Endocrine Abstracts (2019) 68 NETS5.3 | DOI: 10.1530/endoabs.68.NETS5.3

Intratumour Heterogeneity and tumour evolution in neuroendocrine cancers of the lung

Lorelle Brownlee1, Robert Bentham1, Nicholas McGranahan1, Charles Swanton2, David Moore1 & Mariam Jamal-Hanjani1

1University College London Cancer Institute, London, UK; 2UCL and the Francis Crick Institute, London, UK

Lung cancer is globally the biggest cause of cancer-related death, resulting in almost 1.6 million deaths per year. Neuroendocrine tumours amount to up to 25% of all lung cancer diagnoses. Pulmonary neuroendocrine tumours lie on a biological continuum of malignant behaviour, which range from the malignant, but relatively indolent, typical carcinoid tumours to small cell lung carcinoma- the most aggressive of the primary neuroendocrine lung tumours. Although small cell carcinoma and other primary neuroendocrine lung tumours are considered part of the same tumour family, the evolutionary relationship between these tumours is still poorly understood. The TRACERx study (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) is a prospective cohort study across multiple UK centres which explores the genomic evolution of non-small cell lung cancers, identifying specific ‘driver mutations’ which impact tumour behavioural phenotypes. We apply the methodology and resources behind TRACERx to a cohort of primary neuroendocrine lung tumours, across the full range of tumour subtypes in this family. Multi-region sampling has been performed on each tumour whilst fresh, and whole-exome sequencing has been performed on each region of fresh frozen tumour. Utilising the established TRACERx bioinformatics pipeline, we have explored copy number alterations and mutations identified in this group of tumours. We mapped evolutionary profiles and differentiate early clonal genetic changes from later sub-clonal changes. We correlated findings with histological features and clinical data to give a uniquely rounded perspective on the evolutionary behaviour of these tumours. Evolutionary phylogenetic trees illustrate genomic divergence for each tumour and demonstrate genetic intratumour heterogeneity. Differences were found between tumour grades across a number of parameters, including whole genome instability index, tumour mutational burden, clonal and sub clonal mutational burden, and loss of heterozygosity of human leucocyte antigen (HLA). Predicted driver events were also identified, both early and late in tumour evolution.

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