Hereditary pancreatic cancer: a clinical perspective.

Pancreatic cancer is an extraordinarily deadly disease and is responsible for over 220,000 deaths worldwide each year. One of the greatest risk factors for developing pancreatic cancer is a positive family history. Hereditary pancreatitis patients have a greatly elevated pancreatic cancer risk and individuals with cystic fibrosis may rarely develop this cancer, but often at very young ages. Various genetically linked cancer syndromes have been associated with pancreatic cancer in mutation-positive family members. Finally, familial pancreatic cancer-defined as families with two or more first-degree relatives who have pancreatic cancer but do not have a known cancer syndrome-is a known entity whose disease-causing mutation remains unidentified. This article describes research to date on hereditary pancreatic cancer, addresses how best clinicians should recognise hereditary forms of pancreatic cancer and explains the emotional burden of discovering a potentially lethal mutation. Many controversies and unanswered questions in hereditary pancreatic cancer remain.

[1]  Mariza de Andrade,et al.  The Prevalence of BRCA2 Mutations in Familial Pancreatic Cancer , 2007, Cancer Epidemiology Biomarkers & Prevention.

[2]  D. Whitcomb,et al.  Hereditary pancreatitis: new insights, new directions. , 1999, Bailliere's best practice & research. Clinical gastroenterology.

[3]  C. Gupta,et al.  High-grade pancreatic intraepithelial neoplasia in a patient with familial adenomatous polyposis. , 2005, Archives of pathology & laboratory medicine.

[4]  Leonid Kruglyak,et al.  A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32-34. , 2002, American journal of human genetics.

[5]  Michelle A. Anderson,et al.  A Clinical and Economic Evaluation of Endoscopic Ultrasound for Patients at Risk for Familial Pancreatic Adenocarcinoma , 2007, Pancreatology.

[6]  K. Gottlieb,et al.  The pancreas in familial adenomatous polyposis. , 2008, JOP : Journal of the pancreas.

[7]  Y. Murakami,et al.  Development of an intraductal papillary-mucinous neoplasm of the pancreas in a patient with familial adenomatous polyposis. , 2005, Pancreas.

[8]  D. Bishop,et al.  Increased Risk of Cancer Other Than Melanoma in CDKN2A Founder Mutation (p16-Leiden)-Positive Melanoma Families , 2008, Clinical Cancer Research.

[9]  C. Logsdon,et al.  Progress on molecular markers of pancreatic cancer , 2007, Current opinion in gastroenterology.

[10]  T. Rebbeck,et al.  Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. , 2002, Journal of the National Cancer Institute.

[11]  S. Fitzsimmons,et al.  The changing epidemiology of cystic fibrosis. , 1993, The Journal of pediatrics.

[12]  L. Pickle,et al.  Life-style risk factors for pancreatic cancer in Louisiana: a case-control study. , 1988, American journal of epidemiology.

[13]  R. Macdermott,et al.  Adenocarcinoma of the pancreas in four siblings. , 1973, Gastroenterology.

[14]  E. Fishman,et al.  Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[15]  Tatjana Crnogorac-Jurcevic,et al.  Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism , 2006, PLoS medicine.

[16]  J. Neglia,et al.  Cancer risk in nontransplanted and transplanted cystic fibrosis patients: a 10-year study. , 2003, Journal of the National Cancer Institute.

[17]  T. Smyrk,et al.  An update of HNPCC (Lynch syndrome). , 1997, Cancer genetics and cytogenetics.

[18]  M. Goggins,et al.  Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families. , 2000, Gastroenterology.

[19]  H. Lynch,et al.  Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications. , 1997, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[20]  P. Maisonneuve,et al.  Risk of pancreatic cancer in patients with cystic fibrosis , 2007, Gut.

[21]  H. Lynch,et al.  HEREDITY AND MULTIPLE PRIMARY MALIGNANT NEOPLASMS: SIX CANCER FAMILIES , 1967, The American journal of the medical sciences.

[22]  M. Corey,et al.  The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. , 1995, The New England journal of medicine.

[23]  E. Dimagno,et al.  Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. , 1997, Journal of the National Cancer Institute.

[24]  M. Gorry,et al.  Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG) , 1997, The American journal of gastroenterology.

[25]  H. Lynch,et al.  Extracolonic cancer in hereditary nonpolyposis colorectal cancer , 1993 .

[26]  David C Whitcomb,et al.  Role of BRCA1 and BRCA2 mutations in pancreatic cancer , 2006, Gut.

[27]  M. Kimmey,et al.  Familial Fibrocystic Pancreatic Atrophy With Endocrine Cell Hyperplasia and Pancreatic Carcinoma , 2001, The American journal of surgical pathology.

[28]  K. Lillemoe,et al.  Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer , 1999, British Journal of Cancer.

[29]  M. Schäfer,et al.  Pancreatic cancer in cystic fibrosis after bilateral lung transplantation. , 2006, Pancreas.

[30]  A J Krush,et al.  Increased risk of cancer in the Peutz-Jeghers syndrome. , 1987, The New England journal of medicine.

[31]  D. Béchade.  [Strategies for screening for pancreatic adenocarcinoma in high-risk patients]. , 2011, Bulletin du cancer.

[32]  Ruth Etzioni,et al.  Early detection: The case for early detection , 2003, Nature Reviews Cancer.

[33]  R. Hruban,et al.  Genetic progression in the pancreatic ducts. , 2000, The American journal of pathology.

[34]  R. Hruban,et al.  CpG island methylation profile of pancreatic intraepithelial neoplasia , 2008, Modern Pathology.

[35]  Kathleen M Murphy,et al.  Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. , 2002, Cancer research.

[36]  Ucd Building.  Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups , 2005 .

[37]  D. Whitcomb.  New insights into hereditary pancreatitis , 1999, Current gastroenterology reports.

[38]  D. Easton,et al.  Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. , 2001, American journal of human genetics.

[39]  P. Lizardi,et al.  Mutational load distribution analysis yields metrics reflecting genetic instability during pancreatic carcinogenesis , 2008, Proceedings of the National Academy of Sciences.

[40]  W. Greenhalf,et al.  Peutz–Jeghers syndrome and screening for pancreatic cancer , 2006, The British journal of surgery.

[41]  P. Boyle,et al.  Reported family aggregation of pancreatic cancer within a population-based case-control study in the francophone community in Montreal, Canada , 1991, International journal of pancreatology : official journal of the International Association of Pancreatology.

[42]  M. Gorry,et al.  Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene , 1996, Nature Genetics.

[43]  S. Song,et al.  BRCA2 Mutations as a Universal Risk Factor for Pancreatic Cancer Has a Limited Role in Korean Ethnic Group , 2008, Pancreas.

[44]  F. Giardiello,et al.  Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. , 1993, Gut.

[45]  Interobserver agreement for EUS findings in familial pancreatic-cancer kindreds , 2008 .

[46]  L. Tsui,et al.  Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. , 1989, Science.

[47]  R. Brand,et al.  Genetic Predisposition to Pancreatic Cancer: A Brief Review , 2007, The American Journal of Gastroenterology.

[48]  Steven Gallinger,et al.  Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients , 1997, Nature Genetics.

[49]  W. Norris.  Case of Fungoid Disease , 1820, Edinburgh medical and surgical journal.

[50]  W. Greenhalf,et al.  Palladin Mutation Causes Familial Pancreatic Cancer: Absence in European Families , 2007, PLoS medicine.

[51]  R. Hruban,et al.  Familial pancreatic cancer: where are we in 2003? , 2003, Journal of the National Cancer Institute.

[52]  Alison P. Klein,et al.  Prospective Risk of Pancreatic Cancer in Familial Pancreatic Cancer Kindreds , 2004, Cancer Research.

[53]  P. Maisonneuve,et al.  Epidemiology and risk factors for pancreatic cancer. , 2006, Best practice & research. Clinical gastroenterology.

[54]  S. Goodman,et al.  Very high risk of cancer in familial Peutz-Jeghers syndrome. , 2000, Gastroenterology.

[55]  H. Lynch,et al.  Pancreatic cancer and the FAMMM syndrome , 2007, Familial Cancer.

[56]  D. Whitcomb,et al.  The spectrum of complications of hereditary pancreatitis. Is this a model for future gene therapy? , 1999, Gastroenterology clinics of North America.

[57]  R. Brand,et al.  BRCA1 and pancreatic cancer: pedigree findings and their causal relationships. , 2005, Cancer genetics and cytogenetics.

[58]  H. Olsson.  Cancer risks in BRCA2 mutation carriers. , 1999, Journal of the National Cancer Institute.

[59]  M. Kimmey,et al.  Screening and surveillance for hereditary pancreatic cancer. , 2002, Gastrointestinal endoscopy.

[60]  P. Maisonneuve,et al.  Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds. , 2003, Gastroenterology.

[61]  T. Griffin,et al.  Familial pancreatic adenocarcinoma in three generations. A case report and a review of the literature , 1987, Cancer.

[62]  Mark Feldman,et al.  Sleisenger and Fordtran's gastrointestinal and liver disease , 2012 .

[63]  N. Gruis,et al.  Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16‐Leiden) , 2000, International journal of cancer.

[64]  S. Kern,et al.  Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma–pancreatic carcinoma–prone families , 2002, Cancer.

[65]  W. Greenhalf,et al.  Anticipation in familial pancreatic cancer , 2005, Gut.

[66]  H. Lynch,et al.  Clinical selection of candidates for mutational testing for cancer susceptibility. , 2006, Oncology.

[67]  BRCA2 Germline Mutations in Familial Pancreatic Carcinoma , 2003 .

[68]  S. Narod,et al.  Patient responses to the disclosure of BRCA mutation tests in hereditary breast-ovarian cancer families. , 2006, Cancer genetics and cytogenetics.

[69]  R. Hruban,et al.  Advances in counselling and surveillance of patients at risk for pancreatic cancer , 2007, Gut.