Abstract 1228P
Background
Lung cancer is the leading cause of cancer-related death, accounting for nearly 1.4 million deaths worldwide every year. Lung TRACERx is a leading national study employing multi-region and longitudinal genome sequencing to determine the timing of somatic events in relation to distinct genome instability processes and to unravel the evolutionary trajectories of cancers. We have observed that chromosomal instability, rather than mutational heterogeneity, is associated with disease progression. Incorporating the contribution of epigenetic modifications to cancer evolution trajectories within TRACERx could improve our understanding of the intricate relationship between genetic and epigenetic changes in NSCLC evolution.
Methods
Multi-region sampling from 38 TRACERx patients (24 LUAD and 14 LUSC) has been performed in the study. RNA has been extracted and RNAseq performed for gene expression profiling. DNA was processed for reduced representation bisulphite sequencing (RRBS) for assessment of DNA methylation. Whole exome sequencing was performed and somatic copy number alterations (SCNAs) were inferred.
Results
The overall percentage of hypermethylated differentially methylated positions (DMPs) was assessed at the tumour and regional level. We saw an enrichment in SCNAs at genomic loci harboring genes involved in DNA methylation maintenance such as DNMT1 and DNMT3. The presence of SCNAs at those loci were found to be significantly correlated with the extent of hypermethylated DMPs in tumours. This effect is also observed at the intratumoural level. In contrast, a significant correlation was also observed between the extent of copy number gains in the Tet methylcytosine dioxygenase 3 (TET3) and increased hypomethylation status. These copy number changes were functional as observed by changes in gene expression observed in the parallel RNA seq analysis.
Conclusions
We have studied the role of SCNAs influencing expression of global methylation genes on tumour methylation heterogeneity. These data offer insight into the role of SCNAs and DNA methylation changes in lung cancer evolution.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
University College of London and Francis Crick Institute.
Funding
This work was supported by the Biomedical Research Centre and the Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is Royal Society Napier Research Professor and is also funded by the Breast Cancer Research Foundation (BCRF).
Disclosure
C. Swanton: Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): BMS; Advisory/Consultancy, Research grant/Funding (self): Roche-Ventana; Advisory/Consultancy, Research grant/Funding (self): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self): Ono Pharmaceutical; Honoraria (self): Novartis; Honoraria (self): GlaxoSmithKline; Honoraria (self): MSD; Honoraria (self): Celgene; Honoraria (self): Illumina; Honoraria (self): Genentech; Honoraria (self): GRAIL; Honoraria (self): Medicxi; Honoraria (self): Sarah Cannon Research Institute; Honoraria (self): Apogen Biotechnologies; Honoraria (self): Epic Bioscience; Leadership role: Achilles Therapeutics. All other authors have declared no conflicts of interest.