Germline Mutations in DNA Repair Genes in Lung Adenocarcinoma

Abstract

Introduction: Although lung cancer is generally thought to be environmentally provoked, anecdotal familial clustering has been reported, suggesting that there may be genetic susceptibility factors. We systematically tested whether germline mutations in eight candidate genes may be risk factors for lung adenocarcinoma.

Methods: We studied lung adenocarcinoma cases for which germline sequence data had been generated as part of The Cancer Genome Atlas project but had not been previously analyzed. We selected eight genes, ATM serine/threonine kinase gene (ATM), BRCA2, DNA repair associated gene (BRCA2), checkpoint kinase 2 gene (CHEK2), EGFR, parkin RBR E3 ubiquitin protein ligase gene (PARK2), telomerase reverse transcriptase gene (TERT), tumor protein p53 gene (TP53), and Yes associated protein 1 gene (YAP1), on the basis of prior anecdotal association with lung cancer or genome-wide association studies.

Results: Among 555 lung adenocarcinoma cases, we detected 14 pathogenic mutations in five genes; they occurred at a frequency of 2.5% and represented an OR of 66 (95% confidence interval: 33-125, p < 0.0001 [chi-square test]). The mutations fell most commonly in ATM (50%), followed by TP53, BRCA2, EGFR, and PARK2. Most (86%) of these variants had been reported in other familial cancer syndromes. Another 12 cases (2%) carried ultrarare variants that were predicted to be deleterious by three protein prediction programs; these most frequently involved ATM and BRCA2.

Conclusions: A subset of patients with lung adenocarcinoma, at least 2.5% to 4.5%, carry germline variants that have been linked to cancer risk in Mendelian syndromes. The genes fall most frequently in DNA repair pathways. Our data indicate that patients with lung adenocarcinoma, similar to other solid tumors, include a subset of patients with inherited susceptibility.

Keywords: Ataxia Telengiectasia; Li-Fraumeni syndrome; lung adenocarcinoma; poly ADP ribose inhibitors.

Figure 1. Approach to identifying germline cancer-predisposing mutations in sequenced lung adenocarcinoma cases

The flow chart delineates a priori designed strategy for identifying rare pathogenic variants and the numbers bolded indicate the number of cases examined and filtered. MAF, refers to minor allele frequency.

Figure 2. Germline variants in lung adenocarcinoma cases

Schema of ATM, BRCA2, EGFR, PARK2, and TP53 proteins with the 12 unique pathogenic mutations marked at their relative amino acid position with the protein domains schematized. These occurred at a frequency of 2.5% in the studied cohort. ^† Refers to the two mutations identified in two separate individuals, ATM V2716A and TP53 R287Q. The relative frequencies of the mutations by gene are shown in the adjacent pie chart.