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Human Genetics

, Volume 135, Issue 11, pp 1241–1249 | Cite as

Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations

  • Xiaohong R. Yang
  • Melissa Rotunno
  • Yanzi Xiao
  • Christian Ingvar
  • Hildur Helgadottir
  • Lorenza Pastorino
  • Remco van Doorn
  • Hunter Bennett
  • Cole Graham
  • Joshua N. Sampson
  • Michael Malasky
  • Aurelie Vogt
  • Bin Zhu
  • Giovanna Bianchi-Scarra
  • William Bruno
  • Paola Queirolo
  • Giuseppe Fornarini
  • Johan Hansson
  • Rainer Tuominen
  • Laurie Burdett
  • Belynda Hicks
  • Amy Hutchinson
  • Kristine Jones
  • Meredith Yeager
  • Stephen J. Chanock
  • Maria Teresa Landi
  • Veronica Höiom
  • Håkan Olsson
  • Nelleke Gruis
  • Paola Ghiorzo
  • Margaret A. Tucker
  • Alisa M. GoldsteinEmail author
Original Investigation

Abstract

The risk of pancreatic cancer (PC) is increased in melanoma-prone families but the causal relationship between germline CDKN2A mutations and PC risk is uncertain, suggesting the existence of non-CDKN2A factors. One genetic possibility involves patients having mutations in multiple high-risk PC-related genes; however, no systematic examination has yet been conducted. We used next-generation sequencing data to examine 24 putative PC-related genes in 43 PC patients with and 23 PC patients without germline CDKN2A mutations and 1001 controls. For each gene and the four pathways in which they occurred, we tested whether PC patients (overall or CDKN2A+ and CDKN2A− cases separately) had an increased number of rare nonsynonymous variants. Overall, we identified 35 missense variants in PC patients, 14 in CDKN2A+ and 21 in CDKN2A− PC cases. We found nominally significant associations for mismatch repair genes (MLH1, MSH2, MSH6, PMS2) in all PC patients and for ATM, CPA1, and PMS2 in CDKN2A− PC patients. Further, nine CDKN2A+ and four CDKN2A− PC patients had rare potentially deleterious variants in multiple PC-related genes. Loss-of-function variants were only observed in CDKN2A− PC patients, with ATM having the most pathogenic variants. Also, ATM variants (n = 5) were only observed in CDKN2A− PC patients with a family history that included digestive system tumors. Our results suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes.

Keywords

Pancreatic Cancer Patient Pancreatic Cancer Risk Familial Pancreatic Cancer Deleterious Variant CDKN2A Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We are indebted to the participating families, whose generosity and cooperation have made this study possible. We acknowledge the research nurse contributions to this work that were made by Virginia Pichler (NCI), Deborah Zametkin (NCI), Mary Fraser (NCI), and Anita Zander (Lund). We wish to thank Dr. Chiara Baldo from the Galliera Genetic Bank-Network of Telethon Genetic Biobanks (Project No. GTB12001, Telethon, Italy) for providing patients’ lymphoblastoid cell lines. We acknowledge the contribution of members of the NCI DCEG Cancer Sequencing Working Group: Lynn R. Goldin, Mary L. McMaster, Neil E. Caporaso, Bari Ballew, Sharon Savage, Mark H. Greene, Allan Hildesheim, Nan Hu, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, and Guoqin Yu and members of the NCI DCEG Cancer Genomics Research Laboratory: Sarah Bass, Joseph Boland, Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Sally Larson, Kerry Lashley, Hyo Jung Lee, Wen Luo, Michelle Manning, Jason Mitchell, David Roberson, Mingyi Wang. We acknowledge the contributions of the Genoa Pancreatic Cancer Study Group: Virginia Andreotti, Claudia Martinuzzi, Luca Mastracci, Federica Grillo, Vincenzo Savarino, Pietro Dulbecco, Stefania Sciallero, Francesco Spagnolo, Virginia Picasso, Franco DeCian, Barbara Pasini, Paola Ogliara, Daniela Turchetti, Elena Sala.

Compliance with ethical standards

Funding

This work was supported by the Intramural Research Program of the National Cancer Institute, the National Institutes of Health, the Division of Cancer Epidemiology and Genetics. This work was also supported in part by the Swedish Cancer Society, Kamprad Foundation, Gunnar Nilsson Foundation and the ERC advanced Grant 294576-risk factors cancer; the Swedish Medical Research Council, the Swedish Cancer Society, Radiumhemmets research funds, the Stockholm County Council (ALF-project), Karolinska Institutet Research funds; The Paulsson Trust (Lund); AIRC IG 15460 to PG, Italian Ministry of Health 5 × 1000 to IRCCS AOU San Martino-IST to PG and GBS; the work of NAG and RvD was in part supported by the Dutch Cancer Society (UL 2012-5489).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

439_2016_1715_MOESM1_ESM.pdf (411 kb)
Supplementary material 1 (PDF 411 kb)

References

  1. Abecasis GR et al (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073. doi: 10.1038/nature09534 CrossRefPubMedGoogle Scholar
  2. Bergman W, Gruis N (1996) Familial melanoma and pancreatic cancer. N Engl J Med 334:471–472PubMedGoogle Scholar
  3. Borg A et al (2000) High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 92:1260–1266CrossRefPubMedGoogle Scholar
  4. Chen H, Meigs JB, Dupuis J (2013) Sequence kernel association test for quantitative traits in family samples. Genet Epidemiol 37:196–204. doi: 10.1002/gepi.21703 CrossRefPubMedGoogle Scholar
  5. de Snoo FA et al (2008) Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families Clinical cancer research. Off J Am Assoc Cancer Res 14:7151–7157. doi: 10.1158/1078-0432.CCR-08-0403 CrossRefGoogle Scholar
  6. DePristo MA et al (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498. doi: 10.1038/ng.806 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Dong C, Wei P, Jian X, Gibbs R, Boerwinkle E, Wang K, Liu X (2015) Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet 24:2125–2137. doi: 10.1093/hmg/ddu733 CrossRefPubMedGoogle Scholar
  8. Ghiorzo P et al (2004) INK4/ARF germline alterations in pancreatic cancer patients. Ann Oncol Off J Eur Soc Med Oncol/ESMO 15:70–78CrossRefGoogle Scholar
  9. Ghiorzo P et al (2012) Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy. Fam Cancer 11:41–47. doi: 10.1007/s10689-011-9483-5 CrossRefPubMedGoogle Scholar
  10. Goldstein AM (2004) Familial melanoma, pancreatic cancer and germline CDKN2A mutations. Hum Mutat 23:630. doi: 10.1002/humu.9247 CrossRefPubMedGoogle Scholar
  11. Goldstein AM, Tucker MA (2001) Genetic epidemiology of cutaneous melanoma: a global perspective. Arch Dermatol 137:1493–1496CrossRefPubMedGoogle Scholar
  12. Goldstein AM et al (1995) Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 333:970–974CrossRefPubMedGoogle Scholar
  13. Goldstein AM et al (2006) High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across. GenoMEL Cancer Res 66:9818–9828. doi: 10.1158/0008-5472.CAN-06-0494 CrossRefPubMedGoogle Scholar
  14. Grant RC et al (2015) Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology 148:556–564. doi: 10.1053/j.gastro.2014.11.042 CrossRefPubMedGoogle Scholar
  15. Gruis NA et al (1995) Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds. Nat Genet 10:351–353. doi: 10.1038/ng0795-351 CrossRefPubMedGoogle Scholar
  16. Helgadottir H et al (2014) High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families. J Med Genet 51:545–552. doi: 10.1136/jmedgenet-2014-102320 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Klein AP (2013) Identifying people at a high risk of developing pancreatic cancer. Nat Reviews Cancer 13:66–74. doi: 10.1038/nrc3420 CrossRefPubMedGoogle Scholar
  18. Liu X, Jian X, Boerwinkle E (2011) dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat 32:894–899. doi: 10.1002/humu.21517 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lohse M, Bolger AM, Nagel A, Fernie AR, Lunn JE, Stitt M, Usadel B (2012) RobiNA: a user-friendly, integrated software solution for RNA-Seq-based transcriptomics. Nucleic Acids Res 40:W622–W627. doi: 10.1093/nar/gks540 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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 94:84–96CrossRefPubMedGoogle Scholar
  21. Roberts NJ et al (2015) Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov. doi: 10.1158/2159-8290.CD-15-0402 PubMedPubMedCentralGoogle Scholar
  22. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29:308–311CrossRefPubMedPubMedCentralGoogle Scholar
  23. Shi J et al (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 46:482–486. doi: 10.1038/ng.2941 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN (2014) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 133:1–9. doi: 10.1007/s00439-013-1358-4 CrossRefPubMedGoogle Scholar
  25. Svishcheva GR, Belonogova NM, Axenovich TI (2014) FFBSKAT: fast family-based sequence kernel association test. PLoS ONE 9:e99407. doi: 10.1371/journal.pone.0099407 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Tavtigian SV et al (2006) Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43:295–305. doi: 10.1136/jmg.2005.033878 CrossRefPubMedGoogle Scholar
  27. 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 87:809–811. doi: 10.1002/1097-0215(20000915)87:6<809:AID-IJC8>3.0.CO;2-U CrossRefPubMedGoogle Scholar
  28. Wang Z et al (2012) Improved imputation of common and uncommon SNPs with a new reference set. Nat Genet 44:6–7. doi: 10.1038/ng.1044 CrossRefGoogle Scholar
  29. Zhen DB et al (2015) BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med Off J Am Coll Med Genet 17:569–577. doi: 10.1038/gim.2014.153 Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (otside the USA) 2016

Authors and Affiliations

  • Xiaohong R. Yang
    • 1
  • Melissa Rotunno
    • 1
    • 2
  • Yanzi Xiao
    • 1
  • Christian Ingvar
    • 3
  • Hildur Helgadottir
    • 4
  • Lorenza Pastorino
    • 5
    • 11
  • Remco van Doorn
    • 6
  • Hunter Bennett
    • 1
  • Cole Graham
    • 1
  • Joshua N. Sampson
    • 1
  • Michael Malasky
    • 1
    • 7
  • Aurelie Vogt
    • 1
    • 7
  • Bin Zhu
    • 1
    • 7
  • Giovanna Bianchi-Scarra
    • 5
    • 11
  • William Bruno
    • 5
    • 11
  • Paola Queirolo
    • 8
  • Giuseppe Fornarini
    • 8
  • Johan Hansson
    • 4
  • Rainer Tuominen
    • 4
  • Laurie Burdett
    • 1
    • 7
  • Belynda Hicks
    • 1
    • 7
  • Amy Hutchinson
    • 1
    • 7
  • Kristine Jones
    • 1
    • 7
  • Meredith Yeager
    • 1
    • 7
  • Stephen J. Chanock
    • 1
  • Maria Teresa Landi
    • 1
  • Veronica Höiom
    • 4
  • Håkan Olsson
    • 9
  • Nelleke Gruis
    • 6
  • Paola Ghiorzo
    • 5
    • 11
  • Margaret A. Tucker
    • 1
  • Alisa M. Goldstein
    • 1
    • 10
    Email author
  1. 1.Division of Cancer Epidemiology and GeneticsNational Cancer Institute, National Institutes of HealthBethesdaUSA
  2. 2.Division of Cancer Control and Population StudiesNational Cancer Institute, National Institutes of HealthBethesdaUSA
  3. 3.Department of SurgeryLund University HospitalLundSweden
  4. 4.Department of Oncology PathologyKarolinska Institutet and Karolinska University HospitalSolnaSweden
  5. 5.Department of Internal Medicine and Medical SpecialtiesUniversity of GenoaGenoaItaly
  6. 6.Department of DermatologyLeiden University Medical CenterLeidenThe Netherlands
  7. 7.Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer ResearchLeidos Biomedical Research, Inc.FrederickUSA
  8. 8.Medical Oncology UnitIRCCS AOU San Martino-ISTGenoaItaly
  9. 9.Department of OncologyLund University HospitalLundSweden
  10. 10.BethesdaUSA
  11. 11.Genetics of Rare CancersIRCCS AOU San Martino-ISTGenoaItaly

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