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Comparative Study
. 2015 Jul;17(7):569-77.
doi: 10.1038/gim.2014.153. Epub 2014 Nov 20.

BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study

David B Zhen  1 , Kari G Rabe  2 , Steven Gallinger  3 , Sapna Syngal  4 , Ann G Schwartz  5 , Michael G Goggins  6 , Ralph H Hruban  6 , Michele L Cote  5 , Robert R McWilliams  7 , Nicholas J Roberts  8 , Lisa A Cannon-Albright  9 , Donghui Li  10 , Kelsey Moyes  11 , Richard J Wenstrup  11 , Anne-Renee Hartman  11 , Daniela Seminara  12 , Alison P Klein  6 , Gloria M Petersen  2
Affiliations
Comparative Study

BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study

David B Zhen et al. Genet Med. 2015 Jul.

Abstract

Purpose: Familial pancreatic cancer kindreds contain at least two affected first-degree relatives. Comprehensive data are needed to assist clinical risk assessment and genetic testing.

Methods: Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A. We compared prevalence of deleterious mutations between familial pancreatic cancer probands and nonfamilial pancreatic cancer probands (kindreds containing at least two affected biological relatives, but not first-degree relatives). We also examined the impact of family history on breast and ovarian cancers and melanoma.

Results: Prevalence of deleterious mutations (excluding variants of unknown significance) among familial pancreatic cancer probands was: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. Familial pancreatic cancer probands carry more mutations in the four genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%) (odds ratio: 2.40; 95% confidence interval: 1.06-5.44; P = 0.03). The probability of testing positive for deleterious mutations in any of the four genes ranges up to 10.4%, depending on family history of cancers. BRCA2 and CDKN2A account for the majority of mutations in familial pancreatic cancer.

Conclusion: Genetic testing of multiple relevant genes in probands with a positive family history is warranted, particularly for familial pancreatic cancer.

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Conflict of interest statement

Conflict of Interest: Ralph H. Hruban, Michael G. Goggins, and Alison P. Klein receive royalty payments from Myriad Genetics for the PALB2 invention under an agreement through Johns Hopkins University. L.A. Cannon-Albright collaborated with Myriad on gene discovery and receives royalties for BRCA1, BRCA2, and CDKN2A clinical testing under an agreement with the University of Utah.

Figures

Figure 1
Figure 1
Probability (%) that probands affected with pancreatic cancer (PC) will test positive for a deleterious mutation in BRCA1, BRCA2, PALB2, or CDKN2A, if from kindreds with various cancer family histories. Number of PC includes proband. Sizes of sample subsets from which probabilities were estimated are shown in parentheses.
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