLC, 1999). developing these malignancies has obvious clinical implications. Among Jewish people, a single predominant mutation within Familial clustering of cancer, a well known risk factor predis- the BRCA2 gene (6174delT) occurs. This mutation can be detected posing to gastric, pancreatic, and other GI cancer is noted in in individuals at risk for developing breast and ovarian cancer 3–10% of all incident cases of these malignancies (Zanghieri et al, (Abeliovich et al, 1997), in about 1–1.5% of the general Ashkenazi 1990; Lynch et al, 1992; Fernandez et al, 1994). The relative risk (East European) Jews (Ouddoux et al, 1996; Roa et al, 1996), and for developing gastric cancer in first-degree relatives of gastric rarely among non-Ashkenazi Jews (Struewing et al, 1999). cancer patients ranges from 1.7 to 3.5, with an increase in relative Analysis of 245 unselected patients with pancreatic cancer for this risk associated with having more than one affected family member mutation, revealed two mutation carriers (0.8%) and an additional (Zanghieri et al, 1990; Palli et al, 1994; Lissowska et al, 1999). BRCA2 germline mutation carrier in a nearby codon (Goggins et Similarly, familial clustering of pancreatic cancer is associated al, 1996). However, not all patients in this latter study were Jewish with an increased risk for developing these neoplasms in all first individuals. Direct mutational analysis of 39 unselected Jewish Ashkenazi patients with pancreatic cancer, revealed 4 6174delT Received 27 July 2000 BRCA2 (10%) mutation carriers (Ozcelik et al, 1997). Revised 2 November 2000 To test the notion that BRCA2 mutations predispose to gastroin- Accepted 8 November 2000 testinal malignancies other than colorectal cancer, we determined Correspondence to: E Friedman the rate of the BRCA2 6174delT predominant germline mutation in 478 Founder BRCA2 mutation in gastrointestinal cancer 479 Table 1 Clinical and histopathological data of all BRCA2 mutation carriers 70 unselected Jewish Ashkenazi patients with these types of in the present study malignancies who were consecutively treated in a single medical centre in Israel. Pat no. Sex Tumour Age at diagnosis Family history of cancer MATERIALS AND METHODS 1 M Bile duct cancer 60 Father – CRC Son – CRC Patients’ characteristics and tumour material 2 F Gastric 55 None All patients with a clinical and histopathological diagnosis of 3 F Gastric 54 Mother – BC Grandmother – BC gastrointestinal malignancy (excluding colorectal cancer) who were 4 M Pancreas 54 Mother – CRC treated at the Institute of Oncology, Rabin Medical Center from 5 M Pancreas 81 None January 1, 1999 to March 31, 2000, were eligible for participation. 6 M Pancreas 61 Mother – abdominal The study was approved by the institutional review board, and all cancer patients signed an informed consent. All consenting patients filled a detailed questionnaire that includes demographic data, past medical BC = Breast cancer; CRC = colorectal cancer. history, age at diagnosis, family history of cancer, especially gastrointestinal, breast and/or ovarian. Based on the criteria applied for other familial cancers, patients having at least one first-degree cancer (n = 23), oesophageal cancer (n = 7), bile duct cancer (n = relative with GI or BRCA2 related cancer (breast and ovarian), or 4) and one small bowel cancer. Median age at diagnosis was 67 more than two second-degree relatives with cancer one of which is years (range 38–90 years) with a mean age of 65.8±11.8 years; of GI, breast or ovarian origin, were classified as familial cases. 6 patients (8.57%) were diagnosed between 38–49 years; 16 (22.8%) – between 50–59 years; 19 (27.2%) – between 60–69 years; 20 (28.6%) – between 70–79 years; 9 (12.8%) over the age DNA extraction of 80 years. 13 (18.5%) and 12 (17.1%) patients had first-degree Anticoagulated peripheral blood was withdrawn by venopuncture, relatives with gastrointestinal or other cancer, respectively, and 4 and DNA was extracted using standard techniques, using the (5.7%) had at least one first-degree relative with breast cancer. Gentra kit (Gentra Inc., Minneapolis, MN). Germline mutational analysis Mutation analysis of the predominant Jewish mutation in BRCA2 The presence of 6174delT BRCA2 germline mutation was tested in all study participants and 6 carriers were found (6/70–8.6%). The Mutational analyses for the predominant mutation (6174delT) in clinical and pertinent data of the 6 mutation carriers are presented BRCA2, were carried out by restriction enzyme digest of amplified in Table 1. Notably, 3/23 of the patients with pancreatic cancer PCR products using modified amplification primers, to generate (13%), 2/35 (5.7%) of the patients with gastric cancer and 1/4 of novel restriction sites, followed by restriction enzyme analysis to the patients (25%) with bile duct cancer were mutation carriers. distinguish the mutant from the wild-type allele, as previously Surprisingly, only 1/5 individuals with a family history of breast described (Rohlfs et al, 1997), and adopted by us (Bar Sade et al, and/or ovarian cancer was among the mutation carriers, and family 1998). history of other cancer was ascertained in 4/6 mutation carriers (Table 1). In addition, the age at diagnosis in mutation carriers was Statistical analyses not noticeably younger than other individuals with the same cancer type. Comparison of the rates of the founder Jewish mutation in BRCA2 between the general Jewish Ashkenazi population (Hartage et al, 1999) and all GI cancer patients in our study group as well as the Statistical analyses distribution within specific tumour types were performed using There was a statistically significant difference in the carrier rate of Fisher’s Exact test. Odds ratio (OR) and the 95% confidence inter- the 6174delT BRCA2 mutation between the general Jewish vals (CI) were calculated from the tables Ashkenazi population and all cancer types in the present study Even though the numbers for the Jewish Ashkenazi population are based on American Ashkenazi Jews (Hartage et al, 1999), we assumed that it is legitimate to use these numbers for two main Table 2 Comparison between the mutation carrier rate of the predominant reasons: first, the Ashkenazi Jewish population is well character- Jewish mutation in BRCA2 in the study population (Israeli Ashkenazi GI ized as a distinct ethnic entity, regardless of the present place of cancer patients) and the reference Jewish Ashkenazi population (from Hartage et al, 1999) by specific tumour types residence (i.e. Tel-Aviv or Washington). Second, comparisons of Israeli and non-Israeli Ashkenazis with regard to being 185delAG Cancer type Mutation carriers P value OR CI BRCA1 mutation carriers, did not show any differences between Israelis and Americans (Streuwing et al, 1997). Gastric 2/35 (5.7%) 0.06 5.2 1.2–22 Pancreatic 3/23 0.002 12.8 3.7–44.2 Bile duct 1/4 0.05 28.4 2.9–277.2 RESULTS Oesophageal 0/7 NS – – Small intestine 0/1 NS – – Patients’ characteristics Total 6/70 (8.6%) 0.0002 8 3.3–19.2 All 70 were of Ashkenazi origin. The most common malignancy was gastric cancer (n = 35), followed by exocrine pancreatic NS – denotes statistically not significant. © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 478–481 480 A Figer et al combined (59/5089 vs. 6/70, P = 0.0002). Analysis of the rate of neoplasms in Jewish BRCA2 mutation carriers remains to be deter- this mutation within specific tumour types, showed that the rates in mined in a larger, prospective study. pancreatic cancer and bile duct cancer were also statistically significant higher than population controls (Table 2). ACKNOWLEDGEMENT This study was funded in past by generous donation from Mr Ami DISCUSSION Ya’ar in loving memory of his late wife, Ruthi. In the present study, the involvement of the BRCA2 gene in inher- ited predisposition to gastrointestinal cancer other than colorectal cancer was evaluated by direct mutational analysis. The rate of the REFERENCES predominant Jewish mutation in BRCA2 in Ashkenazi patients Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, Zlotogora J, Heching with gastric, exocrine pancreatic cancer and bile duct cancer was N and Peretz T (1997) The founder mutation 185delAG and 5382insC in significantly greater than the rate in the general Jewish Ashkenazi BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of population (Struewing et al, 1997; Hartage et al, 1999). early-onset breast cancer among Ashkenazi women. Am J Hum Genet 60: Furthermore, family history of cancer was elucidated in 4/6 muta- 505–514 tion carriers, as an additional evidence that the mutation found is Bar-Sade RB, Kruglikova A, Modan B, Gak E, Hirsh-Yechezkel G, Theodor L, Novikov I, Gershoni-Baruch R, Risel S, Papa MZ, Ben-Baruch G and not merely an incidental finding, but rather reflects a true inherited Friedman E (1998) The 185delAG BRCA1 mutation originated before the predisposition. dispersion of Jews in the diaspora and is not limited to Ashkenazim. Hum Mol The data presented herein are in agreement with other studies Genet 7: 801–805 showing a higher than expected rate of BRCA2 gene germline Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91: 1310–1316 mutations in pancreatic cancer in ethnically diverse populations, Easton DF, Matthews FE, Ford D, Swerdlow AJ and Peto J (1996) Cancer mortality and in Ashkenazi Jews, in particular. The original observation in relatives of women with ovarian cancer: the OPCS Study. Office of regarding finding of 2/245 (0.8%) 6174delT mutation carriers and Population Censuses and Surveys. Int J Cancer 65: 284–294 4/39 (10%) among unselected patients (Goggins et al, 1996) or Falk RT, Pickle LW, Fontham ET, Correa P and Fraumeni JF Jr (1988) Life-style risk Jewish individuals (Ozelick et al, 1997) with pancreatic cancer has factors for pancrcetic cancer in Louisiana: a case-control study. Am J Epidemiol 128: 324–336 been mentioned. Analysis of 38 Jewish individuals with pancreatic Fernandez E, La Vecchia C, D’Avanzo B, Negri E and Franceschi S (1994) Family cancer, revealed 3 (7.9%) BRCA2 6174delT mutation carriers (Lal history and the risk of liver, gallbladder, and pancrcatic cancer. Cancer et al, 2000). Furthermore, in Iceland, where a single predominant Epidemiol Biomarkers Prev 3: 209–212 mutation (999del5) in BRCA2 exists, first-degree relatives of Ghadirian P, Boyle P, Simard A, Baillargeon J, Maisonneuve P and Perret C (1991) Reported family aggregation of pancrcatic cancer within a population-based mutation carriers had a higher than expected rate of pancreatic case-control study in the Francophone community in Montreal, Canada. Int J cancer (Thorlacius et al, 1997). The role of BRCA2 mutations in Pancreatol 10: 183–196 conferring genetic susceptibility to gastric, oesophageal, hepatic Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, and biliary tract cancer is much less established. A high rate of Jackson CE, Lynch HT, Hruban RH and Kern SE (1996) Germlinc BRCA2 allelic loss at the BRCA2 locus has been reported, but few somatic gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56: 5360–5364 mutations have been detected in BRCA2 in hepatocellular cancer Hartge P, Struewing JP, Wacholder S, Brody LC and Tucker MA (1999) The (Katagiri et al, 1996). Similarly, 93% of oesopahgeal cancer from prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. patients with a family history of the disease (n = 23), displayed Am J Hum Genet 64: 963–970 allelic loss with a marker from the long arm of chromsome 13 Hu N, Roth MJ, Emmert-Buck MR, Tang ZZ, Polymeropolous M, Wang QH, Goldstein AM, Han XY, Dawsey SM, Ding T, Giffen C and Taylor PR (1999) (D13S894) (Hu et al, 1999). Moreover, in the most comprehensive Allelic loss in esophageal squamous cell carcinoma patients with and without study of cancer types other than breast and ovarian, associated family history of upper gastrointestinal tract cancer. Clin Cancer Res 5: with germline BRCA2 mutations, up to five-fold increased risk for 3476–3482 biliary tract and more than double the risk for stomach cancer is Israel Cancer Registry (1998) Cancer in Israel: facts and figures 1992–1995. Jerusalem reported (BCLC, 1999). However, to the best of our knowledge, Katagiri T, Nakamura Y and Miki Y (1996) Mutations in the BRCA2 gene in hepatocellular carcinomas. Cancer Res 56: 4575–4577 no direct mutational analyses studies were ever performed in Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, Redston M and individuals with these latter cancer types. Gallinger S (2000) Inherited predisposition to pancrcetic adenocarcinoma: role The results of the present study which support other lines of of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer indirect evidence as to the involvement of BRCA2 germline muta- Res 60: 409–416 Lissowska J, Groves FD, Sobin LH, Fraumeni JF, Jr; Nasierowska-Guttmejer A, tions in the susceptibility to cancer of the upper gastrointestinal Radziszewski J, Regula J, Hsing AW, Zatonski W, Blot WJ and Chow WH tract, should be reflected in genetic counselling. The increased risk (1999) Family history and risk of stomach cancer in Warsaw, Poland. Eur J for developing these malignancies should be incorporated into the Cancer Prev 8: 223–227 routine counselling process, and surveillance schemes aimed at Lynch HT, Fasuro L and Lynch JF (1992) Familial pancreatic cancer. A family study. early detection of these cancer types should be devised and tested. Pancreas 7: 511–515 Odduoux C, Streuwing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, Haas Furthermore, the subset of Ashkenazi Jewish patients with either B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H and Offit K (1996) The gastric, pancreatic cancer or bile duct cancer and a strong family carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish history of cancer should probably all be tested for being BRCA2 individuals is approximately 1%. Nat Genet 14: 188–190 mutation carriers. Ozcelik H, Schmocker B, Di Nicola N, Shi XH, Langer B, Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL, Gallinger S and Redston M (1997) In conclusion, in Jewish individuals, germline mutations in the Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer BRCA2 gene seem to contribute to the genetic susceptibility to patients. Nat Genet 16: 17–18 gastric, exocrine pancreatic and/or biliary tract cancer, and a Palli D, Galli M, Caporaso NE, Cipriani F, Decarli A, Saieva C, Fraumeni JF Jr and family history of these or related cancer types. The predictive Buiatti E (1994) Family history and risk of stomach cancer in Italy. Cancer value, penetrance and the lifetime risk for developing these Epidemiol Biomarkers Prev 3: 15–18 British Journal of Cancer (2001) 84(4), 478–481 © 2001 Cancer Research Campaign Founder BRCA2 mutation in gastrointestinal cancer 481 Phelan CM, Lancaster JM, Tonin P, Gumbs C, Cochran C, Carter R, Ghadirian P, Struewing JP, Coriaty ZM, Ron E, Livoff A, Konichezky M, Cohen P, Resnick MB, Perret C, Moslchi R, Dion F, Faucher MC, Dole K, Karimi S, Foulkes W, Lifzchiz-Mcrecrl B, Lew S and Iscovich J (1999) Founder BRCA1/2 mutations Lounis H, Warner E, Goss P, Anderson D, Larsson C, Narod SA and Futreal PA among male patients with breast cancer in Israel. Am J Hum Genet 65: (1996) Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer 1800–1802 families. Nat Genet 13: 120–122 Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Roa BB, Boyd AA, Volick K and Richards CS (1996) Ashkenazi Jewish population Tryggvadottir L, Tulinius H and Eyfjord JE (1997) Study of a single BRCA2 frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14: mutation with high carrier frequency in a small population. Am J Hum Genet 185–187 60: 1079–1084 Rohlfs EM, Learning WG, Friedman KJ, Couch FJ, Weber BL and Silverman LM Tulinius H, Egilsson V, Olafsdottir GH and Sigvaldason H (1992) Risk of prostate, (1997) Direct detection of mutations in the breast and ovarian cancer ovarian and endometrial cancer among relatives of women with breast cancer. susceptibility gene BRCA1 by PCR-mediated site-directed mutagenesis. Clin Br Med J 305: 855–857 Chem 43: 24–29 Zanghieri G, Di Gregorio C, Sacchetti C, Fante R, Sassatelli R, Cannizzo G, Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Carriero A, Ponz de and Leon M (1990) Familial occurrence of gastric Timmerman MM, Brody LC and Tucker MA (1997) The risk of cancer cancer in the 2-year experience of a population-based registry. Cancer 66: associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi 2047–2051 Jews. N Engl J Med 336: 1401–1408 © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 478–481 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel

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Publisher
Springer Journals
Copyright
Copyright © 2001 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
eISSN
1532-1827
DOI
10.1054/bjoc.2000.1605
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Abstract

British Journal of Cancer (2001) 84(4), 478–481 © 2001 Cancer Research Campaign http://www.bjcancer.com doi: 10.1054/ bjoc.2000.1605, available online at http://www.idealibrary.com on The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel 1 1,3 1 1 2 1 3 A Figer , L Irmin, R Geva, D Flex , J Sulkes, A Sulkes and E Friedman 1 2 3 Institute of Oncology and the Epidemiology Unit, Rabin Medical Center (Belinson Campus), Petach Tikva; the Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, 52621, and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Summary Inherited predisposition occurs in 5–10% of all gastrointestinal (GI) cancer patients, but with the exception of colorectal cancer (CRC), the genes involved in conferring genetic susceptibility remain largely unknown. Indirect evidence indicates that germline mutations in BRCA2 might be associated with an increased risk for various GI malignancies. A single mutation (6174delT) occurs in the BRCA2 gene in high-risk breast ovarian cancer families of Jewish Ashkenazi origin, in about 1% of the general Ashkenazi population, and rarely in non- Ashkenazi Jews. In order to assess the contribution of this germline mutation to non-CRC GI cancer in Jewish Israeli patients, we tested 70 unselected, consecutive Jewish Ashkenazi patients with gastrointestinal malignancies for this mutation by PCR amplification and modified restriction enzyme digests. Patients’ age range was 38–90 years (mean 65.8±11.8 years). The most common malignancies were gastric cancer (n = 35) and exocrine pancreatic cancer (n = 23). Overall, 6 mutation carriers were detected: 3/23 (13%) of the patients with pancreatic cancer, 2/35 (5.7%) of patients with gastric cancer and 1/4 (25%) of patients with bile duct cancer. The 8.6% mutation carrier rate among patients is a rate significantly higher than that of the general Ashkenazi population (1.16% P = 0.0002). We conclude that the rate of the predominant Jewish BRCA2 mutation in patients with gastric and pancreatic cancer significantly differ from that of the general population of the same ethnic origin. Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information. © 2001 Cancer Research Campaign http://www.bjcancer.com Keywords: BRCA 2; Jewish founder mutation; non-colon cancer; inherited predisposition to cancer Gastrointestinal malignancies other than colorectal cancer (CRC) degree relatives (Ghadirian et al, 1991; Lynch et al, 1992). These are common. In Israel in 1995, gastric cancer was diagnosed in observations suggest an inherited predisposition to these cancer 572 Jewish individuals, pancreatic cancer in 368, 140 were diag- types in a subset of patients, but the genes that underlie this genetic nosed with primary liver or biliary tract cancer, and 110 had susceptibility remain largely unknown. Clustering of ovarian and oesophageal cancer (Israel Cancer Registry, 1998). Furthermore, gastric cancer (Easton et al, 1996) and breast/ovarian and exocrine the mortality rate from gastric and pancreatic cancer is high: in pancreatic cancer (Tulinius et al, 1992) have been reported, Israel the age stratified rate (ASR) for gastric cancer mortality is suggesting a role for BRCA2 gene mutations in pancreatic cancer 10.9/100 000 in Jewish men and 5.6/100 000 in Jewish women, predisposition (Phelan et al, 1996). Furthermore, a large study compared with an ASR for morbidity of 14.2/100 000 and 7.7/ encompassing more than 3000 BRCA2 mutation carriers and their 100 000, respectively (Israel Cancer Registry, 1998). This high first-degree relatives, estimated the relative risk (RR) for devel- mortality rate stems in part from the paucity of early symptoms oping cancers other than breast/ovarian: for pancreatic cancer the and hence the advanced stage at which these neoplasms are RR was 3.51, for gallbladder and bile duct cancer – 4.97 and for usually diagnosed. Thus, identifying individuals at high risk for stomach cancer – 2.59 (BCLC, 1999). developing these malignancies has obvious clinical implications. Among Jewish people, a single predominant mutation within Familial clustering of cancer, a well known risk factor predis- the BRCA2 gene (6174delT) occurs. This mutation can be detected posing to gastric, pancreatic, and other GI cancer is noted in in individuals at risk for developing breast and ovarian cancer 3–10% of all incident cases of these malignancies (Zanghieri et al, (Abeliovich et al, 1997), in about 1–1.5% of the general Ashkenazi 1990; Lynch et al, 1992; Fernandez et al, 1994). The relative risk (East European) Jews (Ouddoux et al, 1996; Roa et al, 1996), and for developing gastric cancer in first-degree relatives of gastric rarely among non-Ashkenazi Jews (Struewing et al, 1999). cancer patients ranges from 1.7 to 3.5, with an increase in relative Analysis of 245 unselected patients with pancreatic cancer for this risk associated with having more than one affected family member mutation, revealed two mutation carriers (0.8%) and an additional (Zanghieri et al, 1990; Palli et al, 1994; Lissowska et al, 1999). BRCA2 germline mutation carrier in a nearby codon (Goggins et Similarly, familial clustering of pancreatic cancer is associated al, 1996). However, not all patients in this latter study were Jewish with an increased risk for developing these neoplasms in all first individuals. Direct mutational analysis of 39 unselected Jewish Ashkenazi patients with pancreatic cancer, revealed 4 6174delT Received 27 July 2000 BRCA2 (10%) mutation carriers (Ozcelik et al, 1997). Revised 2 November 2000 To test the notion that BRCA2 mutations predispose to gastroin- Accepted 8 November 2000 testinal malignancies other than colorectal cancer, we determined Correspondence to: E Friedman the rate of the BRCA2 6174delT predominant germline mutation in 478 Founder BRCA2 mutation in gastrointestinal cancer 479 Table 1 Clinical and histopathological data of all BRCA2 mutation carriers 70 unselected Jewish Ashkenazi patients with these types of in the present study malignancies who were consecutively treated in a single medical centre in Israel. Pat no. Sex Tumour Age at diagnosis Family history of cancer MATERIALS AND METHODS 1 M Bile duct cancer 60 Father – CRC Son – CRC Patients’ characteristics and tumour material 2 F Gastric 55 None All patients with a clinical and histopathological diagnosis of 3 F Gastric 54 Mother – BC Grandmother – BC gastrointestinal malignancy (excluding colorectal cancer) who were 4 M Pancreas 54 Mother – CRC treated at the Institute of Oncology, Rabin Medical Center from 5 M Pancreas 81 None January 1, 1999 to March 31, 2000, were eligible for participation. 6 M Pancreas 61 Mother – abdominal The study was approved by the institutional review board, and all cancer patients signed an informed consent. All consenting patients filled a detailed questionnaire that includes demographic data, past medical BC = Breast cancer; CRC = colorectal cancer. history, age at diagnosis, family history of cancer, especially gastrointestinal, breast and/or ovarian. Based on the criteria applied for other familial cancers, patients having at least one first-degree cancer (n = 23), oesophageal cancer (n = 7), bile duct cancer (n = relative with GI or BRCA2 related cancer (breast and ovarian), or 4) and one small bowel cancer. Median age at diagnosis was 67 more than two second-degree relatives with cancer one of which is years (range 38–90 years) with a mean age of 65.8±11.8 years; of GI, breast or ovarian origin, were classified as familial cases. 6 patients (8.57%) were diagnosed between 38–49 years; 16 (22.8%) – between 50–59 years; 19 (27.2%) – between 60–69 years; 20 (28.6%) – between 70–79 years; 9 (12.8%) over the age DNA extraction of 80 years. 13 (18.5%) and 12 (17.1%) patients had first-degree Anticoagulated peripheral blood was withdrawn by venopuncture, relatives with gastrointestinal or other cancer, respectively, and 4 and DNA was extracted using standard techniques, using the (5.7%) had at least one first-degree relative with breast cancer. Gentra kit (Gentra Inc., Minneapolis, MN). Germline mutational analysis Mutation analysis of the predominant Jewish mutation in BRCA2 The presence of 6174delT BRCA2 germline mutation was tested in all study participants and 6 carriers were found (6/70–8.6%). The Mutational analyses for the predominant mutation (6174delT) in clinical and pertinent data of the 6 mutation carriers are presented BRCA2, were carried out by restriction enzyme digest of amplified in Table 1. Notably, 3/23 of the patients with pancreatic cancer PCR products using modified amplification primers, to generate (13%), 2/35 (5.7%) of the patients with gastric cancer and 1/4 of novel restriction sites, followed by restriction enzyme analysis to the patients (25%) with bile duct cancer were mutation carriers. distinguish the mutant from the wild-type allele, as previously Surprisingly, only 1/5 individuals with a family history of breast described (Rohlfs et al, 1997), and adopted by us (Bar Sade et al, and/or ovarian cancer was among the mutation carriers, and family 1998). history of other cancer was ascertained in 4/6 mutation carriers (Table 1). In addition, the age at diagnosis in mutation carriers was Statistical analyses not noticeably younger than other individuals with the same cancer type. Comparison of the rates of the founder Jewish mutation in BRCA2 between the general Jewish Ashkenazi population (Hartage et al, 1999) and all GI cancer patients in our study group as well as the Statistical analyses distribution within specific tumour types were performed using There was a statistically significant difference in the carrier rate of Fisher’s Exact test. Odds ratio (OR) and the 95% confidence inter- the 6174delT BRCA2 mutation between the general Jewish vals (CI) were calculated from the tables Ashkenazi population and all cancer types in the present study Even though the numbers for the Jewish Ashkenazi population are based on American Ashkenazi Jews (Hartage et al, 1999), we assumed that it is legitimate to use these numbers for two main Table 2 Comparison between the mutation carrier rate of the predominant reasons: first, the Ashkenazi Jewish population is well character- Jewish mutation in BRCA2 in the study population (Israeli Ashkenazi GI ized as a distinct ethnic entity, regardless of the present place of cancer patients) and the reference Jewish Ashkenazi population (from Hartage et al, 1999) by specific tumour types residence (i.e. Tel-Aviv or Washington). Second, comparisons of Israeli and non-Israeli Ashkenazis with regard to being 185delAG Cancer type Mutation carriers P value OR CI BRCA1 mutation carriers, did not show any differences between Israelis and Americans (Streuwing et al, 1997). Gastric 2/35 (5.7%) 0.06 5.2 1.2–22 Pancreatic 3/23 0.002 12.8 3.7–44.2 Bile duct 1/4 0.05 28.4 2.9–277.2 RESULTS Oesophageal 0/7 NS – – Small intestine 0/1 NS – – Patients’ characteristics Total 6/70 (8.6%) 0.0002 8 3.3–19.2 All 70 were of Ashkenazi origin. The most common malignancy was gastric cancer (n = 35), followed by exocrine pancreatic NS – denotes statistically not significant. © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 478–481 480 A Figer et al combined (59/5089 vs. 6/70, P = 0.0002). Analysis of the rate of neoplasms in Jewish BRCA2 mutation carriers remains to be deter- this mutation within specific tumour types, showed that the rates in mined in a larger, prospective study. pancreatic cancer and bile duct cancer were also statistically significant higher than population controls (Table 2). ACKNOWLEDGEMENT This study was funded in past by generous donation from Mr Ami DISCUSSION Ya’ar in loving memory of his late wife, Ruthi. In the present study, the involvement of the BRCA2 gene in inher- ited predisposition to gastrointestinal cancer other than colorectal cancer was evaluated by direct mutational analysis. 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British Journal of CancerSpringer Journals

Published: Feb 13, 2001

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