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
- Magali Svrcek1,2,3,
- Olivier Buhard2,3,
- Chrystelle Colas2,3,4,
- Florence Coulet2,4,
- Sylvie Dumont2,
- Illiasse Massaoudi3,
- Amel Lamri2,3,
- Richard Hamelin2,3,
- Jacques Cosnes2,5,
- Carla Oliveira6,
- Raquel Seruca6,
- Marie-Pierre Gaub7,
- Michèle Legrain7,
- Ada Collura2,3,
- Olivier Lascols2,8,
- Emmanuel Tiret2,9,
- Jean-François Fléjou1,2,3,
- Alex Duval2,3
- 1AP-HP, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France
- 2Université Pierre et Marie Curie-Paris6, Paris, France
- 3INSERM, UMR S 938-Centre de Recherche Saint-Antoine, Equipe ‘Instabilité des Microsatellites et Cancers’, Paris, France
- 4AP-HP, Hôpital Pitié-Salpêtrière, Service d'Oncogénétique, Paris, France
- 5AP-HP, Hôpital Saint-Antoine, Service de Gastroentérologie et Nutrition, Paris, France
- 6Instituto de Patologia e Immunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal
- 7INSERM, U682, Développement et Physiopathologie de l'Intestin et du Pancréas, Strasbourg, France
- 8AP-HP, Hôpital Saint-Antoine, Service de Biochimie, Paris, France
- 9AP-HP, Hôpital Saint-Antoine, Service de Chirurgie Viscérale, Paris, France
- Correspondence to Dr Alex Duval, INSERM UMRS 938, Equipe ‘Instabilité des Microsatellites et Cancers’, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F75571 Paris cedex 12;
- Received 31 July 2009
- Accepted 5 July 2010
Background and aims O6-Methylguanine-DNA methyltransferase (MGMT) removes methyl adducts from O6-guanine. Known as methylation tolerance, selection for mismatch repair (MMR)-deficient cells that are unable to initiate lethal processing of O6-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.
- O6-Methylguanine DNA methyltransferase (MGMT)
- risk factor
- colorectal cancer
- mismatch repair deficiency
- microsatellite instability
Competing interests None.
Ethics approval This study was conducted with the approval of the Human Research Ethics Committee of Saint-Antoine hospital.
Provenance and peer review Not commissioned; externally peer reviewed.