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Familial Cancer

, Volume 17, Issue 2, pp 235–245 | Cite as

The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes

  • Thomas P. Slavin
  • Susan L. Neuhausen
  • Bita Nehoray
  • Mariana Niell-Swiller
  • Ilana Solomon
  • Christina Rybak
  • Kathleen Blazer
  • Aaron Adamson
  • Kai Yang
  • Sharon Sand
  • Nancy Guerrero-Llamas
  • Danielle Castillo
  • Josef Herzog
  • Xiwei Wu
  • Shu Tao
  • Shivali Raja
  • Vincent Chung
  • Gagandeep Singh
  • Sue Nadesan
  • Sandra Brown
  • Marcia Cruz-Correa
  • Gloria M. Petersen
  • Jeffrey Weitzel
  • Clinical Cancer Genomics Community Research Network (CCGCRN)
Original Article

Abstract

Approximately 5–10% of all pancreatic cancer patients carry a predisposing mutation in a known susceptibility gene. Since >90% of patients present with late stage disease, it is crucial to identify high risk individuals who may be amenable to early detection or other prevention. To explore the spectrum of hereditary pancreatic cancer susceptibility, we evaluated germline DNA from pancreatic cancer participants (n = 53) from a large hereditary cancer registry. For those without a known predisposition mutation gene (n = 49), germline next generation sequencing was completed using targeted capture for 706 candidate genes. We identified 16 of 53 participants (30%) with a pathogenic (P) or likely pathogenic (LP) variant that may be related to their hereditary pancreatic cancer predisposition; seven had mutations in genes associated with well-known cancer syndromes (13%) [ATM (2), BRCA2 (3), MSH2 (1), MSH6 (1)]. Many had mutations in Fanconi anemia complex genes [BRCA2 (3 participants), FANCF, FANCM]. Eight participants had rare protein truncating variants of uncertain significance with no other P or LP variants. Earlier age of pancreatic cancer diagnosis (57.5 vs 64.8 years) was indicative of possessing a P or LP variant, as was cancer family history (p values <0.0001). Our multigene panel approach for identifying known cancer predisposing genetic susceptibility in those at risk for hereditary pancreatic cancer may have direct applicability to clinical practice in cases with mutations in actionable genes. Future pancreatic cancer predisposition studies should include evaluation of the Fanconi anemia genes.

Keywords

Pancreatic cancer Germline Hereditary Susceptibility BRCA2 

Notes

Acknowledgements

The research reported in this publication was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award number P30CA33572 (Integrative Genomics and Bioinformatics Cores). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The City of Hope Clinical Cancer Genomics Community Research Network and the Hereditary Cancer Research Registry was supported in part by the NCI NIH award number RC4CA153828 (PI: J. Weitzel). Other sources of support include: Breast Cancer Research Foundation (PI: J. Weitzel), Morris and Horowitz Families Professor (S. Neuhausen), 2015 STOP CANCER Research Career Development Award (PI: T. Slavin), and the Oxnard Foundation (PI: T. Slavin). We would like to thank all sites that contributed research effort to the Clinical Cancer Genomics Community Research Network as well as the patients who allow this research to be completed. We would like to thank Drs. Yuan Chun Ding and Yuan Yate-Ching for help accessing informatics resources. We would also like to thank the following research assistants: Tanya Chavez, Lily Van Tongeren, and Rosa Mejia.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedure performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10689_2017_19_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 17 KB)
10689_2017_19_MOESM2_ESM.pdf (196 kb)
Supplementary material 2 (PDF 196 KB)

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Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Thomas P. Slavin
    • 1
    • 4
  • Susan L. Neuhausen
    • 1
  • Bita Nehoray
    • 1
  • Mariana Niell-Swiller
    • 2
  • Ilana Solomon
    • 1
  • Christina Rybak
    • 1
  • Kathleen Blazer
    • 1
  • Aaron Adamson
    • 1
  • Kai Yang
    • 1
  • Sharon Sand
    • 1
  • Nancy Guerrero-Llamas
    • 1
  • Danielle Castillo
    • 1
  • Josef Herzog
    • 1
  • Xiwei Wu
    • 3
  • Shu Tao
    • 3
  • Shivali Raja
    • 1
  • Vincent Chung
    • 4
  • Gagandeep Singh
    • 5
  • Sue Nadesan
    • 6
  • Sandra Brown
    • 7
  • Marcia Cruz-Correa
    • 8
  • Gloria M. Petersen
    • 9
  • Jeffrey Weitzel
    • 1
    • 4
  • Clinical Cancer Genomics Community Research Network (CCGCRN)
  1. 1.Department of Population SciencesCity of Hope National Medical CenterDuarteUSA
  2. 2.HealthQuestDyson Center for Cancer CarePoughkeepsieUSA
  3. 3.Department of Molecular and Cellular BiologyCity of Hope National Medical CenterDuarteUSA
  4. 4.Division of Clinical Cancer Genetics, Department of Medical OncologyCity of Hope National Medical CenterDuarteUSA
  5. 5.Department of SurgeryCity of Hope National Medical CenterDuarteUSA
  6. 6.Harrington Cancer CenterAmarilloUSA
  7. 7.St. Joseph HospitalOrangeUSA
  8. 8.University of Puerto RicoSan JuanPuerto Rico
  9. 9.Mayo ClinicRochesterUSA

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