Germline Pathogenic Variants Impact Clinicopathology of Advanced Lung Cancer.
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Mukherjee Semanti, Bandlamudi Chaitanya, Hellmann Matthew D, Kemel Yelena, Drill Esther, Rizvi Hira, Tkachuk Kaitlyn, Khurram Aliya, Walsh Michael F, Zauderer Marjorie G, Mandelker Diana, Topka Sabine, Zehir Ahmet, Srinivasan Preethi, Esai Selvan Myvizhi, Carlo Maria I, Cadoo Karen A, Latham Alicia, Hamilton Jada G, Liu Ying L, Lipkin Steven M, Belhadj Sami, Bond Gareth L, Gümüş Zeynep H, Klein Robert J, Ladanyi Marc, Solit David B, Robson Mark E, Jones David R, Kris Mark G, Vijai Joseph, Stadler Zsofia K, Amos Christopher I, Taylor Barry S, Berger Michael F, Rudin Charles M, Offit Kenneth
Аннотация
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 = 54), CHEK2 (n = 30), and ATM (n = 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 = 1.7e-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.