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J Thorac Oncol. 2017 Aug 23. pii: S1556-0864(17)30686-X. doi: 10.1016/j.jtho.2017.08.011. [Epub ahead of print]

Germline mutations in DNA repair genes in lung adenocarcinoma.

Author information

1
Osler Medical Housestaff Training Program; Department of Medicine.
2
Medical Scientist Training Program; Department of Oncology; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
3
Department of Oncology; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
4
Department of Medicine; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
5
Department of Oncology; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287; Sidney Kimmel Comprehensive Cancer Center. Electronic address: marmani1@jhmi.edu.

Abstract

INTRODUCTION:

While lung cancer is generally thought to be environmentally provoked, anecdotal familial clustering has been reported suggesting 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 whom germline sequence data had been generated as part of The Cancer Genome Atlas (TCGA) project, but that had not been previously analyzed. We selected eight genes, ATM, BRCA2, CHEK2, EGFR, PARK2, TERT, TP53, and YAP1, based on 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 odds ratio of 66 (95 confidence interval, 33 to 125, P<0.0001, chi-square test). The mutations fell most commonly in ATM (50%), followed by TP53, BRCA2, EGFR and PARK2. The majority (86%) of these variants had been reported in other familial cancer syndromes. Another 12 cases (2%) carried ultra-rare variants that were predicted to be deleterious by three protein prediction programs; these most frequently involved ATM and BRCA2.

CONCLUSIONS:

A subset of lung adenocarcinoma patients, at least 2.5% to 4.5%, carries 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 lung adenocarcinoma, similar to other solid tumors, contains a subset of patients with inherited susceptibility.

PMID:
28843361
DOI:
10.1016/j.jtho.2017.08.011
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