LBA36 - Evolution of the genomic landscape in non-small cell lung cancer

Date 28 September 2014
Event ESMO 2014
Session NSCLC early stage
Topics Non-Small-Cell Lung Cancer, Early Stage
Pathology/Molecular Biology
Translational Research
Presenter Mariam Jamal-Hanjani
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors M. Jamal-Hanjani1, G. Wilson1, E. De Bruin1, N. McGranahan2, R. Mitter3, M. Salm3, D. Wedge4, A. Rowan2, P. Campbell4, C. Swanton2
  • 1Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, WC1E 6BT - London/GB
  • 2Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, WC2A 3LY - London/GB
  • 3Bioinformatics And Biostatistics, Cancer Research UK London Research Institute, WC2A 3LY - London/GB
  • 4Cancer Genome Project, Wellcome Trust Sanger Institute, CB10 1SA - Cambridge/GB

 

Abstract

Aim

Few studies have investigated the clonal architecture of non-small cell lung cancer (NSCLC) and its evolution over time. With increasing evidence for the potential impact of intratumour heterogeneity (ITH) on clinical outcome, and its recognition as a driver of cancer progression, there is an unmet need to elicit the implications of ITH for biomarker validation, therapeutic response, and therefore survival.

Methods

In a cohort of 11 primary NSCLC tumours, multi-region whole-exome sequencing at a mean depth of 214x was performed on a total of 37 tumour regions. Single nucleotide variants, indels and copy number data were identified using VarScan2 (v2.3.6). Non-silent mutations were validated using ultra-deep amplicon sequencing (mean depth 1189x). The subclonal composition of each tumor was used to construct phylogenetic trees. Candidate driver genes were selected by referencing large-scale lung cancer or pan-cancer sequencing studies, and the Catalogue of Somatic Mutations in Cancer (COSMIC) gene census.

Results

ITH was evident in all tumours, with a median of 33% heterogeneous mutations (range 5–61%). Phylogenetic tree analysis revealed branched tumour evolution, with mutations in potential driver genes occurring both early (trunk) and late (branch). Thirty-five percent (range 8-67%) of mutations in potential driver genes were heterogeneous, and included TP53, EGFR, KRAS, BRAF, ALK and ROS1. Overall, heterogeneous non-silent somatic mutations and copy number aberrations occurred frequently.

Conclusions

This study demonstrates spatial and temporal heterogeneity of both driver mutations and copy number events, suggesting that NSCLCs may follow multiple distinct evolutionary pathways simultaneously. Knowledge of these pathways may help identify novel therapeutic targets to improve clinical outcomes, and large-scale longitudinal genomic studies, such as TRACERx (TRAcking NSCLC Evolution through therapy (Rx), NCT01888601), may become a central component to the delivery of precision cancer medicine.

Disclosure

All authors have declared no conflicts of interest.