부산대학교 도서관

Simple Summary: Colorectal cancer (CRC) is a major public health issue due to its incidence and mortality. Thus, the development of molecular biomarkers is essential to optimize its therapeutic management. Such markers could be identified among the members of the RASSF/Hippo pathway. Indeed, epigenetic alterations are strongly implicated in colorectal carcinogenesis and this pathway is altered in many cancers, mainly by hypermethylation of the promoter of the gene coding for its members. The objectives of the study were to map the hypermethylation of the RASSF/Hippo pathway promoters in a morphologically, clinically, and prognostically well-characterized population of colon cancers. This first report of a whole systematic analysis of the Hippo pathway in colon cancer highlights RASSF2 gene promoter hypermethylation as a worst prognostic factor and a tool to be sought in clinical practice to improve therapeutic management. The aims of this study were to assess the frequency of promoter hypermethylation of the genes encoding the Ras associated domain family (RASSF)/Hippo pathway, as well as the impact on overall (OS) and progression-free survival (PFS) in a single-center retrospective cohort of 229 patients operated on for colon cancers. Hypermethylation status was investigated by methylation-specific PCR on the promoters of the RASSF1/2, STK4/3 (encoding Mammalian Ste20-like protein 1 and 2 (MST1 and 2), respectively), and LATS1/2 genes. Clinicopathological characteristics, recurrence-free survival, and overall survival were analysed. We found the RASSF/Hippo pathway to be highly silenced in colon cancer, and particularly RASSF2 (86%). The other promoters were hypermethylated with a lesser frequency of 16, 3, 1, 10 and 6%, respectively for RASSF1, STK4, STK3, LATS1, and LATS2 genes. As the hypermethylation of one RASSF/Hippo family member was by no means exclusive from the others, 27% of colon cancers displayed the hypermethylation of at least two RASSF/Hippo member promotors. The median overall survival of the cohort was 60.2 months, and the median recurrence-free survival was 46.9 months. Survival analyses showed a significantly poorer overall survival of patients when the RASSF2 promoter was hypermethylated (p = 0.03). The median OS was 53.5 months for patients with colon cancer with a hypermethylated RASSF2 promoter versus still not reached after 80 months follow-up for other patients, upon univariate analysis (HR = 1.86, [95% CI: 1.05–3.3], p < 0.03). Such difference was not significant for relapse-free survival as in multivariate analysis. A logistic regression model showed that RASSF2 hypermethylation was an independent factor. In conclusion, RASSF2 hypermethylation is a frequent event and an independent poor prognostic factor in colon cancer. This biomarker could be investigated in clinical practice. [ABSTRACT FROM AUTHOR]