The evolution of lung cancer and impact of subclonal selection in TRACERx

Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

The evolution of non-small cell lung cancer metastases in TRACERx

“…In the accompanying Article, we found that patients whose tumours contained a recent large subclonal expansion in at least one primary tumour region had reduced disease-free survival 17 . We therefore examined the differences in the size of expansions between seeding and non-seeding clusters in the primary tumour and whether this reflected selection.…”

“…(monoclonal) or multiple genetically distinct subclones (polyclonal) from the primary tumour, multi-region sampling and clonal architecture analysis together with clinical case report forms and imaging analyses were used. Both our tree-building and clonal architecture methods were extensively benchmarked to ensure the validity of the results 4,17 . In the following analysis we refer to metastatic monoclonal and polyclonal dissemination relative to the primary tumour, across all sampled metastases within an individual case (Fig.…”

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

“…The data from this study are part of the first 421 patients prospectively analysed from the TRACERx cohort (NCT01888601 approved by the National Research Ethics Service Committee London, with sponsor's approval of the study by University College London with the following details: REC reference 13/LO/1546, protocol number UCL/12/0279, IRAS project ID 138871). Data obtention followed similar steps to those described in the study of the first 100 patients 52,53 and is described in full in the accompanying studies [54][55][56] . Informed consent for entry into the TRACERx study was mandatory and was obtained from every patient.…”

“…Transcriptomic data (50 million paired reads per sample with a length of 75 bp or 100 bp per read) analysed in this study were derived from the TRACERx cohort that is described in full in the accompanying studies [54][55][56] . Data obtention followed similar steps to those previously described 57 .…”

“…Whole-exome sequencing data (median depth of 413×) analysed in this study were derived from the TRACERx cohort that is described in full in the accompanying studies [54][55][56] . Only driver single-nucleotide variants (SNVs) and indels in TP53, EGFR and KRAS were included for analysis.…”