Prevalence of germline BRCA & MMR gene mutations in pancreatic cancer

Abstract B113: AACR

AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA

Background: Germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 are known to increase risk of pancreatic cancer. However, the prevalence of pathogenic germline mutations of these genes among pancreatic cancer patients is unknown. Accurately characterizing the frequencies of mutations of these genes will inform patient selection for future gene discovery studies and, clinically, foster screening strategies and tailored treatments.

Objective: To determine the prevalence of pathogenic germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 in a cohort of pancreatic cancer patients, and to determine the association between mutation carrier status and personal and family history of cancer.

Methods: The Ontario Pancreas Cancer Study (OPCS) enrolls all consenting participants with a diagnosis of pancreatic cancer into a province-wide electronic pathology database. A cross-sectional sample of 300 patients from 715 OPCS probands enrolled between April 2003 and August 2012 were randomly selected from three strata based on a family history of pancreatic, breast, and ovarian cancer. Targeted next-generation sequencing was successfully performed on germline DNA from 291 of the 300 selected probands. Mutations were classified as benign, of unknown significance, or pathogenic by literature and database review. Pathogenic mutations were confirmed with Sanger sequencing. Prevalence estimates representing the whole OPCS were estimated using the Horvitz-Thompson estimator. Univariate analysis determined association between carrier status and clinical covariates, and regression analysis for overall survival.

Results: A total of 7 pathogenic germline mutations were identified: 1 BRCA1, 2 BRCA2, 1 MLH1, 2 MSH2, and 1 MSH6. The estimated prevalence of pathogenic mutations in BRCA1 and BRCA2 among probands in this OPCS series was 1.1% (95% confidence interval: 0.1-2.0%); in the mismatch repair genes MLH1, MSH2 , and MSH6 it was 1.5% (0.3-2.6%). Both a personal history of colorectal cancer and a first-degree relative with colorectal cancer, breast cancer, or melanoma were significantly associated (p<0.001 and p<0.01, respectively) with MMR mutations. There were no significant differences in tumor location within the pancreas (head/uncinate versus body/tail), clinical nodal status, rates of resection, age at diagnosis, BMI, history of smoking, history of pancreatitis, family history of pancreatic cancer, family history of colorectal cancer, or differences in survival between the MMR or sporadic cohorts.

Conclusion: This study is the first to quantify population-based prevalences of germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 in pancreatic cancer. Surprisingly, the prevalence of pathogenic germline mutations of the MMR genes in pancreatic cancer is higher than expected, and is comparable to that of BRCA1 and BRCA2. The prevalence of the MMR germline mutations is also comparable to the prevalence of MMR germline mutations in colorectal cancer cohorts. Relatives who carry MMR gene mutations can benefit from tailored cancer prevention strategies; thus mutational analysis of MLH1 , MSH2, and MSH6 should be included in molecular genetic testing and counseling strategies for pancreatic cancer patients, especially those with a family history of malignancy. Translational studies will follow to determine if stratifying pancreatic cancer risk by familial susceptibility genes, as in colorectal cancer, fosters tailored and cost-effective primary and secondary prevention strategies for carriers. Moreover, unique chemotherapy sensitivity and resistance patterns would be expected for MMR-associated pancreatic cancer, as is emerging for BRCA-associated pancreatic cancer.