121P - DNA methylation co-operates with genomic alterations during non-small cell lung cancer evolution

Background

Aberrant DNA methylation patterns have been described in nearly all human cancers, yet their interplay with genomic alterations during tumor evolution is poorly understood.

Methods

To explore this crosstalk, we performed reduced representation bisulfite sequencing on 217 tumor regions from 59 patients from the TRACERx study, all with matched normal adjacent tissue. We applied our CAMDAC (Copy number-Aware Methylation Deconvolution Analysis of Cancers) tool to model the pure tumor methylation rates, MethSig to identify DNA methylation drivers, ASCAT to infer copy number alterations from whole exome sequencing data and RNA sequencing for transcriptomic analyses.

Results

We observed parallel DNA methylation and genomic alterations of canonical driver genes and combined two new metrics for integrative evolutionary analysis. I-TMD (intra-tumoral methylation distance) quantifies intra-tumor DNA methylation heterogeneity which significantly correlated with somatic copy-number intra tumor heterogeneity (ITH) and intra-tumoral expression distance. M_R/M_N classifies genes based on the rate of hypermethylation at regulatory (M_R) vs non-regulatory (M_N) CpGs to identify driver genes exhibiting recurrent functional hypermethylation with high specificity and sensitivity. Application of M_R/M_N to MethSig enabled the identification of DNA methylation drivers CIDEB and PCDHGA3 associated with poor disease-free survival. We also describe a novel mechanism enabling copy number alteration-affected chromatin to undergo the epigenetic equivalent of an allosteric activity transition leading to DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes.

Conclusions

Our identification of hypermethylated driver genes under positive selection may open new avenues for therapeutic stratification of patients with non-small cell lung cancer.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

TRACERx consortium.

Funding

The Francis Crick Institute which receives its core funding from Cancer Research UK (CC2008, CC2041), the UK Medical Research Council (CC2008, CC2041), and the Wellcome Trust (CC2008, CC2041).

Disclosure

N. Kanu: Financial Interests, Institutional, Sponsor/Funding: The Rosetrees Trust; Financial Interests, Institutional, Research Grant: AstraZeneca. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Cancer cachexia research advisory board: Pfizer; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, Personal, Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. N. McGranahan: Financial Interests, Institutional, Stocks/Shares: Achilles Therapeutics. J. Demeulemeester: Financial Interests, Institutional, Advisory Board: AvH. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, Ad Board - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Advisory Board, Scientific Advisory Board and Stock options from September 2023: Relay Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: SAGA Diagnostics; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Personal, Stocks/Shares, Stock options: Relay Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. All other authors have declared no conflicts of interest.