Analysis of intratumor heterogeneity unravels lung cancer evolution

Abstract

Lung cancer is a disease with dismal outcome. We recently reported a detailed intratumor heterogeneity analysis in 7 non-small cell lung cancer samples, revealing spatially separated driver events as well as the temporal dynamics of mutational processes and demonstrating an important role for APOBEC-mediated heterogeneity later in disease evolution.

Keywords: APOBEC; intratumor heterogeneity; lung cancer; multi-region sequencing.

Figure 1.

Multiregion DNA sequencing allows analysis of genetic diversity within a tumor. Certain mutations are present in all tumor regions, whereas others are only present in certain tumor regions, as presented in a heatmap. 2D-Dirichlet analyses of mutations corrected for copy number shows the clonality of each mutation within each region (upper graph). The presence of 2 copies of multiple mutations can indicate a genome-doubling event, in which the entire tumor genome has been duplicated. Mutations present in 2 copies were present prior to the doubling event whereas those present at one copy occurred after the doubling (lower graph). The mutational diversity can also reveal a tumor's life history. Exploring ‘early’ versus ‘late’ mutational signatures sheds light on how mutational processes change over time. In NSCLC adenocarcinomas, ‘early’ mutations are mainly caused by smoking whereas ‘late’ mutations are mainly caused by apolipoprotein-B mRNA editing catalytic polypeptide-like (APOBEC) cytidine deaminase activity.