Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history

Abstract

Background Panel-based genetic testing has identified increasing numbers of patients with pancreatic ductal adenocarcinoma (PDAC) who carry germline mutations. However, small sample sizes or number of genes evaluated limit prevalence estimates of these mutations. We estimated prevalence of mutations in PDAC patients with positive family history. Methods We sequenced 25 cancer susceptibility genes in lymphocyte DNA from 302 PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreatic Research Registry. Kindreds containing at least two first-degree relatives with PDAC met criteria for Familial Pancreatic Cancer (FPC), while the remaining were familial, but not FPC. Results Thirty-six patients (12%) carried at least one deleterious mutation in one of 11 genes. Of FPC patients, 25/185 (14%) were carriers, while 11/117 (9%) non-FPC patients with family history were carriers. Deleterious mutations (n) identified in PDAC patients were BRCA2 (11), ATM (8), CDKN2A (4), CHEK2 (4), MUTYH/MYH (3 heterozygotes, not biallelic), BRCA1 (2), and 1 each in BARD1, MSH2, NBN, PALB2, and PMS2. Novel mutations were found in ATM, BARD1, and PMS2. Conclusions Multiple susceptibility gene testing in PDAC patients with family history of pancreatic cancer is warranted regardless of FPC status, and will inform genetic risk counseling for families.

Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer

“…12 Although mutations in PALB2 are thought to increase risk of pancreatic cancer, 7,8 the current study did not find a significant association after Bonferroni correction. CHEK2 mutations were also not significantly associated with pancreatic cancer, even though mutations were frequently observed.…”

Inherited pancreatic cancer

“…Pancreatic cancer is the third most common cancer associated with BRCA1 /2 mutations, though the penetrance at age 70 is much lower 28–31 . The prevalence of BRCA2 mutations in pancreatic cancer patients is 1.4-8.2% for patients unselected for family history 32–36 , about 6-16% among FPC patients 37–42 , and up to 17.2% in families with 3 or more pancreatic cancers 38,41,43 . Comparing to the general population, the risk of pancreatic cancer is about 2-6 fold in BRCA2 carriers 28,44 and 2-5 fold in BRCA1 carriers 29,30,44 .…”

“…In the subsequent analysis, four additional ATM mutations were found in 166 FPC patients compared to none in 190 spouse controls 56 . To date, ATM mutations are found in 1-5% patients with pancreatic cancer 35,36,42,57–59 .…”

“…This gene encodes a cell-cycle checkpoint kinase that cooperates with p53, BRCA1 and ATM and regulates cell division in response to DNA damage 153 . Germline mutations and variants of CHEK2 had been implicated in susceptibility to several cancer types 154–158 , including familial pancreatic cancer 41,42,159 .…”

The importance of a well-structured pancreatic screening program for familial and hereditary pancreatic cancer

“…Approximately 3-10% of all patients with PDAC have a positive family history for this cancer [2], and 4% have an underlying gene defect, with ATM, BRCA1 & BRCA2, and PALB2 being the most commonly effected genes [3][4][5][6] (Table 1). Familial pancreatic cancer (FPC) is defined by the occurrence of PDAC in two or more first-degree relatives, in the absence of an underlying gene defect [2].…”