Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia.
OBJECTIVE
Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression.


METHODS
Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples).


RESULTS
Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma.


CONCLUSIONS
Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma.
Nieminen
Taina T
TT
Department of Medical Genetics, University of Helsinki, Helsinki, Finland. taina.nieminen@helsinki.fi
Gylling
Annette
A
Abdel-Rahman
Wael M
WM
Nuorva
Kyösti
K
Aarnio
Markku
M
Renkonen-Sinisalo
Laura
L
Järvinen
Heikki J
HJ
Mecklin
Jukka-Pekka
JP
Bützow
Ralf
R
Peltomäki
Päivi
P
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008745:Methylation; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis
D014408:Biomarkers, Tumor