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J.
Cancer Mol. 4: 123-127, 2008
[Research
Paper]
Methylation Profiles of hMLH1 Proximal Promoter in Colorectal
Tumor Progression
Romain
Marignol, Jeanne Ramos, Pascal Pujol, Thierry Maudelonde, and Jean-Marc
Rey
Laboratoire de Biologie Cellulaire et Hormonale, Hôpital Arnaud de
Villeneuve, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier cedex
5, France [R. Marignol, T. Maudelonde, J.-M. Rey]; Laboratoire
d'Anatomie Pathologique, Hôpital Gui de Chauliac, 2 avenue Bertin Sans,
34295 Montpellier cedex 5, France [J. Ramos]; Service de Génétique
Médicale, UF d'Oncogénétique, Hôpital Arnaud de Villeneuve, 371 avenue
du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France [P. Pujol]
Abstract:
AIM:
Even though hereditary colorectal cancer (CRC) risk could be predicted
in healthy siblings when a mismatch-repair germline mutation is found,
no biologic test is available to predict sporadic CRCs. In these
tumors, methylation of the whole hMLH1 promoter leading to the
lack of hMLH1 protein expression has been related to carcinogenesis.
The aim of this study was to identify a region in hMLH1 promoter
which methylation may confer to benign lesion a high risk of
carcinogenesis.
METHODS:
To test the methylation status of the proximal hMLH1 promoter, we
analyzed tumor samples obtained from 18 patients [6 showing benign
polyps with microsatellite stability (MSS), 6 showing MSS CRCs and 6
showing CRCs with microsatellite instability (MSI)] by bisulfite
sequencing.
RESULTS:
All tissues tested showed methylated CpG(s) 43 and 44. Among MSI CRCs,
3 showed a methylated status and no hMLH1 staining, and 3 showed an
unmethylated status and hMLH1 staining. One benign polyp showed CpG(s)
1 to 37 methylated and 1 CRC sample with MSS status showed CpG(s) 1 to
23 methylated. Immunohistochemistry showed large areas with loss of
hMLH1 expression in the benign polyp even though hMLH1 was detected in
the CRC tissue sample with MSS status.
CONCLUSION:
The methylation of CpG(s) located in the 5' end of the
hMLH1 promoter until CpG 37 may be an early event of
colorectal carcinogenesis. The hMLH1 promoter region containing
CpG(s) 23 to 37 might be a target zone to optimize a predictive
bisulfite sequencing test to identify polyps with high risk of
carcinogenesis.
(Keywords: colorectal
cancer; methylation profile; hMLH1; polyp; promoter)
Received 7/11/08; Revised 9/19/08; Accepted 9/26/08.
1Correspondence:
Dr. Jean-Marc Rey, Laboratoire de Biologie Cellulaire et Hormonale,
Hopital Arnaud de Villeneuve, 371 avenue du Doyen Gaston Giraud, 34295
Montpellier cedex 5, France. Phone: 33-467-335877. Fax: 33-467-339590.
E-mail:
jm-rey@chu-montpellier.fr
2Abbreviations:
CRC, colorectal cancer; HNPCCs, hereditary non-polyposis colorectal
cancers; MMR, mismatch repair; MSI, microsatellite instability; MSS,
microsatellite stability.
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