Linking molecular signatures and gene regulatory programmes in Lung Carcinoids


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Clara Domingo-Sabugo1, Amit Mandal, Sarah Dwyer, Matthew Edwards, Deborah Morris-Rosendahl, Eric Lim, Andrew G. Nicholson, Mark Lathrop, William Cookson, Miriam Moffatt
1Imperial College London

Abstract

Background

Lung Carcinoids (LCars) are rare and slow growing neuroendocrine tumours that remain poorly characterised at the molecular level.

Method

Whole-exome sequencing, SNP genotyping and Whole-Genome Bisulphite Sequencing were used to detect aberration both at the genetic and methylome level in 30 paired tumour-normal LCar samples. Genomic Regions for Enrichment of Annotations Tool (GREAT) was used to assess the functional significance of cis-regulatory regions, and enriched Transcription Factor (TF) binding motif identified using the HOMER algorithm.

Results

An average of 6.4 Mutations per Mb and only 5.4% of their genomes harbouring copy number alterations were detected in our LCar cohort, in contrast to 8 and 12 Mutations per Mb reported1 for Lung Adenocarcinoma and Small Cell Lung Carcinoma, respectively. Global DNA methylation was significantly lower in LCars compared with adjacent normal tissue (P = 7x10-06), observed mainly at intergenic, intronic and enhancer regions (P < 1x10-6). Hypomethylated enhancers and intergenic regions were associated with cis-regulatory regions of T-cell activation and inflammatory associated pathways (Padj = 6x10-25; Normalized Enrichment Score (NES): 10.6); and were found enriched for the dimeric AP-1 (activating protein 1) transcription factor complex (P = 1x10-23) and the activation transcription factor 3 (ATF3) (P = 1 x10-22) DNA-binding motifs.

Conclusion

We have identified a spectrum of genetic, epigenetic and transcriptomic signatures that may link somatic aberrations with altered signalling pathways in LCars. We hypothesise that marked global DNA hypomethylation observed in LCars, in spite of the low mutational burden, could be triggering altered chromatin organisation and induction of inflammatory pathways. These observations could open new avenues for biomarker selection and treatment for LCar patients.


1. Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 1–14 (2017).

Impact statement

Genetic and epigenetic profiling of rare lung tumour type, Lung Carcinoid, in this study indicates mechanisms of chromatin dysregulation in spite of low mutation burden, which could lead to improvement in the molecular classification for personalized therapeutic approaches.