Background:Despite extensive knowledge about genomic alterations in tumor cells, less is known about germline alterations in patients with lung cancer. In this study, we explore the association between germline alterations in cancer-predisposition genes across lung cancer patients with different tumor histologies and smoking status.

Methods:To compare the alterations in cancer-predisposing genes through germline profiling, we analyzed 11,740 tumors from primary Lung patients (any stage/ subtype) sequenced with Tempus xT tumor/normal matched assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Prevalence of pathogenic/likely pathogenic (P/LP) germline alterations in 46 genes was compared between smokers and non-smokers, non-smoker somatic EGFR altered (sEGFRalt) and non-smoker somatic EGFR wild-type (sEGFRwt), non-small cell lung histology (NSCLC) and small cell histology (SCLC), and lastly NSCLC sEGFRalt and NSCLC sEGFRwt. Due to the low prevalence of germline, most differences were insignificant, although statistics of interest are reported.

Results:Of 10,419 lung cancer patients with known smoking status (89%) 8845 were smokers and 1574 non-smokers. MUTYH germline alterations were detected in 1.3% vs. 1.1%, ATM 0.7% vs. 1.0%, and EGFR< 0.1% vs. 0.4% in smokers and non-smokers with lung cancer respectively. Among non-smokers, 549 were sEGFRalt and 1025 were sEGFRwt. MUTYH germline alterations were detected in 1.1% non-smoker sEGFRalt vs. 1.1% non-smoker sEGFRwt, ATM 0.7% vs. 1.1%, and EGFR 1.1% vs. 0%. Germline EGFR was significant after FDR adjustment (q < 0.037). There were 10115 patients identified with NSCLC histology and 595 with SCLC histology. MUTYH germline alterations were detected in 1.3% NSCLC vs. 0.3% SCLC, ATM 0.8% vs. 0.3%, and BRCA2 0.7% vs. 0%. Of note, SCLC was more likely to be smokers than NSCLC (93% vs. 85%, p < 0.001). Among NSCLC, 1,141 were sEGFRalt and 8,974 were sEGFRwt. MUTYH germline alterations were detected in 1.6% NSCLC sEGFRalt vs. 1.3% NSCLC sEGFRwt, ATM 0.5% vs. 0.8%, EGFR 1.3% vs. 0%, and BRCA2 0.8% vs. 0.6%. Germline EGFR was significant after FDR adjustment (q < 0.001). A separate analysis of the United Kingdom Biobank data found the prevalence of P/LP germline alterations in the same 46 genes in 4.3% of 1132 smokers with lung cancer and 5.1% in 198 never-smokers with lung cancer. The most common germline alterations involved ATM (0.8%), BRCA 2 (0.79%), MUTYH (0.62%) among smokers and MUTYH (1.5%), and CHEK2 (1.01%) among non-smokers.

Conclusions:Currently, there are no standard guidelines for germline analysis for patients with lung cancer. The Tempus database enables the identification of pathogenic or likely pathogenic germline alterations in a variety of lung cancer subtypes along with their distribution frequency among various groups. The findings suggest that germline P/LP alterations in the select panel of 46 genes occur infrequently across subgroups of lung cancer.

VIEW THE PUBLICATION

VIEW THE SLIDE DECK