2026-04-17T16:04:10Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1559432025-12-05T09:34:12Zcom_2072_1057col_2072_478799col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Belhadj, Sami author Moutinho, Cátia author Mur, Pilar author Llinàs-Arias, Pere author Pérez Salvia, Montserrat author Pons, Tirso author Pineda Riu, Marta author Brunet, Joan author Navarro, Matilde author Esteller, Manel author Valle Velasco, Laura author 2020-04-20T09:53:12Z 2020-04-20T09:53:12Z 2019-04-10 2020-04-20T09:53:12Z Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research. Càncer colorectal Genètica Reparació de l'ADN Metilació Cèl·lules germinals Colorectal cancer Genetics DNA repair Methylation Germ cells Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer