| Title: | Germline alterations in patients with lung cancer |
| Journal: | Annals of Oncology |
| Published: | 16 Dec 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41412497/ |
| DOI: | https://doi.org/10.1016/j.annonc.2025.12.008 |
Publication 17127
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Abstract
BACKGROUND: Germline alterations and smoking status in lung cancer could inform etiology and clinical decisions. We explored germline alteration prevalence in predisposition genes across lung cancer histologies from two large populations.</p>
METHODS: Germline sequencing of 11,740 primary lung cancers was performed with Tempus xT tumor-normal matched assay (DNAseq of 648 genes at average 500x coverage, normal specimens at 150x coverage, full transcriptome RNA-seq). 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 (NSCLC) and small cell (SCLC) histologies; and NSCLC sEGFRalt and NSCLC sEGFRwt. P/LP variants were investigated in these 46 genes in 1,330 patients with lung cancer from the UK BioBank by smoking status.</p>
FINDINGS: Tempus sequencing revealed P/LP alterations in 4·8% of smokers and 5·8% of never smokers, with most alterations in MUTYH (1·3% vs. 1·1%), ATM (0·7% vs. 1·0%), BRCA2 (0·6% vs. 0·9%) and EGFR (< 0·1% vs. 0·4%). Never-smoker sEGFRalt (n=549) and sEGFRwt (n=1025) tumors had alterations in MUTYH (1·1% vs. 1·1%), ATM (0·7% vs. 1·1%), and EGFR (1·1% vs. 0%). NSCLC and SCLC tumors had alterations in MUTYH (1·3% vs. 0·3%), ATM (0·8% vs. 0·3%), and BRCA2 (0·7% vs. 0%). sEGFRalt and sEGFRwt NSCLC tumors had germline alterations in MUTYH (1·6% vs 1·3%), ATM (0·5% vs. 0·8%), EGFR (1·3% vs. 0%), and BRCA2 (0·8% vs. 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.</p>
INTERPRETATION: Similar distribution of P/LP potential germline alterations in lung cancer subtypes from distinct populations by smoking status suggests increased next-generation germline sequencing may improve risk assessment.</p>
9 Authors
- R Govindan
- K Navo
- M Huang
- J Liu
- C Chao
- X Zong
- S Sankararaman
- K Bolton
- Y Cao
1 Application
| Application ID | Title |
|---|---|
| 55288 | Early life, adulthood, and genomic risk factors for early-onset cancers |
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