Endocrine Abstracts

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer as it lacks known targets of therapy. 5-year survival is only 5% and patients quickly develop therapy resistance by yet unknown mechanisms. The lack of advances is also related to the fact that SCLC is not part of the ICGC or TCGA cancer genomics projects, and patient material is hard to obtain. SCLC presents frequent amplifications in genes of the MYC family, which are known regulators of splicing factors, but the role of splicing in therapy and resistance is not known yet. We have recently shown that splicing alterations provide new mechanisms of tumor progression [1], and that by analyzing the somatic mutations according to RNA selection processes, new impacts on RNA-processing can be uncovered [2] We have now expanded these efforts to study non-coding variants and RNA-processing alterations in SCLC. We have collected the largest compendium of somatic mutation and RNA-seq data available to date for SCLC samples from multiple sources [3–5]. By integrating this data we have obtained a total of 2.579 splicing altering somatic mutations on 63 samples. Genes with the largest splicing changes included several linked previously with cancer, like LIMS1. Intron retention cases include genes involved in DNA repair, like POLD3; or the NOTCH pathway, like KIT. Among the cryptic junctions showing expression in SCLC we recovered the cases previously reported for RB1 and TP73, plus 86 new ones, including cases in the genes of the Wnt signaling pathway ASPM and CTNND2. This is the largest analysis performed to date of RNA processing alterations in SCLC. The results could lead to the uncovering of novel targets of therapy.

References:

1. Sebestyén et al. Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks. Genome Res. 2016;26:732–44.

2. Singh et al. Genome Sequencing and RNA-motif Analysis Reveal Novel Damaging Non-coding Mutations in Human Tumors. Mol. Cancer Res. 2018;

3. Iwakawa et al. Expression and clinical significance of genes frequently mutated in small cell lung cancers defined by whole exome/RNA sequencing. Carcinogenesis. 2015;36:616–21.

4. George et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47–53.

5. Rudin et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat. Genet. 2012;44:1111–6.