Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer

Robert C. Grant, Iris Selander, Ashton A. Connor, Shamini Selvarajah, Ayelet Borgida, Laurent Briollais, Gloria M. Petersen, Jordan Lerner-Ellis, Spring Holter, Steven Gallinger

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132 Scopus citations

Abstract

Background & Aims We investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer. Methods The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database; 708 probands were enrolled from April 2003 through August 2012. To improve the precision of BRCA2 prevalence estimates, 290 probands were selected from 3 strata, based on family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort. Results Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%-5.6%). Carrier status was associated significantly with breast cancer in the proband or first-degree relative (P <.01), and with colorectal cancer in the proband or first-degree relative (P <.01), but not family history of pancreatic cancer, age at diagnosis, or stage at diagnosis. Of patients with a personal or family history of breast and colorectal cancer, 10.7% (95% confidence interval, 4.4%-17.0%) and 11.1% (95% confidence interval, 3.0%-19.1%) carried pathogenic mutations, respectively. Conclusions A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study shows the value of using a multiple-gene panel in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)556-564
Number of pages9
JournalGastroenterology
Volume148
Issue number3
DOIs
StatePublished - Mar 1 2015

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Keywords

  • Cancer Risk
  • Familial Pancreatic Cancer
  • Pancreatic Cancer Genetics

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Grant, R. C., Selander, I., Connor, A. A., Selvarajah, S., Borgida, A., Briollais, L., Petersen, G. M., Lerner-Ellis, J., Holter, S., & Gallinger, S. (2015). Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology, 148(3), 556-564. https://doi.org/10.1053/j.gastro.2014.11.042