Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers
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...
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MDPI AG
2021-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/23/5957 |
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| author | Marc Riffet Yassine Eid Maxime Faisant Audrey Fohlen Benjamin Menahem Arnaud Alves Fatéméh Dubois Guénaelle Levallet Céline Bazille |
| author_facet | Marc Riffet Yassine Eid Maxime Faisant Audrey Fohlen Benjamin Menahem Arnaud Alves Fatéméh Dubois Guénaelle Levallet Céline Bazille |
| author_sort | Marc Riffet |
| collection | DOAJ |
| description | 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 <i>RASSF1/2</i>, <i>STK4/3</i> (encoding Mammalian Ste20-like protein 1 and 2 (MST1 and 2), respectively), and <i>LATS1/2</i> 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 <i>RASSF1</i>, <i>STK4</i>, <i>STK3</i>, <i>LATS1</i>, and <i>LATS2</i> 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 <i>RASSF2</i> promoter was hypermethylated (<i>p</i> = 0.03). The median OS was 53.5 months for patients with colon cancer with a hypermethylated <i>RASSF2</i> 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], <i>p</i> < 0.03). Such difference was not significant for relapse-free survival as in multivariate analysis. A logistic regression model showed that <i>RASSF2</i> hypermethylation was an independent factor. In conclusion, <i>RASSF2</i> hypermethylation is a frequent event and an independent poor prognostic factor in colon cancer. This biomarker could be investigated in clinical practice. |
| first_indexed | 2024-03-10T04:55:53Z |
| format | Article |
| id | doaj.art-0a34dbe877ff4c5ea4bebd9149928baf |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:55:53Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0a34dbe877ff4c5ea4bebd9149928baf2023-11-23T02:12:09ZengMDPI AGCancers2072-66942021-11-011323595710.3390/cancers13235957Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon CancersMarc Riffet0Yassine Eid1Maxime Faisant2Audrey Fohlen3Benjamin Menahem4Arnaud Alves5Fatéméh Dubois6Guénaelle Levallet7Céline Bazille8Department of Pathology, CHU de Caen, 14000 Caen, FrancePolyclinique du Parc, 14000 Caen, FranceDepartment of Pathology, CHU de Caen, 14000 Caen, FranceNormandie Université, UNICAEN, CEA, CNRS, ISTCT, CERVOxy Group, GIP CYCERON, 14074 Caen, FranceNormandie Université, UNICAEN, INSERM UMR 1086, ANTICIPE, 14000 Caen, FranceNormandie Université, UNICAEN, INSERM UMR 1086, ANTICIPE, 14000 Caen, FranceDepartment of Pathology, CHU de Caen, 14000 Caen, FranceDepartment of Pathology, CHU de Caen, 14000 Caen, FranceDepartment of Pathology, CHU de Caen, 14000 Caen, FranceThe 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 <i>RASSF1/2</i>, <i>STK4/3</i> (encoding Mammalian Ste20-like protein 1 and 2 (MST1 and 2), respectively), and <i>LATS1/2</i> 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 <i>RASSF1</i>, <i>STK4</i>, <i>STK3</i>, <i>LATS1</i>, and <i>LATS2</i> 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 <i>RASSF2</i> promoter was hypermethylated (<i>p</i> = 0.03). The median OS was 53.5 months for patients with colon cancer with a hypermethylated <i>RASSF2</i> 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], <i>p</i> < 0.03). Such difference was not significant for relapse-free survival as in multivariate analysis. A logistic regression model showed that <i>RASSF2</i> hypermethylation was an independent factor. In conclusion, <i>RASSF2</i> hypermethylation is a frequent event and an independent poor prognostic factor in colon cancer. This biomarker could be investigated in clinical practice.https://www.mdpi.com/2072-6694/13/23/5957colon cancersRASSF/Hippo pathwaymolecular biomarker |
| spellingShingle | Marc Riffet Yassine Eid Maxime Faisant Audrey Fohlen Benjamin Menahem Arnaud Alves Fatéméh Dubois Guénaelle Levallet Céline Bazille Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers Cancers colon cancers RASSF/Hippo pathway molecular biomarker |
| title | Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers |
| title_full | Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers |
| title_fullStr | Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers |
| title_full_unstemmed | Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers |
| title_short | Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers |
| title_sort | deciphering promoter hypermethylation of genes encoding for rassf hippo pathway reveals the poor prognostic factor of rassf2 gene silencing in colon cancers |
| topic | colon cancers RASSF/Hippo pathway molecular biomarker |
| url | https://www.mdpi.com/2072-6694/13/23/5957 |
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