Abstract 167P
Background
Intra-tumour heterogeneity (ITH) fuels tumour evolution and copy number (CN) ITH has been shown to be a prognostic indicator in non-small cell lung cancer (NSCLC). We aimed to better understand the tumour landscape and genomic underpinnings of prognostic ITH in NSCLC, with a particular focus on CN ITH.
Methods
We performed an analysis of CN profiles of 1385 tumour regions taken from 421 tumour samples in the TRACERx421 dataset of paired primary and metastatic NSCLC tumours which had undergone multi-region sampling and high depth whole exome sequencing. TRACERx421 provides a unique longitudinal cohort of patients tracked through disease from primary to relapse and metastasis, facilitating the evaluation of tumour evolution and ITH over time. Tumour region level CN estimates were used to calculate a measure of CN ITH.
Results
We found that in a cohort of metastatic tumours only, regions with mutations which seeded metastases (seeding regions) had significantly lower CN diversity than non-seeding regions (p = 4.4 x10-5). This was largely driven by tumours with metastasis-seeding mutations present in all cancer cells of the primary tumour (homogeneous seeding tumours). This may be explained by these tumours undergoing multiple successive clonal sweeps, shown by significantly higher branch ratio (proportion of mutations present in all tumour cells relative to mutations present only in the most recent clones) (p = 0.0098), and was not explained by smoking. Critically, in a cohort of metastatic and non-metastatic tumours, tumours comprising both non-seeding and seeding regions (heterogeneous seeding tumours) had significantly higher CN diversity than non-metastatic and homogeneous seeding tumours (p = 2.2 x10-9 and p = 3.2 x10-5 respectively). The higher CN ITH may be explained by increased subclonal expansion (p = 3.4 x10-5).
Conclusions
This work highlights previously unknown associations of seeding patterns with CN ITH and suggests mechanisms for the link with propensity for metastasis, and consequently poor prognosis. This research suggests the clinical importance of CN ITH which shows promise for future practice, such as through its implementation in stratification of patients into risk groups for treatment and monitoring.
Legal entity responsible for the study
CRUK.
Funding
Achilles.
Disclosure
N. McGranahan: Financial Interests, Personal, Invited Speaker: Achilles. All other authors have declared no conflicts of interest.