Identification of MET exon14 skipping by targeted DNA- and RNA-based next-generation sequencing in pulmonary sarcomatoid carcinomas.

BACKGROUND: Pulmonary sarcomatoid carcinomas (PSCs) constitutes a heterogeneous group of NSCLCs, which show poor prognosis even with aggressive surgical treatment and postoperative chemotherapy. The detection MET exon14 skipping (METex14 skipping) in PSCs suggests the targeted therapeutic opportunities with MET TKIs. PATIENTS AND METHODS: We detected MET exon14 alterations using both targeted DNA- and RNA-based Next Generation Sequencing (NGS) and elucidated the driver mutation profile of 77 Chinese PSC patients. We also collected and analyzed the demographic features and clinical outcomes of patients harboring METex14 skipping mutation. RESULTS: METex14 skipping was detected in 20.8% of PSCs. A concordance of 96.1% was observed for DNA- and RNA-based NGS. 13 different genomic variants were revealed to induce METex14 skipping, including indels (N = 1) at splice acceptor sites, base substitutions (N = 4) and indels (N = 5) at splice donor sites, indels (N = 2) in the ∼20bp intronic noncoding region adjacent to the splice acceptor site, and indels (N = 1) in the exonic region. Patients harboring METex14 skipping tended to be older than others. In most cases, METex14 skipping were exclusive to other tumor driver alterations, however, we detected one case with METex14 skipping and a concurrent KRAS mutation. In survival analysis, we identified METex14 skipping as an unfavorable factor for Disease Free Survival (DFS) of PSCs. CONCLUSION: Although a high concordance of 96.1% was observed for DNA- and RNA-based NGS in detecting METex14 skipping, RNA-based sequencing appears the most accurate method, because some somatic variants not covering METex14 splices sites might also induce skipping. Without targeted treatment, patients with METex14 skipping had a shorter DFS. Because of the clinical significance of METex14 skipping and emerging effective treatment with MET TKI, the clinical screening for METex14 skipping should be encouraged, particularly in PSC patients who have poor prognosis with no effective treatments.

Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.

Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.

Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing.

Gastric cancer (GC) is the second most common cause of cancer-related deaths. It is known to be a heterogeneous disease with several molecular and histological subtypes. Here we perform whole-genome sequencing of 49 GCs with diffuse (N=31) and intestinal (N=18) histological subtypes and identify three mutational signatures, impacting TpT, CpG and TpCp[A/T] nucleotides. The diffuse-type GCs show significantly lower clonality and smaller numbers of somatic and structural variants compared with intestinal subtype. We further divide the diffuse subtype into one with infrequent genetic changes/low clonality and another with relatively higher clonality and mutations impacting TpT dinucleotide. Notably, we discover frequent and exclusive mutations in Ephrins and SLIT/ROBO signalling pathway genes. Overall, this study delivers new insights into the mutational heterogeneity underlying distinct histologic subtypes of GC that could have important implications for future research in the diagnosis and treatment of GC.