Polypose liée à MUTYH

Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors N. Al-Tassan, N.H. Chmiel, J. Maynard, et al (2002) Nat Genet 2:227–32

Résumé

Les défauts liés à une déficience du système BER (Base Excision Repair) n’ont pas été associés à une pathologie génétique humaine. Les mutations des gènes MutM et MutY dans Escherichia coli conduisent à l’accumulation de transversions G:C → T:A (remplacement d’une paire guanine: cytosine par une paire thymine: adénine). L’article rapporte l’étude d’une famille N, présentant plusieurs cas de polyposes multiples avec des cancers colorectaux sans aucune mutation identifiée sur APC. Sur 11 tumeurs provenant de 3 frères malades, 18 inactivations somatiques d’APC ont été identifiées dont 15 étaient des transversions G:C → T:A. Ce ratio était beaucoup plus important que ce qui est habituellement observé dans les CCR sporadiques ou liés à une PAF. L’analyse du gène humain, homologue de mutY, MYH a montré que les frères étaient hétérozygotes composites pour deux mutations G382D et Y185C. Ces mutations affectaient des zones conservées de la séquence de mutY et réduisaient significativement la fonction de la protéine. Les résultats de cette étude confirment que des mutations héritées sur MYH sont responsables des mutations somatiques observées sur APC et impliquent pour la première fois le système BER dans les syndromes prédisposant aux cancers colorectaux.

Abstract

Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C—>A transversions—a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans.

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Correspondence to J. H. Lefevre.

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Lefevre, J.H. Polypose liée à MUTYH. Colon Rectum 7, 107–109 (2013). https://doi.org/10.1007/s11725-013-0448-8

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Mots clés

  • Polypose
  • APC
  • MYH
  • Cancer colorectal

Keywords

  • Polyposis
  • APC
  • MUTYH
  • Colorectal cancer