Multigene Hereditary Cancer Panels Reveal High-Risk Pancreatic Cancer Susceptibility Genes.

Chunling Hu,Abigail Thomas,Jill S Dolinsky,Kun Y Lee,Holly Laduca,Hermela Shimelis,Mary Helen Black,Jie Na,Fergus J Couch,Steven N Hart,Tina Pesaran,Brigette Tippin Davis,Eric C Polley,David E Goldgar,Jenna Lilyquist

doi:10.1200/po.17.00291

Chunling Hu, Abigail Thomas + Show 13 more

Open Access

https://doi.org/10.1200/po.17.00291

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Abstract

PurposeThe relevance of inherited pathogenic mutations in cancer predisposition genes in pancreatic cancer is not well understood. We aimed to assess the characteristics of patients with pancreatic cancer referred for hereditary cancer genetic testing and to estimate the risk of pancreatic cancer associated with mutations in panel-based cancer predisposition genes in this high-risk population.MethodsPatients with pancreatic cancer (N = 1,652) were identified from a 140,000-patient cohort undergoing multigene panel testing of predisposition genes between March 2012 and June 2016. Gene-level mutation frequencies relative to Exome Aggregation Consortium and Genome Aggregation Database reference controls were assessed.ResultsThe frequency of germline cancer predisposition gene mutations among patients with pancreatic cancer was 20.73%. Mutations in ATM, BRCA2, CDKN2A, MSH2, MSH6, PALB2, and TP53 were associated with high pancreatic cancer risk (odds ratio, > 5), and mutations in BRCA1 were associated with moderate risk (odds ratio, > 2). In a logistic regression model adjusted for age at diagnosis and family history of cancer, ATM and BRCA2 mutations were associated with personal history of breast or pancreatic cancer, whereas PALB2 mutations were associated with family history of breast or pancreatic cancer.ConclusionThese findings provide insight into the spectrum of mutations expected in patients with pancreatic cancer referred for cancer predisposition testing. Mutations in eight genes confer high or moderate risk of pancreatic cancer and may prove useful for risk assessment for pancreatic and other cancers. Family and personal histories of breast cancer are strong predictors of germline mutations.

Highlights

Pancreatic cancer (PC) is the fourth most common cause of death resulting from cancer in the United States.[1]
Mutations in ATM, BRCA2, CDKN2A, MSH2, MSH6, PALB2, and TP53 were associated with high pancreatic cancer risk, and mutations in BRCA1 were associated with moderate risk
In a logistic regression model adjusted for age at diagnosis and family history of cancer, ATM and BRCA2 mutations were associated with personal history of breast or pancreatic cancer, whereas PALB2 mutations were associated with family history of breast or pancreatic cancer

Summary

Introduction

Pancreatic cancer (PC) is the fourth most common cause of death resulting from cancer in the United States.[1] Epidemiologic studies have suggested that 10% to 20% of PCs are associated with an inherited component, with familial PC, defined as kindreds containing at least two affected first-degree relatives, as an established entity of inherited disease.[2] PC is a component of hereditary breast-ovarian cancer syndrome,[3,4] Lynch syndrome,[5,6] familial adenomatous polyposis,[7] familial atypical multiple mole melanoma syndrome,[8] hereditary pancreatitis,[9] Peutz-Jeghers syndrome,[10] and Li-Fraumeni syndrome.[11] Recent studies involving familial PC kindreds have further characterized the role of BRCA1/2, CDKN2A, ATM, and PALB2 in PC susceptibility.[12,13,14] Until recently, germline studies of PCs have focused on single cancer predisposition genes.[15,16] The first panel-based study of 13 cancer predisposition genes among patients with PC identified 11 mutations (3.8%) in ATM, BRCA1/2, MLH1, MSH2, MSH6, and TP53,17 whereas a 22-gene panel–based study identified ATM, BRCA1/2, CHEK2, and PALB2 mutations in 13% of 96 sequentially collected PCs.[18] A majority of these mutations were identified in PCs with a family history of pancreatic, breast, ovarian, or colorectal cancer, suggesting that a better understanding of PC risk will depend on evaluation of families with broad constellations of tumors.[18] More recently, panel-based approaches identified germline mutations in 4% (33 of 854) of patients with apparently sporadic PC19 and in 25% (44 of 176) of patients with advanced PC.[20] Here, we report results from panel-based clinical testing of 1,652 patients with PC from a large cohort of > 140,000 patients evaluated by a single diagnostic laboratory and calculate gene-specific risks of PC by comparison with Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD) reference controls.[21,22]

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