Germline alterations in patients with lung cancer

Germline alterations and smoking status in lung cancer could inform etiology and clinical decisions. We investigated the prevalence of germline alterations in predisposition genes across various lung cancer histologies in two large populations.

Germline sequencing of 11 740 primary lung cancers was carried out with Tempus xT tumor-normal matched assay (DNA sequencing of 648 genes at an average coverage of 500×, normal specimens at 150× coverage, full transcriptome RNA sequencing). Pathogenic/likely pathogenic (P/LP) potential germline alterations in 46 genes were compared between smokers and never smokers; never smokers somatic EGFR altered (sEGFRalt) and wild type (sEGFRwt); non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) histologies; and NSCLC sEGFRalt and NSCLC sEGFRwt. P/LP variants were investigated in these 46 genes in 1330 patients with lung cancer from the UK Biobank by smoking status.

Tempus sequencing revealed P/LP alterations in 4.8% of smokers and 5.8% of never smokers, with most alterations in MUTYH (1.3% versus 1.1%), ATM (0.7% versus 1.0%), BRCA2 (0.6% versus 0.9%), and EGFR (<0.1% versus 0.4%). Never smoker sEGFRalt (n = 549) and sEGFRwt (n = 1025) tumors had alterations in MUTYH (1.1% versus 1.1%), ATM (0.7% versus 1.1%), and EGFR (1.1% versus 0%). NSCLC and SCLC tumors had alterations in MUTYH (1.3% versus 0.3%), ATM (0.8% versus 0.3%), and BRCA2 (0.7% versus 0%). sEGFRalt and sEGFRwt NSCLC tumors had germline alterations in MUTYH (1.6% versus 1.3%), ATM (0.5% versus 0.8%), EGFR (1.3% versus 0%), and BRCA2 (0.8% versus 0.6%). UK Biobank patients had similar P/LP alterations: 4.3% of smokers and 5.1% of never smokers, with most germline alterations in ATM (0.8%), BRCA2 (0.79%), and MUTYH (0.62%) in smokers and MUTYH (1.5%) and CHEK2 (1.01%) in never smokers.

Similar distribution of P/LP potential germline alterations in lung cancer subtypes from distinct populations by smoking status suggests that increased next-generation germline sequencing may improve risk assessment.