Frequent HOXA11 and THBS2 Promoter Methylation, and a Methylator Phenotype in Endometrial Adenocarcinoma

• Published in: Clinical cancer research Vol. 9; no. 6; pp. 2277 - 2287
• Main Authors: WHITCOMB, Bradford P, MUTCH, David G, HERZOG, Thomas J, RADER, Janet S, GIBB, Randall K, GOODFELLOW, Paul J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-06-2003
• Subjects: Adenocarcinoma - genetics; beta Catenin; Biological and medical sciences; Cell Line, Tumor; Cytoskeletal Proteins - genetics; DNA Methylation; Endometrial Neoplasms - genetics; Female; Female genital diseases; Genes, p16; Gynecology. Andrology. Obstetrics; Homeodomain Proteins - genetics; Humans; Medical sciences; Phenotype; Promoter Regions, Genetic; Thrombospondin 1 - genetics; Thrombospondins - genetics; Trans-Activators - genetics; Tumors; Adenocarcinoma; Human; Prognosis; Transcription promoter; Malignant tumor; In vitro; Female genital diseases; Phenotype; Uterine diseases; Female; Predictive factor; Methylation; Endometrium
• ISSN: 1078-0432; 1557-3265

Purpose: This study was designed to determine whether there is a methylator phenotype in stage I and II endometrioid endometrial adenocarcinoma,
and if so, whether methylation correlates with recurrence.
Experimental Design: Bisulfite-converted DNAs from 24 stage I and II primary cancers (12 recurrent and 12 nonrecurrent), and 5 endometrial cancer
cell lines were analyzed for methylation in the promoter regions of seven genes. A methylation index (MeI) was calculated
for each tumor. Frequent HOXA11 and THBS2 methylation prompted analysis of case-matched bloods and 25 additional nonrecurrent primary cancers. Statistical analysis
included Fisher’s exact and Student t tests.
Results: Rates of methylation in the initial tumor series were as follows: HOXA11 , 70.8%; THBS2 , 62.5%; MLH1 , 33.3%; CTNNB1 , 16.7%; VDR , 4.2%; CDKN2A , 4.2%; and THBS1 , 0%. There was no difference in the MeI of recurrent and nonrecurrent cases. However, cell lines had higher mean MeI. High
rates of HOXA11 and THBS2 methylation were confirmed in the additional nonrecurrent tumors. None of the 24 case-matched bloods had HOXA11 methylation, whereas three blood DNAs showed THBS2 methylation. There was a statistically significant difference in the rate of HOXA11 methylation in recurrent and nonrecurrent tumors ( P = 0.0167).
Conclusions: Endometrial adenocarcinomas have a methylator phenotype. No correlation between MeI and clinicopathologic variables in early
stage tumors was observed. High rates of methylation were found in the HOXA11 and THBS2 promoter regions. HOXA11 promoter methylation was significantly more frequent in recurrent than nonrecurrent cases. HOXA11 methylation in early stage endometrial cancer is associated with poor outcome.