Abstract 1611: DNA methylation co-operates with genomic alterations during non-small cell lung cancer evolution

Abstract Aberrant DNA methylation patterns have been described in nearly all human cancers, yet their interplay with genomic alterations during tumor evolution is poorly understood. To explore this crosstalk, we performed reduced representation bisulfite sequencing on 217 tumor regions from 59 patients from the TRACERx study, all with matched adjacent normal tissue, to deconvolve tumor methylation rates. We combined two new metrics for integrative evolutionary analysis with DNA and RNA sequencing data. I-TMD (intra-tumoral methylation distance) quantifies intra-tumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus non-regulatory (MN) CpGs, to identify driver genes exhibiting recurrent functional hypermethylation. We observed early DNA methylation of VIPR2 and ZNF714 co-occurring with driver mutations in CDKN2A and STK11, respectively. Finally, we found DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. Our identification of hypermethylated driver genes under positive selection may open new avenues for therapeutic stratification of patients with non-small cell lung cancer. Citation Format: Francisco Gimeno-Valiente, Carla Castignani, Elizabeth Cadieux L. Cadieux, Nana E. Mensah, Olga Chervova, Mariam Jamal-Hanjani, Nicholas McGranahan, Stephan Beck, Jonas Demeulemeester, Miljana Tanic, Charles Swanton, Peter Van Loo, Nnennya Kanu. DNA methylation co-operates with genomic alterations during non-small cell lung cancer evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1611.