Abstract 84P
Background
MUTYH is a critical gene involved in the base excision repair pathway, which rectifies oxidative DNA damage. Biallelic germline MUTYH mutations (gMUTYHm) are linked to MUTYH-associated polyposis, an autosomal recessive hereditary cancer syndrome that predisposes individuals to colorectal cancer and potentially other malignancies. However, the clinical significance of monoallelic gMUTYHm and their association with the risk of lung cancers remains unclear.
Methods
We conducted a retrospective, cross-sectional analysis of the Foundation Medicine genomic database of lung cancer patients at the University of California, Irvine (UCI), where plasma samples were profiled using next-generation sequencing (NGS) between January 1, 2021, and October 1, 2024. Germline MUTYH mutations were identified based on a variant allele frequency (VAF) of 49–51%, and their association with actionable driver alterations was evaluated. Additionally, data from 26,851 Non-Small Cell Lung Cancer (NSCLC) patients in the AACR GENIE database (version 16.1) from 2017 to 2023 were analyzed for comparison.
Results
At UCI, 12 lung cancer patients with gMUTYHm were identified. The cohort included 8 adenocarcinomas, 2 squamous cell carcinomas, 1 mixed adenocarcinoma and squamous cell carcinoma, and 1 small cell lung cancer. Notably, all 8 adenocarcinoma cases harbored actionable driver mutations, including 2 EML4-ALK fusions, 5 EGFR mutations (2 E746_A750 deletions, 1 L858R, 1 exon 20 insertion, 1 L861Q), and 1 BRAF V600E mutation. Analysis of 26,851 NSCLC cases in the GENIE database revealed 317 patients with somatic MUTYH mutations, of whom 99 had concurrent actionable driver mutations, including 44 KRAS G12C, 26 EGFR (12 L858R, 11 E746_A750 deletions, 1 L747_P753 deletion, 2 S768I), 17 ERBB2, 5 BRAF V600E, 2 ALK, 2 RET, 2 NRG1, and 1 ROS1.
Conclusions
Our findings reveal a significantly higher prevalence of actionable driver mutations in NSCLC patients with gMUTYHm (73%, 8/11) compared to those with somatic MUTYHm (31%, 99/317). 100% (8/8) adenocarcinoma cases with gMUTYHm harbored targetable alterations. These results suggest a potential association between gMUTYHm and actionable mutations in NSCLC, warranting further investigation into this relationship.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
Z.L. Arter: Financial Interests, Personal, Advisory Board: catalyst. M. Nagasaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Eli Lilly, Bayer, Regeneron, BMS and Genentech; Financial Interests, Personal, Other, consultant: Caris Life Sciences; Financial Interests, Personal, Invited Speaker: Blueprint, Janssen, Mirati, Takeda; Financial Interests, Personal, Other, Travel support: AnHeart; Financial Interests, Personal, Stocks/Shares: MBrace Therapeutics. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology, AnHeart Therapeutics, BMS, Daiichi Sankyo; Financial Interests, Personal, Ownership Interest: MBrace Therapeutics, BlossomHill Therapeutics; Financial Interests, Personal, Stocks/Shares: Nuvalent; Financial Interests, Institutional, Invited Speaker: Pfizer, Mirati, JNJ/Janssen, Merus, Revolution Medicine. All other authors have declared no conflicts of interest.