Skip to main content
SpringerLink
Log in

Familial Pancreatic Cancer

  • Chapter
  • First Online:
Textbook of Pancreatic Cancer

  • 2658 Accesses

Abstract

One important factor influencing pancreatic tumorigenesis is inherited genetic variation. Knowledge of a patient’s underlying susceptibility due to germline variants has become an essential component of care for patients with pancreatic cancer and their families. In this chapter, we review the definition of familial pancreatic cancer and key genes that are known to contribute to germline pancreatic cancer risk, several of which have implications for choosing the most effective chemotherapeutic agents. In addition, we discuss germline alterations in susceptibility genes in patients with sporadic pancreatic cancer as well as screening approaches for patients at high-risk for pancreatic cancer. Despite these advances, the genetic basis for the majority of familial pancreatic cancer remains unknown, and further research is needed to translate discoveries into improved patient care.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Villarroel MC, Rajeshkumar NV, Garrido-Laguna I, et al. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther. 2011;10:3–8.

    Article  CAS  PubMed  Google Scholar 

  2. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381:317–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. MacDermott RP, Kramer P. Adenocarcinoma of the pancreas in four siblings. Gastroenterology. 1973;65:137–9.

    Article  CAS  PubMed  Google Scholar 

  5. Katkhouda N, Mouiel J. Pancreatic cancer in mother and daughter. Lancet. 1986;2:747.

    Article  CAS  PubMed  Google Scholar 

  6. Reimer RR, Fraumeni JF Jr, Ozols RF, et al. Pancreatic cancer in father and son. Lancet. 1977;1:911.

    Article  CAS  PubMed  Google Scholar 

  7. Klein AP. Identifying people at a high risk of developing pancreatic cancer. Nat Rev Cancer. 2013;13:66–74.

    Article  CAS  PubMed  Google Scholar 

  8. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 2004;64:2634–8.

    Article  CAS  PubMed  Google Scholar 

  9. Roberts NJ, Norris AL, Petersen GM, et al. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov. 2016;6:166–75.

    Article  CAS  PubMed  Google Scholar 

  10. Tamura K, Yu J, Hata T, et al. Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc Natl Acad Sci U S A. 2018;115:4767–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nissim S, Leshchiner I, Mancias JD, et al. Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nat Genet. 2019;51:1308–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wong C, Chen F, Alirezaie N, et al. A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene. PLoS Genet. 2019;15:e1008344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog. 2012;51:14–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41–6.

    Article  CAS  PubMed  Google Scholar 

  15. Swift M, Morrell D, Massey RB, et al. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991;325:1831–6.

    Article  CAS  PubMed  Google Scholar 

  16. Helgason H, Rafnar T, Olafsdottir HS, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet. 2015;47:906–10.

    Article  CAS  PubMed  Google Scholar 

  17. Na R, Zheng SL, Han M, et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur Urol. 2017;71:740–7.

    Article  CAS  PubMed  Google Scholar 

  18. Takai E, Yachida S, Shimizu K, et al. Germline mutations in Japanese familial pancreatic cancer patients. Oncotarget. 2016;7:74227–35.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hu C, Hart SN, Polley EC, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319:2401–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hutchings D, Jiang Z, Skaro M, et al. Histomorphology of pancreatic cancer in patients with inherited ATM serine/threonine kinase pathogenic variants. Mod Pathol. 2019;32:1806–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhen DB, Rabe KG, Gallinger S, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015;17:569–77.

    Article  CAS  PubMed  Google Scholar 

  22. Chaffee KG, Oberg AL, McWilliams RR, et al. Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. Genet Med. 2018;20:119–27.

    Article  CAS  PubMed  Google Scholar 

  23. Catts ZA, Baig MK, Milewski B, et al. Statewide retrospective review of familial pancreatic cancer in Delaware, and frequency of genetic mutations in pancreatic cancer kindreds. Ann Surg Oncol. 2016;23:1729–35.

    Article  PubMed  Google Scholar 

  24. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Slater EP, Langer P, Niemczyk E, et al. PALB2 mutations in European familial pancreatic cancer families. Clin Genet. 2010;78:490–4.

    Article  CAS  PubMed  Google Scholar 

  26. Chen F, Roberts NJ, Klein AP. Inherited pancreatic cancer. Chin Clin Oncol. 2017;6:58.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Vasen HF, Gruis NA, Frants RR, 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). Int J Cancer. 2000;87:809–11.

    Article  CAS  PubMed  Google Scholar 

  28. Goldstein AM. Familial melanoma, pancreatic cancer and germline CDKN2A mutations. Hum Mutat. 2004;23:630.

    Article  PubMed  Google Scholar 

  29. Goldstein AM, Chan M, Harland M, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. 2007;44:99–106.

    Article  CAS  PubMed  Google Scholar 

  30. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14:141–5.

    Article  CAS  PubMed  Google Scholar 

  31. Lowenfels AB, Maisonneuve P, DiMagno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst. 1997;89:442–6.

    Article  CAS  PubMed  Google Scholar 

  32. Cohn JA, Friedman KJ, Noone PG, et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med. 1998;339:653–8.

    Article  CAS  PubMed  Google Scholar 

  33. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000;119:1447–53.

    Article  CAS  PubMed  Google Scholar 

  34. Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009;302:1790–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wilentz RE, Goggins M, Redston M, et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol. 2000;156:1641–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Goggins M, Schutte M, Lu J, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996;56:5360–4.

    CAS  PubMed  Google Scholar 

  37. Grant RC, Selander I, Connor AA, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. 2015;148:556–64.

    Article  CAS  PubMed  Google Scholar 

  38. Holter S, Borgida A, Dodd A, et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol. 2015;33:3124–9.

    Article  CAS  PubMed  Google Scholar 

  39. Hu C, Hart SN, Bamlet WR, et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. Cancer Epidemiol Biomark Prev. 2016;25:207–11.

    Article  CAS  Google Scholar 

  40. Salo-Mullen EE, O’Reilly EM, Kelsen DP, et al. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer. 2015;121:4382–8.

    Article  CAS  PubMed  Google Scholar 

  41. Shindo K, Yu J, Suenaga M, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol. 2017;35:3382–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lowery MA, Wong W, Jordan EJ, et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms. J Natl Cancer Inst. 2018;110:1067–74.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Mandelker D, Zhang L, Kemel Y, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA. 2017;318:825–35.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Smith AL, Wong C, Cuggia A, et al. Reflex testing for germline BRCA1, BRCA2, PALB2, and ATM mutations in pancreatic cancer: mutation prevalence and clinical outcomes from two Canadian research registries. JCO Precis Oncol. 2018;2:1–16.

    PubMed  Google Scholar 

  45. Singhi AD, George B, Greenbowe JR, et al. Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology. 2019;156:2242–53. e4

    Article  CAS  PubMed  Google Scholar 

  46. Yurgelun MB, Chittenden AB, Morales-Oyarvide V, et al. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med. 2019;21:213–23.

    Article  CAS  PubMed  Google Scholar 

  47. Tempero MA. NCCN guidelines updates: pancreatic cancer. J Natl Compr Cancer Netw. 2019;17:603–5.

    CAS  Google Scholar 

  48. Tanaka M, Fernandez-Del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17:738–53.

    Article  PubMed  Google Scholar 

  49. Vege SS, Ziring B, Jain R, et al. American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015;148:819–22; quiz e12–3.

    Article  PubMed  Google Scholar 

  50. Martinez de Juan F, Reolid Escribano M, Martinez Lapiedra C, et al. Pancreatic adenosquamous carcinoma and intraductal papillary mucinous neoplasm in a CDKN2A germline mutation carrier. World J Gastrointest Oncol. 2017;9:390–6.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sato N, Rosty C, Jansen M, et al. STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol. 2001;159:2017–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lubezky N, Ben-Haim M, Lahat G, et al. Intraductal papillary mucinous neoplasm of the pancreas: associated cancers, family history, genetic predisposition? Surgery. 2012;151:70–5.

    Article  PubMed  Google Scholar 

  53. Skaro M, Nanda N, Gauthier C, et al. Prevalence of germline mutations associated with cancer risk in patients with intraductal papillary mucinous neoplasms. Gastroenterology. 2019;156:1905–13.

    Article  CAS  PubMed  Google Scholar 

  54. Canto MI, Almario JA, Schulick RD, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology. 2018;155:740–51.e2.

    Article  PubMed  Google Scholar 

  55. Abe T, Blackford AL, Tamura K, et al. Deleterious germline mutations are a risk factor for neoplastic progression among high-risk individuals undergoing pancreatic surveillance. J Clin Oncol. 2019;37:1070–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Goggins M, Overbeek KA, Brand R, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69:7–17.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Nicholas J. Roberts & Laura D. Wood

Authors
  1. Nicholas J. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura D. Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura D. Wood .

Editor information

Editors and Affiliations

  1. Stavanger University Hospital, The University of Bergen, Bergen, Norway

    Kjetil Søreide

  2. Chirurgie (VTT), Innsbruck Medical University, Innsbruck, Tirol, Austria

    Stefan Stättner

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Roberts, N.J., Wood, L.D. (2021). Familial Pancreatic Cancer. In: Søreide, K., Stättner, S. (eds) Textbook of Pancreatic Cancer. Springer, Cham. https://doi.org/10.1007/978-3-030-53786-9_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-53786-9_4

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-53785-2

  • Online ISBN: 978-3-030-53786-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation