Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers

被引：46

作者：

Svrcek, Magali ^{[2
,3
]}

Buhard, Olivier ^{[2
,3
]}

Colas, Chrystelle ^{[2
,3
,4
]}

Coulet, Florence ^{[2
,4
]}

Dumont, Sylvie ^{[2
]}

Massaoudi, Illiasse ^{[3
]}

Lamri, Amel ^{[2
,3
]}

Hamelin, Richard ^{[2
,3
]}

Cosnes, Jacques ^{[2
,5
]}

Oliveira, Carla ^{[6
]}

Seruca, Raquel ^{[6
]}

Gaub, Marie-Pierre ^{[7
]}

Legrain, Michele ^{[7
]}

Collura, Ada ^{[2
,3
]}

Lascols, Olivier ^{[2
,8
]}

Tiret, Emmanuel ^{[2
,9
]}

Flejou, Jean-Francois ^{[2
,3
]}

Duval, Alex ^{[1
,2
,3
]}

机构：

[1] Hop St Antoine, AP HP, Equipe Instabil Microsatellites & Canc, Serv Anat & Cytol Pathol,INSERM,UMRS 938, F-75571 Paris 12, France

[2] Univ Paris 06, Paris, France

[3] INSERM, UMR S 938, Ctr Rech St Antoine, Equipe Instabil Microsatellites & Canc, Paris, France

[4] Hop La Pitie Salpetriere, AP HP, Serv Oncogenet, Paris, France

[5] Hop St Antoine, AP HP, Serv Gastroenterol & Nutr, F-75571 Paris 12, France

[6] Univ Porto IPATIMUP, Inst Patol & Immunol Mol, Oporto, Portugal

[7] INSERM, U682, Strasbourg, France

[8] Hop St Antoine, AP HP, Serv Biochim, F-75571 Paris 12, France

[9] Hop St Antoine, AP HP, Serv Chirurg Viscerale, F-75571 Paris 12, France

来源：

GUT | 2010年 / 59卷 / 11期

关键词：

LEVEL MICROSATELLITE INSTABILITY; PROMOTER HYPERMETHYLATION; ALKYLATING AGENT; G-C; MUTATIONS; GENE; EXPRESSION; PHENOTYPE; MLH1; CPG;

D O I：

10.1136/gut.2009.194787

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background and aims O-6-Methylguanine-DNA methyltransferase (MGMT) removes methyl adducts from O-6-guanine. Known as methylation tolerance, selection for mismatch repair (MMR)-deficient cells that are unable to initiate lethal processing of O-6-methylguanine-induced mismatches in DNA is observed in vitro as a consequence of MGMT deficiency. It was therefore hypothesised that an MGMT field defect may constitute a preneoplastic event for the development of MMR-deficient tumours displaying microsatellite instability (MSI). Methods MGMT expression was investigated by immunohistochemistry and the methylation status of the gene promoter by PCR in neoplastic, adjacent and distant mucosal tissues of patients with MSI or non-MSI (MSS) colorectal cancer (CRC). The cancers were familial (42 MSI, 13 MSS) or sporadic (40 MSI, 49 MSS) in origin, or arose in the context of inflammatory bowel disease (IBD; 13 MSI, 36 MSS). Colonic mucosa from patients with diverticulitis (n=20) or IBD (n=39 in 27 patients) without cancer served as controls. Results Loss of MGMT expression was more frequent in MSI than MSS CRC (p=0.047). In comparison with MSS tumours, MSI CRC occurred more frequently adjacent to patches of mucosa that lacked MGMT expression (p=0.002). Overall, loss of MGMT expression was associated with MGMT gene promoter methylation (p=0.03). Conclusion MGMT field defects are more frequently associated with MSI than MSS CRC. These findings indicate that methylation tolerance may be a crucial initiating step prior to MMR deficiency in the development of MSI CRC in familial, sporadic and IBD settings.

引用

页码：1516 / 1526

页数：11