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

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.

Keywords: Cancer Risk; Familial Pancreatic Cancer; Pancreatic Cancer Genetics.

Figure 1

The number of variants of unknown significance detected in each gene versus bases sequenced of each gene (correlation coefficient=0.88; p<0.001).

Figure 2

The prevalence of germline mutations in thirteen genes sequenced in a population-based cohort of pancreatic cancer patients (N=708), estimated from a random sample (N=290), with genes grouped by the predominantly associated cancer. The squares reflect point estimates, the bands reflect 95% confidence intervals, and the diamonds reflect summary estimates and corresponding 95% confidence intervals.

Figure 3

The prevalence of germline mutations in thirteen genes sequenced in a population-based cohort of pancreatic cancer patients (N=708), estimated from a random sample (N=290), with the cohort subdivided by the presence of pancreatic cancer in a first-degree relative, and the presence of breast or colorectal cancer in the proband or a first-degree relative. The squares reflect point estimates, the bands reflect 95% confidence intervals, and the diamonds reflect summary estimates and the corresponding 95% confidence intervals.