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International Journal of Colorectal Disease
Published in: International Journal of Colorectal Disease 2/2014

01-02-2014 | Review

Familial pancreatic cancer—status quo

Authors: Volker Fendrich, Peter Langer, Detlef K. Bartsch

Published in: International Journal of Colorectal Disease | Issue 2/2014

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Abstract

Introduction

Familial pancreatic cancer (FPC) is defined by families with at least two first-degree relatives with confirmed pancreatic ductal adenocarcinoma (PDAC) that do not fulfill the criteria of other inherited tumor syndromes with an increased risk for the development of PDAC, such as hereditary pancreatitis or hereditary breast and ovarian cancer. FPC is mostly autosomal dominant inherited and presents with a heterogeneous phenotype. Although the major gene defect has not yet been identified, some important germline mutations in the BRCA2-, PALB2-, and ATM-genes are causative in some FPC families.

FPC screening

It is suggested by experts to include high-risk individuals in a screening program with a multidisciplinary approach under research protocol conditions. However, neither biomarkers nor reliable imaging modalities for the detection of high-grade precursor lesions are yet available. Most screening programs are currently based on endoscopic ultrasound and magnetic resonance imaging, and first data demonstrated that precursor lesions (pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm) of PDAC can be identified. Timing and extent of surgery are still a matter of debate.

Scope of the review

The present review focuses on the clinical phenotype of FPC, its histopathological characteristics, known underlying genetic changes, genetic counseling, and screening.
Literature
1.
Ehrenthal D, Haeger L, Griffin T, Compton C (1987) Familial pancreatic adenocarcinoma in three generations. A case report and a review of the literature. Cancer 59:1661–1664PubMedCrossRef
2.
MacDermott RP, Kramer P (1973) Adenocarcinoma of the pancreas in four siblings. Gastroenterology 65:137–139PubMed
3.
Reimer RR, Fraumeni JF Jr, Ozols RF, Bender R (1977) Pancreatic cancer in father and son. Lancet 23:1911
4.
Lynch HT, Lanspa SJ, Fitzgibbons RJ Jr, Smyrk T, Fitzsimmons ML, McClellan J (1989) Familial pancreatic cancer (part 1): genetic pathology review. Nebr Med J 74:109–112PubMed
5.
Hruban RH, Petersen GM, Ha PK, Kern SE (1998) Genetics of pancreatic cancer. From genes to families. Surg Oncol Clin N Am 7:1–23PubMed
6.
Applebaum SE, Kant JA, Whitcomb DC, Ellis IH (2000) Genetic testing. Counselling, laboratory, and regulatory issues and the EUROPAC protocol for ethical research in multicenter studies of inherited pancreatic diseases. Med Clin North Am 84:575–588PubMedCrossRef
7.
8.
Del Chiaro M et al (2010) Familial pancreatic cancer in Italy. Risk assessment, screening programs and clinical approach: a position paper from the Italian registry. Dig Liver Dis 42:597–605PubMedCrossRef
9.
10.
Del Chiaro M et al (2007) Cancer risk among the relatives of patients with pancreatic ductal adenocarcinoma. Pancreatology 7:459–469PubMedCrossRef
11.
Bartsch DK et al (2004) Prevalence of familial pancreatic cancer in Germany. Int J Cancer 20:110902–110906
12.
Hemminki K, Li X (2003) Familial and second primary pancreatic cancers: a nationwide epidemiologic study from Sweden. Int J Cancer 10:525–530CrossRef
13.
Permuth-Wey J, Egan KM (2009) Family history is a significant risk factor for pancreatic cancer: results from a systematic review and metaanalysis. Fam Cancer 8:109–117PubMedCrossRef
14.
15.
Jenne DE et al (1998) Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18:38–43PubMedCrossRef
16.
Giardiello FM et al (1987) Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 316:1511–1514PubMedCrossRef
17.
Goldstein AM et al (1995) Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 12:333970–333974
18.
Whelan AJ, Bartsch DK, Goodfellow PJ (1995) Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med 12:333975–333977
19.
Lynch HT et al (2002) Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 1:9484–9496
20.
Bartsch DK et al (2010) Clinical and genetic analysis of 18 pancreatic carcinoma/melanoma-prone families. Clin Genet 77:333–41PubMedCrossRef
21.
Vasen HF, Gruis NA, Frants RR, van Der Velden PA, Hille ET, Bergman W (2000) Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer 15:87809–87811
22.
The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310–1316CrossRef
23.
van Asperen CJ et al (2005) Cancer risk in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42:711–719PubMedCrossRef
24.
Thompson D, Easton DF (2002) Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358–1365PubMedCrossRef
25.
Moran A et al (2011) Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer 11:235–42CrossRef
26.
Lynch HT, Voorhees GJ, Lanspa SJ, McGreevy PS, Lynch JF (1985) Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br J Cancer 52:271–273PubMedCrossRefPubMedCentral
27.
Aarnio M et al (1999) Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81:214–218PubMedCrossRef
28.
Kastrinos F et al (2009) Risk of pancreatic cancer in families with Lynch syndrome. JAMA 302:1790–1795PubMedCrossRef
29.
Maire F et al (2002) Intraductal papillary and mucinous pancreatic tumour: a new extracolonic tumour in familial adenomatous polyposis. Gut 51:446–449PubMedCrossRef
30.
Giardello FM et al (1993) Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut 34:1394–1396CrossRef
31.
Whitcomb D et al (1996) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14:141–145PubMedCrossRef
32.
Witt H et al (2000) Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 25:213–216PubMedCrossRef
33.
Lowenfels AB, Maisonneuve P, Whitcomb DC (2000) Risk factors for cancer in hereditary pancreatitis. International Hereditary Pancreatitis Study Group. Med Clin North Am 84:565–573PubMedCrossRef
34.
Lowenfels AB, Maisonneuve P, Whitcomb DC, Lerch MM, DiMagno EP (2001) Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. JAMA 11:286169–286170
35.
Maisonneuve P, Marshall BC, Lowenfels AB (2007) Risk of pancreatic cancer in patients with cystic fibrosis. Gut 56:1327–1328PubMedCrossRef
36.
Brand RE et al (2007) Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut 56:1460–1469PubMedCrossRef
37.
Lynch HT, Brand RE, Deters CA, Shaw TG, Lynch JF (2001) Hereditary pancreatic cancer. Pancreatology 1:466–471PubMedCrossRef
38.
39.
Schneider R et al (2011) German national case collection for familial pancreatic cancer (FaPaCa): ten years experience. Fam Cancer 10:323–330PubMedCrossRef
40.
41.
Rulyak SJ, Lowenfels AB, Maisonneuve P, Brentnall TA (2003) Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds. Gastroenterology 124:1292–1299PubMedCrossRef
42.
Wang L et al (2009) Elevated cancer mortality in the relatives of patients with pancreatic cancer. Cancer Epidemiol Biomark Prev 18:2829–2834CrossRef
43.
Klein AP et al (2004) Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 64:2634–2638PubMedCrossRef
44.
Tersmette AC et al (2001) Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 7:738–744PubMed
45.
Brune KA et al (2010) Importance of age of onset in pancreatic cancer kindreds. J Natl Cancer Inst 102:119–126PubMedCrossRef
46.
Aichler M et al (2013) Origin of pancreatic ductal adenocarcinoma from atypical flat lesions: a comparative study in transgenic mice and human tissues. J Pathol 226:723–34CrossRef
47.
Brune K et al (2006) Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am J Surg Path 30:1067–1076PubMedPubMedCentral
48.
49.
Langer P, Gress TM, Bartsch DK (2010) Pancreatic cancer screening in individuals at risk—too early for a general implementation on a health care basis. Gut 59:1006–1007CrossRef
50.
Ingkakul T, Sadakari Y, Jenaga J, Satho N, Takahata S, Tanaka M (2010) Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas. Ann Surg 251:70–75PubMedCrossRef
51.
Uehara H et al (2008) Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut 57:1561–1565PubMedCrossRef
52.
Klein AP, Beaty TH, Bailey-Wilson JE, Brune KA, Hruban RH, Petersen GM (2002) Evidence for a major gene influencing risk of pancreatic cancer. Genet Epidemiol 23:133–137PubMedCrossRef
53.
54.
55.
56.
Klein AP et al (2009) Absence of deleterious palladin mutations in patients with familial pancreatic cancer. Cancer Epidemiol Biomark Prev 18:1328–1330CrossRef
57.
Bartsch DK et al (2002) CDKN2A germline mutations in familial pancreatic cancer. Ann Surg 236:730–737PubMedCrossRef
58.
Slater E et al (2010) Prevalence of BRCA2 and CDKN2a mutations in German Familial pancreatic cancer families. Fam Cancer 9:335–343PubMedCrossRef
59.
Hahn SA et al (2003) BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 95:214–221PubMedCrossRef
60.
Murphy KM et al (2002) Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 62:3789–3793PubMed
61.
Couch FJ et al (2007) The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomark Prev 16:342–346CrossRef
62.
Skoulidis F et al (2010) Germline Brca2 heterozygosity promotes Kras(G12D)-driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell 18:499–509PubMedCrossRef
63.
Rowley M et al (2011) Inactivation of BRCA2 promotes TP53-asociated but inhibits KrasG12D-dependent pancreatic cancer development in mice. Gastroenterology 140:1303–1313PubMedCrossRefPubMedCentral
64.
Feldmann G et al (2011) Inactivation of Brca2 cooperates with Trp53(R172H) to induce invasive pancreatic ductal adenocarcinomas in mice: a mouse model of familial pancreatic cancer. Cancer Biol Ther 11:959–968PubMedCrossRef
65.
Bryant HE et al (2005) Specific killing of BRCA2-deficient tumors with inhibitors of poly (ADP-ribose) polymerase. Nature 434:913–917PubMedCrossRef
66.
James E, Waldron-Lynch MG, Saif MW (2009) Prolonged survival in a patient with BRCA2 associated metastatic pancreatic cancer after exposure to camptothecin: a case report and review of literature. Anticancer Drugs 20:634–638PubMedCrossRef
67.
68.
Slater EP et al (2010) PALB2 mutations in European familial pancreatic cancer families. Clin Genet 78:490–494PubMedCrossRef
69.
Harinck F et al (2012) Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated. Eur J Hum Genet 20:577–9PubMedCrossRef
70.
van der Heijden MS, Yeo CJ, Hruban RH, Kern SE (2003) Fanconi anemia gene mutations in young onset pancreatic cancer. Cancer Res 63:2585–2588PubMed
71.
Couch FJ et al (2005) Germ line Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res 65:383–386PubMed
72.
73.
Axilbund JE, Brune KA, Canto MI, Brehon BC, Wroblewski LD, Griffin CA (2005) Patient perspective on the value of genetic counselling for familial pancreas cancer. Hered Cancer Clin Pract 3:115–122PubMedCrossRefPubMedCentral
74.
75.
Leonardi M et al (2012) “PancPro” as a tool for selecting families eligible for pancreatic cancer screening: an Italian study of incident cases. Dig Liver Dis 44:585–8PubMedCrossRef
76.
American Society of Clinical Oncology (2003) American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 21:2397–2406CrossRef
77.
Canto MI et al (2012) On behalf of the International CAPS Consortium International Consensus Recommendations on the management of patients with increased risk for familial pancreatic cancer (Cancer of the Pancreas Screening Consortium (CAPS) 2011 Summit). To be presented at the Digestive Disease Week (DDW), San Diego, California, USA, May 19–22
78.
Bussom S, Saif MW (2010) Methods and rationale for the early detection of pancreatic cancer. Highlights from the “2010 ASCO Gastrointestinal Cancers Symposium”. JOP 11:128–130PubMed
79.
Brentnall TA et al (1999) Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med 131:247–255PubMedCrossRef
80.
Kimmey MB et al (2002) Screening and surveillance for hereditary pancreatic cancer. Gastrointest Endosc 56:S82–S86PubMedCrossRef
81.
Canto MI et al (2004) Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol 2:606–621PubMedCrossRef
82.
Canto MI et al (2006) Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 4:766–781PubMedCrossRef
83.
Poley JW et al (2009) The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer. Am J Gastroenterol 104:2175–2181PubMedCrossRef
84.
Langer P et al (2009) Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer. Gut 58:1410–1418PubMedCrossRef
85.
Verna EC et al (2010) Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics. Clin Cancer Res 16:5028–5037PubMedCrossRef
86.
87.
Rulyak SJ et al (2001) Inherited pancreatic cancer: surveillance and treatment strategies for affected families. Pancreatology 1:477–485PubMedCrossRef
88.
Raut CP et al (2003) Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration in patients with presumed pancreatic cancer. J GastrointestSurg 7:118–126CrossRef
89.
90.
Al-Sukhni W et al (2012) Screening for pancreatic cancer in a high-risk cohort: an eight-year experience. J Gastrointest Surg 16:771–783PubMedCrossRef
91.
Vasen HF et al (2011) Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation. Gastroenterology 140:850–856PubMedCrossRef
92.
93.
Harinck F et al (2011) Feasibility of a pancreatic cancer surveillance program from a psychological point of view. Genet Med 13:1015–1024PubMedCrossRef
94.
95.
Maheu C et al (2010) Pancreatic cancer risk counselling and screening: impact on perceived risk and psychological functioning. Fam Cancer 9:617–624PubMedCrossRef
Metadata
Title
Familial pancreatic cancer—status quo
Authors
Volker Fendrich
Peter Langer
Detlef K. Bartsch
Publication date
01-02-2014
Publisher
Springer Berlin Heidelberg
Published in
International Journal of Colorectal Disease / Issue 2/2014
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI
https://doi.org/10.1007/s00384-013-1760-3

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