RT Journal Article
SR Electronic
T1 Molecular Analysis of Endometrial Tumorigenesis: Importance of Complex Hyperplasia Regardless of Atypia
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5772
OP 5783
DO 10.1158/1078-0432.CCR-09-0506
VO 15
IS 18
A1 Nieminen, Taina T.
A1 Gylling, Annette
A1 Abdel-Rahman, Wael M.
A1 Nuorva, Kyösti
A1 Aarnio, Markku
A1 Renkonen-Sinisalo, Laura
A1 Järvinen, Heikki J.
A1 Mecklin, Jukka-Pekka
A1 Bützow, Ralf
A1 Peltomäki, Päivi
YR 2009
UL http://clincancerres.aacrjournals.org/content/15/18/5772.abstract
AB Purpose: 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.Experimental Design: 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. (Clin Cancer Res 2009;15(18):5772–83)