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1.
Br J Cancer ; 126(11): 1595-1603, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35197584

RESUMO

BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Instabilidade de Microssatélites , Neoplasias Encefálicas , Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Mutação , Síndromes Neoplásicas Hereditárias
2.
Carcinogenesis ; 41(11): 1498-1506, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-32911537

RESUMO

Accumulating evidence supports the fact that the mere presence of mucinous differentiation in colorectal cancer (CRC), rather than its proportion, is a more accurate representative of a particular CRC subtype with distinct clinical and molecular features. In addition, the prognostic significance of the mucinous carcinoma (MC) subtype remains poorly understood and biomarkers have been barely explored in this disease. Herein, we have performed a systematic and comprehensive analysis in MCs and non-MCs and identified a panel of microRNAs (miRNAs) that are differentially expressed between these two subtypes of CRC. Next, we interrogated their clinical significance and demonstrated their robust diagnostic and prognostic clinical ability in CRCs with mucinous differentiation. Finally, we established an integrative risk-assessment model by combining the miRNA-based risk scores together with TNM staging, which was a superior predictor of prognosis in mucinous CRC patients. Collectively, we report a novel miRNA biomarker panel for the identification and predicting survival in CRC patients with mucinous differentiation.


Assuntos
Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/genética , Diferenciação Celular , Neoplasias Colorretais/patologia , MicroRNAs/genética , Adenocarcinoma Mucinoso/genética , Idoso , Neoplasias Colorretais/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
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