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Germline mutations and age at onset of lung adenocarcinoma
Author(s) -
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.
Publication year - 2021
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.33573
Subject(s) - medicine , germline , lung cancer , germline mutation , adenocarcinoma , oncology , cancer , gene , genetics , mutation , biology
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.