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Title: Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
Author: Belhadj, Sami
Moutinho, Cátia
Mur, Pilar
Llinàs-Arias, Pere
Pérez Salvia, Montserrat
Pons, Tirso
Pineda Riu, Marta
Brunet, Joan
Navarro, Matilde
Esteller, Manel
Valle Velasco, Laura
Keywords: Càncer colorectal
Reparació de l'ADN
Cèl·lules germinals
Colorectal cancer
DNA repair
Germ cells
Issue Date: 10-Apr-2019
Publisher: Elsevier B.V.
Abstract: 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.
Note: Versió postprint del document publicat a:
It is part of: Cancer Letters, 2019, vol. 447, p. 86-92
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ISSN: 0304-3835
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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