Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing

Abstract

SUMMARY Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for over 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole genome sequence analysis revealed frequent structural re-arrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

“…These genomic events include somatic EGFR mutations within regions of either the extracellular domain, in glioblastoma, or the kinase domain in lung adenocarcinoma,3, 4 as well as through gene amplification as observed in many other types of solid tumors 5, 6. In addition, several intragenic deletions within either the extracellular or C‐terminal domain of EGFR have also been reported to be oncogenic in a subset of glioblastoma and lung adenocarcinoma 7, 8, 9…”

“…Furthermore, accumulating data suggest that the downstream signaling pathways activated by oncogenic mutant EGFR differ from those activated by ligand stimulated wild‐type EGFR 17, 18, 19. Notably, C‐terminal deletion EGFR mutants, lacking some or all of the autophosphorylation sites that have been identified in GBM and lung adenocarcinoma, are able to induce cellular transformation 8, 9, 20. These observations have raised the question whether autophosphorylation of oncogenic mutant EGFR, which is a consequence of constitutive receptor dimerization, is required for oncogenic activation and induction of cellular transformation by cancer‐derived EGFR mutants.…”

New therapeutic perspectives in CCDC6 deficient lung cancer cells

“…16 Recently, CCDC6-RET fusions and CCDC6 inactivating mutations (N394Y, T462A, S351Y, E227K; www.sanger.ac.uk/genetics/ CGP/cosmic) have been reported in NSCLC. 21,22 In this study, we examined CCDC6 protein and mRNA levels in a group of NSCLC cell lines along with DNA repair proficiency, DNA damage response and platinum-based therapy as a single agent or in combination with PARP inhibitors. We further analyzed CCDC6 expression in a wide range of early resectable or locally advanced NSCL primary tumors to establish the predictive power of CCDC6 expression in the clinics.…”

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

“…The genetic features of these mutations and mouse model studies suggest that U2AF1, SF3B1 and SRSF2 promote cancer formation by gain of function or altered function mechanisms and therefore are potentially proto-oncogenes [64]. Recurrent mutations in U2AF1 and the RBM5 paralog RBM10 were also associated with lung adenocarcinomas [23]. In addition, 220 somatic mutations in RBM5 have been identified in various cancers as annotated in the Cancer Genome Atlas (TCGA) (www.cancergenome.nih.gov).…”

“…RBM5 and its paralog RBM6 are located in the human chromosome 3p21.3 region and were identified as candidate tumor suppressors of lung cancers and other solid tumors [16–22]. RBM10 , another paralog of RBM5 , is also frequently mutated in lung adenocarcinoma samples [23]. In mice and human, RBM5 can reduce lung cancer progression [24,25].…”