Synapse - Germline pathogenic variants impact clinicopathology of advanced lung cancer

Germline pathogenic variants impact clinicopathology of advanced lung cancer Journal Article

Authors:	Mukherjee, S.; Bandlamudi, C.; Hellmann, M. D.; Kemel, Y.; Drill, E.; Rizvi, H.; Tkachuk, K.; Khurram, A.; Walsh, M. F.; Zauderer, M. G.; Mandelker, D.; Topka, S.; Zehir, A.; Srinivasan, P.; Selvan, M. E.; Carlo, M. I.; Cadoo, K. A.; Latham, A.; Hamilton, J. G.; Liu, Y. L.; Lipkin, S. M.; Belhadj, S.; Bond, G. L.; Gümüş, Z. H.; Klein, R. J.; Ladanyi, M.; Solit, D. B.; Robson, M. E.; Jones, D. R.; Kris, M. G.; Vijai, J.; Stadler, Z. K.; Amos, C. I.; Taylor, B. S.; Berger, M. F.; Rudin, C. M.; Offit, K.
Article Title:	Germline pathogenic variants impact clinicopathology of advanced lung cancer
Abstract:	Background: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer. Methods: We studied clinical and tumor characteristics of germline PV in 5,118 patients who underwent prospective genomic profiling using paired tumor–normal tissue samples in 468 cancer genes. Results: Germline PV in high/moderate-penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n 1⁄4 54), CHEK2 (n 1⁄4 30), and ATM (n 1⁄4 26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared with noncarriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1, and MEN1) were diagnosed at younger age compared with noncarriers, and of tumor suppressors, 75% demonstrated biallelic inactivation in tumors. A significantly higher proportion of germline PV in high/moderate-penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors, or early age at diagnosis compared with unselected patients (10.5% vs. 4.1%; P 1⁄4 1.7e-04). Conclusions: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer. Impact: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance. ©2022 American Association for Cancer Research
Keywords:	genetics; prospective study; prospective studies; genetic predisposition to disease; germ cell; lung neoplasms; lung tumor; germ cells; genetic predisposition; germ-line mutation; germline mutation; humans; human
Journal Title:	Cancer Epidemiology Biomarkers and Prevention
Volume:	31
Issue:	7
ISSN:	1055-9965
Publisher:	American Association for Cancer Research
Date Published:	2022-07-01
Language:	English
DOI:	10.1158/1055-9965.Epi-21-1287
PUBMED:	35477182
PROVIDER:	scopus
PMCID:	PMC9250622
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85133980527&doi=10.1158%2f1055-9965.EPI-21-1287&partnerID=40&md5=6a70eea64fc8354d8fc2aaa679f91a2a
Notes:	Article -- Export Date: 1 August 2022 -- Source: Scopus