| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS | REGISTER |
|
|
|
|
|||||||||||||
|
|
|||||||||||||||
a Cancer
and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute
of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK, b Department of Medical Genetics, Haartman
Institute, University of Helsinki, Finland, c Department of Colorectal Surgery,
John Radcliffe Hospital, Oxford, UK
Correspondence to: Dr Wheeler, wheelerj{at}icrf.icnet.uk
Revised version received 29 March 2000;
Accepted for publication 10
April 2000
INTRODUCTION
Hypermethylation of
the promoter region of the hMLH1 gene is
associated with absent expression of MLH1 protein in sporadic colorectal cancers with microsatellite instability (MSI+), and it has
been proposed that methylation may be a mechanism of inactivation in
Knudson's hypothesis. The incidence of hypermethylation of the
hMLH1 promoter in hereditary non-polyposis
colorectal cancer (HNPCC) versus MSI+ sporadic colorectal cancer was
investigated and compared.
METHODSDNA was available from 10 HNPCC colorectal cancers (median age 58 years, range 39-67) with
germline mutations in hMLH1 and 10 MSI+
sporadic colorectal cancers (mean age 79 years, range 41-85). MSI was
determined by amplification of BAT26 and TGF-
RII. The methylation
status of the hMLH1 promoter was studied by
the polymerase chain reaction (PCR) based
HpaII restriction enzyme assay technique.
Evidence of allelic loss at hMLH1 was searched for in the HNPCC colorectal cancers.
RESULTSAll cases were confirmed to
be MSI+. The promoter region of hMLH1 was
hypermethylated in seven of 10 MSI+ sporadic cancers versus 0 of 10 HNPCC cancers (p<0.002). Evidence of loss of heterozygosity at
hMLH1 was observed in eight of the 10 HNPCC
colorectal cancers.
CONCLUSIONWhile mutations and
allelic loss are responsible for the MSI+ phenotype in HNPCC cancers,
the majority of MSI+ sporadic cancers are hypermethylated in the
promoter region of hMLH1. These data further
support our argument that tumours from HNPCC patients, which almost
always acquire a raised mutation rate, mostly follow a different
pathway from MSI+ sporadic tumours.
This article has been cited by other articles:
|
|
 |
|
  W. Bodmer and L. A. Loeb Genetic Instability Is Not a Requirement for Tumor Development Cancer Res., May 15, 2008; 68(10): 3558 - 3561. [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. O'Dwyer, S. G. Eckhardt, D. G. Haller, J. Tepper, D. Ahnen, S. Hamilton, A. B. Benson III, M. Rothenberg, N. Petrelli, H.-J. Lenz, et al. Priorities in Colorectal Cancer Research: Recommendations From the Gastrointestinal Scientific Leadership Council of the Coalition of Cancer Cooperative Groups J. Clin. Oncol., June 1, 2007; 25(16): 2313 - 2321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Schottenfeld and J. Beebe-Dimmer Alleviating the Burden of Cancer: A Perspective on Advances, Challenges, and Future Directions. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2049 - 2055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Wark, M. P. Weijenberg, P. van 't Veer, G. van Wijhe, M. Luchtenborg, G. N.P. van Muijen, A. F.P.M. de Goeij, R. A. Goldbohm, and P. A. van den Brandt Fruits, Vegetables, and hMLH1 Protein-Deficient and -Proficient Colon Cancer: The Netherlands Cohort Study Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1619 - 1625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.R. Lipton, V. Johnson, C. Cummings, S. Fisher, P. Risby, A.T. Eftekhar Sadat, T. Cranston, L. Izatt, P. Sasieni, S.V. Hodgson, et al. Refining the Amsterdam Criteria and Bethesda Guidelines: Testing Algorithms for the Prediction of Mismatch Repair Mutation Status in the Familial Cancer Clinic J. Clin. Oncol., December 15, 2004; 22(24): 4934 - 4943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Shibata, F. Sato, Y. Mori, K. Perry, J. Yin, S. Wang, Y. Xu, A. Olaru, F. Selaru, K. Spring, et al. Hypermethylation of HPP1 Is Associated with hMLH1 Hypermethylation in Gastric Adenocarcinomas Cancer Res., October 15, 2002; 62(20): 5637 - 5640. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kucherlapati, K. Yang, M. Kuraguchi, J. Zhao, M. Lia, J. Heyer, M. F. Kane, K. Fan, R. Russell, A. M. C. Brown, et al. Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression PNAS, July 23, 2002; 99(15): 9924 - 9929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Kuismanen, A.-L. Moisio, P. Schweizer, K. Truninger, R. Salovaara, J. Arola, R. Butzow, J. Jiricny, M. Nystrom-Lahti, and P. Peltomaki Endometrial and Colorectal Tumors from Patients with Hereditary Nonpolyposis Colon Cancer Display Different Patterns of Microsatellite Instability Am. J. Pathol., June 1, 2002; 160(6): 1953 - 1958. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I M Frayling Methods of molecular analysis: mutation detection in solid tumours Mol. Pathol., April 1, 2002; 55(2): 73 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Duval, M. Reperant, A. Compoint, R. Seruca, G. N. Ranzani, B. Iacopetta, and R. Hamelin Target Gene Mutation Profile Differs between Gastrointestinal and Endometrial Tumors with Mismatch Repair Deficiency Cancer Res., March 1, 2002; 62(6): 1609 - 1612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Esteller, M. F. Fraga, M. Guo, J. Garcia-Foncillas, I. Hedenfalk, A. K. Godwin, J. Trojan, C. Vaurs-Barriere, Y.-J. Bignon, S. Ramus, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis Hum. Mol. Genet., December 1, 2001; 10(26): 3001 - 3007. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS | REGISTER |
