Germline mutations and age at onset of lung adenocarcinoma

• Published in: Cancer Vol. 127; no. 15; pp. 2801 - 2806
• Main Authors: Reckamp, Karen L., Behrendt, Carolyn E., Slavin, Thomas P., Gray, Stacy W., Castillo, Danielle K., Koczywas, Marianna, Cristea, Mihaela C., Babski, Kirsten M., Stearns, Donna, Marcum, Catherine A., Rodriguez, Yenni P., Hass, Amie J., Vecchio, Mary M., Mora, Pamela, Cervantes, Aleck E., Sand, Sharon R., Mejia, Rosa M., Tsou, Terrence C., Salgia, Ravi, Weitzel, Jeffrey N.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2021
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - genetics; Adult; Age; Age of Onset; Aged; Aged, 80 and over; Anemia; BRCA2; BRCA2 protein; Breast cancer; Cancer screening; Confidence intervals; Deoxyribonucleic acid; Diagnosis; DNA; DNA repair; Early Detection of Cancer; EGFR; Epidermal growth factor receptors; Failure times; Fanconi syndrome; Female; Genes; Genetic Predisposition to Disease; Genetics; Germ-Line Mutation; germline pathogenic variants; hereditary lung cancer; Humans; Lung cancer; Lung Neoplasms - epidemiology; Lung Neoplasms - genetics; Medical screening; Middle Aged; Minority & ethnic groups; Mutation; Oncology; p53 Protein; Repair; Retrospective Studies; Risk groups; Smoking; TP53; hereditary lung cancer; adenocarcinoma; germline pathogenic variants; BRCA2; TP53; EGFR
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.33573

Background To identify additional at‐risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset. Methods The authors assembled a retrospective cohort (1999‐2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non‐FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model. Results Subjects (n = 187; age, 28‐89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack‐years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5‐20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5‐16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, –1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking. Conclusions Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high‐risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis. Carried by 1 in 8 patients with lung adenocarcinoma who have a family history of cancer, germline pathogenic variants of TP53, EGFR, BRCA2, and other Fanconi anemia genes are associated with earlier onset of lung cancer in nonsmokers and smokers alike.