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 precision of BRCA2 prevalence estimates, 290 probands were
randomly 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 significantly associated with breast cancer in the proband or first-degree relative (P<.01), and colorectal cancer in
the proband or first-degree relative (P<.01), but not family history
of pancreatic cancer, age of diagnosis, or stage at diagnosis. Of
patients with a personal or family history of breast and colorectal
cancer, 10.7% (4.4%-17.0%) and 11.1% (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 demonstrates the
value of using a multiple-gene panel in pancreatic cancer.
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