The high frequency of de novo promoter methylation in synchronous primary endometrial and ovarian carcinomas.
OBJECTIVE
The methylation status of hMLH1, CDKN2A, and MGMT was investigated in a panel of synchronous cancers of the ovary and endometrium, fulfilling the clinicopathologic criteria for independent primary tumors to define the possible role of epigenetic mechanisms in the development of these cancers.


METHODS
Bisulfite-converted DNA from 31 tumors (13 endometrial and 18 ovarian carcinomas) and from matched normal tissue of 13 patients was analyzed by a methylation-specific PCR assay at the CpG-rich 5' regions of all three genes. In all tumors, we also investigated the presence of microsatellite instability and hMLH1 immunohistochemical expression in relation to hMLH1 hypermethylation status.


RESULTS
Methylation of hMLH1, CDKN2A, and MGMT was detected in 39%, 41%, and 48% of endometrial and ovarian tumors, respectively. hMLH1 hypermethylation was observed in all tumors of five patients, and it was invariably associated with loss of hMLH1 protein and presence of microsatellite instability. CDKN2A and MGMT methylation was randomly detected among both endometrial (45% and 24% of cases, respectively) and ovarian carcinomas (39% and 39% of cases, respectively). Concordant methylation at two or three genes was observed in 35% of cases.


CONCLUSIONS
Epigenetic inactivation of hMLH1, CDKN2A, and MGMT may be a common and early event in the development of synchronous primary endometrial and ovarian carcinomas and may qualify as a marker of a field cancerization encompassing the ovary and endometrium. Detection of MGMT hypermethylation may be useful to define a set of gynecologic malignancies with a specific sensitivity to alkylating chemotherapy.
Furlan
Daniela
D
Anatomic Pathology Unit, Department of Human Morphology, University of Insubria, Varese, Italy. daniela.furlan@uninsubria.it
Carnevali
Ileana
I
Marcomini
Barbara
B
Cerutti
Roberta
R
Dainese
Emanuele
E
Capella
Carlo
C
Riva
Cristina
C
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009367:Neoplasm Staging; D009378:Neoplasms, Multiple Primary / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes