FaCD Online Syndrome Fact Sheet

Last updated: 27 Jun 2012

Name: Pancreatic Cancer, Familial Clustering of

Synonym: incl.: Hereditary Pancreatic Adenocarcinoma, Insulin-Dependent Diabetes Mellitus - Exocrine Insufficiency - Familial Pancreatic Cancer, PNCA1

Mode of Inheritance: multifact?/ AD

OMIM number: 260350   606856  

Genes

ATM, mapped to 11q22.3
BRCA2, mapped to 13q12.3
PALB2/FANCN, mapped to 16p12
PALLD, mapped to 4q32.3

Tumor features

breast cancer
ovarian cancer (i.e. epithelial origin)
pancreatic adenocarcinoma

Non-tumor features

diabetes mellitus

Comment

There are a number of reports of familial clustering of pancreatic cancer[1-5] and inherited factors may play a significant role in perhaps 3-10% of the total pancreatic cancer burden[1;6-8]. A family history of cancer in general has been reported in 9% of a series of 81 patients[9]. First degree relatives of patients with pancreatic cancer were shown to have a relative risk (RR) ranging from 1 to 5.89[2,10,11,21], with a summary RR of 1.80[22]. A family history of ovarian cancer and breast cancer also increases the risk of developing pancreatic cancer[12-14]. Possibly site-specific hereditary pancreatic cancer exists and in some of these families insulin dependent diabetes mellitus may act as a marker for pancreatic cancer[1;15-17]. Survival of pancreatic cancer is apparently not influenced by the presence or absence of a family history of cancer[9].

Lai et al.[18] searched for germline p16, hMLH1, hMSH2, BRCA1 and BRCA2 mutations in pancreatic cancer patients. No mutations were identified if a family history of pancreatic cancer was the sole genetic risk factor (however, n=4 patients). One mutation (BRCA2) was detected in the subgroup of 10 patients with early-onset (i.e. <51 years) pancreatic cancer. Germline PALB2 mutations have been identified in a few families with pancreatic cancer[23,26]. In a rare case of familial pancreatic cancer a germline mutation in PALLD has been detected[19,20]. The chance of finding a CDKN2A mutation in families with pancreatic cancer without melanoma appears to be small[24,25,26]. ATM mutations have been found to segregate in a few pancreatic cancer families [27].

Links

European Registry Of Hereditary Pancreatitis And Familial Pancreatic Cancer 20 3 08

References

[1] Lynch HT, Smyrk T, Kern SE, Hruban RH, Lightdale CJ, Lemon SJ, Lynch JF, Fusaro LR, Fusaro RM, Ghadirian P. Familial pancreatic cancer: A review. Semin Oncol 23[2], 251-275. 1996.
[2] Flanders TY, Foulkes WD. Pancreatic adenocarcinoma: epideliology and genetics. J Med Genet 1996; 33:889-898.
[3] Lumadue JA, Griffin CA, Osman M, Hruban RH. Familial pancreatic cancer and the genetics of pancreatic cancer. Surg Clin North Am 1995; 75:845.
[4] Hruban RH, Petersen GM, Ha PK, Kern SE. Genetics of pancreatic cancer. From genes to families. Surg Oncol Clin N Am 1998; 7(1):1-23.
[5] Hruban RH, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, Falatko F, Yeo CJ, Kern SE. Familial pancreatic cancer. Ann Oncol 1999; 10 Suppl 4: 69-73:69-73.
[6] Fernandez E, La Vecchia C, Decarli A. Attributable risks for pancreatic cancer in northern Italy. Cancer Epidemiol Biomarkers Prev 1996; 5(1):23-27.
[7] Brand RE, Lynch HT. Hereditary pancreatic adenocarcinoma. A clinical perspective. Med Clin North Am 2000; 84(3):665-675.
[8] Banke MG, Mulvihill JJ, Aston CE. Inheritance of pancreatic cancer in pancreatic cancer-prone families. Med Clin North Am 2000; 84(3):677-90.
[9] Dergham ST, Dugan MC, Arlauskas P, Du W, Vaitkevicius VK, Crissman JD, Sarkar FH. Relationship of family cancer history to the expression of p53, p21(WAF-1), HER-2/neu, and K-ras mutation in pancreatic adenocarcinoma. Int.J.Pancreatol. 21[3], 225-234. 1997.
[10] 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(3):209-212.
[11] Falk RT, Pickle LW, Fontham ET, Correra P, Fraumeni jr JF. Life-style risk factors for pancreatic cancer in Louisiana: a case-control study. Am J Epidemiol 1988; 128(2):324-336.
[12] Kerber RA, Slattery ML. The impact of family history on ovarian cancer risk: The Utah population database. Arch Intern Med 1995; 155:905-912.
[13] Tulinius H, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Bjarnadottir K. Neoplastic diseases in families of breast cancer patients. J Med Genet 1994; 31:618-621.
[14] Auranen A, Grenman S, Makinen J, Pukkala E, Sankila R, Salmi T. Borderline ovarian tumors in Finland: Epidemiology and familial occurrence. Am J Epidemiol 144[6], 548-553. 1996.
[15] Ehrenthal D, Haeger L, Griffin T, Compton C. Familial pancreatic adenocarcinoma in three generations. A case report and review of the literature. Cancer 1987; 59:1661-1664.
[16] Burke W, Bennett RL, Schmidt R, Dellinger P, Evans JP. Autosomal dominant transmission of pancreatic cancer with diabetes and exocrine insuficiency in a large kindred (Abstract). Am J Hum Genet 1992; 51:A50.
[17] Evans JP, Burke W, Chen R, Bennett RL, Schmidt RA, Dellinger EP, Kimmey M, Crispin D, Brentnall TA, Byrd DR. Familial pancreatic adenocarcinoma: Association with diabetes and early molecular diagnosis. J Med Genet 1995; 32:330-335.
[18] Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, Redston M, Gallinger S. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res 2000; 60(2):409-416.
[19] Pogue-Geile KL, Chen R, Bronner MP, Crnogorac-Jurcevic T, Moyes KW, Dowen S, Otey CA, Crispin DA, George RD, Whitcomb DC, Brentnall TA. Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism. PLoS medicine 2006; 3(12):e516.
[20] Slater E, Amrillaeva V, Fendrich V, Bartsch D, Earl J, Vitone LJ, Neoptolemos JP, Greenhalf W. Palladin mutation causes familial pancreatic cancer: absence in European families. PLoS medicine 2007; 4(4):e164.
[21] McWilliams RR, Rabe KG, Olswold C, De Andrade M, Petersen GM. Risk of malignancy in first-degree relatives of patients with pancreatic carcinoma. Cancer 2005; 104(2):388-94.
[22] Permuth-Wey J, Egan KM. Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis. Familial cancer 2008; epub ahead of print .
[23] Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP. Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene. Science. 2009 Mar 5. [Epub ahead of print]
[24] Slater EP, Langer P, Fendrich V, Habbe N, Chaloupka B, Matthäi E, Sina M, Hahn SA, Bartsch DK. Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families. Fam Cancer. 2010 Feb 27. [Epub ahead of print]
[25] Bartsch DK, Sina-Frey M, Lang S, Wild A, Gerdes B, Barth P, Kress R, Grützmann R, Colombo-Benkmann M, Ziegler A, Hahn SA, Rothmund M, Rieder H. CDKN2A germline mutations in familial pancreatic cancer. Ann Surg. 2002 Dec;236(6):730-7.
[26] Schneider R, Slater EP, Sina M, Habbe N, Fendrich V, Matthäi E, Langer P, Bartsch DK. German national case collection for familial pancreatic cancer (FaPaCa): ten years experience. Fam Cancer. 2011 Jun;10(2):323-30.
[27] Roberts NJ et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer discovery 2012; 2:41-6.