RESUMO
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.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/genética , Idoso , Estudos de Coortes , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Helicobacter pylori/genética , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Componente Principal , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Neoplasias Gástricas/terapia , Análise Serial de Tecidos , Pesquisa Translacional Biomédica , Resultado do Tratamento , Proteína Supressora de Tumor p53/genéticaRESUMO
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.
