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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Association Between Rare Germline Variants in Cancer Susceptibility Genes and Lung Cancer Risk
Sierra R Broad1, Jun Wei2, Keri Denson1
1Department of Cardiovascular and Thoracic Surgery, Rush University Medical Center, Chicago, Illinois.
Background:
Few germline susceptibility genes have been well established for lung cancer. We aimed to evaluate associations between germline variants in known hereditary cancer genes and lung cancer risk.
Methods:
We analyzed participants of European ancestry from 2 data sets: 2273 lung cancer cases and 185,510 controls from the UK Biobank; and 824 lung cancer cases from Rush University Medical Center (RUSH) with 56,878 population controls from the Genome Aggregation Database (gnomAD). Rare pathogenic germline variants in 123 ClinGen-curated hereditary cancer genes were first tested for lung cancer risk in the UK Biobank by gene-based burden testing (robust optimal sequence kernel association test). Genes with suggestive associations were further evaluated in the RUSH/gnomAD data set. Meta-analysis of the 2 data sets was performed to estimate overall evidence and pooled odds ratios.
Results:
Rare germline variants in 10 genes showed nominally significant associations with lung cancer in the UK Biobank (P < .05), and TP53 showed a borderline signal (P = .11). These genes were tested in the RUSH/gnomAD data set, and meta-analysis identified suggestive evidence supporting 8 genes associated with increased lung cancer risk (P < .05), including 3 previously reported lung cancer genes (ATM, BRCA2, TP53) and 5 novel genes (RB1, MET, CYLD, PDGFRA, CTNNA1). In the UK Biobank incident lung cancer cohort, aggregated rare pathogenic variants in these 8 genes were significantly associated with lung cancer risk and earlier age at lung cancer diagnosis, independent of and complementary to smoking history at recruitment.
Conclusions:
Suggestive evidence supporting associations between rare germline variants in 8 hereditary cancer genes and lung cancer was obtained from 2 large independent data sets.
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