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Impact de la génétique moléculaire sur le dépistage du cancer colorectal héréditaire non polypoïde

The impact of molecular genetics on screening of hereditary non-polyposis colorectal cancer

  • Published:
Acta Endoscopica

Résumé

Le syndrome HPNCC (Cancer colorectal héréditaire non polypoïde) connu aussi sous l’appellation de «Syndrome de Lynch» est une prédisposition précancéreuse autosomale dominante responsable d’environ 2 à 5 % des cancers colorectaux (CCR). En outre, le risque de développer des lésions malignes extra coliques est très élevé dans ce syndrome. Le syndrome HPNCC résulte de mutations de lignée germinale au niveau d’au moins un des cinq gènes codant les protéines, ce qui conduit à un défaut d’appariement au niveau du complexe MMR. Ce complexe (avec d’autres) assure la stabilité du génome au cours de la division cellulaire. Les mutations au niveau d’un seul des gènes MMR conduit à une perte de capacité réparatrice du complexe MMR avec pour conséquence une instabilité de l’ADN encore appelée instabilité microsatellite (MSI).

La reconnaissance des gènes MMR permet l’identification des patients atteints de syndrome HNPCC, entité encore gênée par le manque d’un phénotype non équivoque de cette maladie. Par conséquent, ceci a conduit à une définition clinique du syndrome HNPCC (c’est-à-dire porteurs ou non de tumeurs extra-coliques propres au syndrome). Par ailleurs, la surveillance des personnes à risque de HNPCC pourrait être nettement améliorée.

L’identification des gènes MMR et la compréhension de leur rôle favorisent une meilleure connaissance de la carcinogenèse du CCR. En dehors des tumeurs dues au syndrome HNPCC, plus de 20 % des CCR sporadiques sont causés par des déficiences du complexe MMR. Nous savons à présent que ces cancers se développent différemment des 80 % de cancers restants. A l’avenir, ces différences devraient influencer leur traitement.

Summary

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant precancerous condition accounting for about 2–5 % of colorectal cancers. In addition, the risk to develop extracolonic malignancies is markedly elevated in affected persons. HNPCC is caused by germline mutations in one of at least five genes coding for proteins which build up the human mismatch repair (MMR) complex. This complex (among others) cares for stability of the genome during cell division. Mutations in one of the MMR genes lead to loss of repair capacity of the MMR complex and subsequently to a type of DNA instability which is called microsatellite instability (MSI).

Identification of the MMR genes enabled the identification of HNPCC patients, which is hampered by lack of an unambiguous phenotype of the disease. Thus, it helped also with the clinical definition of HNPCC (e. g., which extracolonic tumours belong to the syndrome and which do not). Furthermore, surveillance in persons at risk for HNPCC could be clearly improved.

Identification of the MMR genes and understanding of their function, on the other side, has led to an expansion of our knowledge about colorectal carcinogenesis. Not only tumours in HNPCC patients, but up to 20 % of sporadic colorectal cancers are caused by defects of the mismatch repair complex. We now know that these tumours develop differently from the remaining 80 % of CRC. In the future, these differences may even influence our treatment.

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  1. R. Caspari

    Present address: Dept. of Oncology, Bayerwaldklinik, Cham, Germany

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    Ch. Lamberti

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Caspari, R., Lamberti, C. Impact de la génétique moléculaire sur le dépistage du cancer colorectal héréditaire non polypoïde. Acta Endosc 37, 165–179 (2007). https://doi.org/10.1007/BF02961788

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