Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers

Marc Riffet (1, 2) , Yassine Eid (3, 4) , Maxime Faisant (1) , Audrey Fohlen (2, 5) , Benjamin Menahem (3, 6) , Arnaud Alves (3, 6) , Fatéméh Dubois (2, 1) , Guénaëlle Levallet (2, 1) , Céline Bazille (2, 1)

1 Département de Pathologie [CHU Caen]
2 ISTCT - Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales
3 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
4 Elsan Polyclinique du Parc - Caen
5 Service de Radiologie [CHU Caen]
6 Service de Chirurgie Viscérale et Digestive [CHU Caen]

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.

Mots clés: colon cancers; RASSF/Hippo pathway; molecular biomarker

Domaines: Cancer; Hépatologie et Gastroentérologie; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Marc Riffet, Yassine Eid, Maxime Faisant, Audrey Fohlen, Benjamin Menahem, et al.. Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers. Cancers, 2021, 13 (23), pp.5957. ⟨10.3390/cancers13235957⟩. ⟨hal-03467069⟩