Polymorphisms in genes hydroxysteroid-dehydrogenase-17b type 2 and type 4 and endometrial cancer risk

Abstract

Objective-Hydroxysteroid-dehydrogenase-17b (HSD17b) genes control the last step in estrogen biosynthesis. The isoenzymes HSD17b2 and HSD17b4 in the uterus preferentially catalyze the conversion of estradiol, the most potent and active form of estrogen, to estrone, the inactive form of estrogen. Endometrial adenocarcinoma is linked to excessive exposure to estrogens. We hypothesized that single nucleotide polymorphisms (SNPs) in genes HSD17b2 and HSD17b4 may alter the enzyme activity, estradiol levels and risk of disease.Methods-Pairwise tag SNPs were selected from the HapMap Caucasian database to capture all known common (minor allele frequency>0.05) genetic variation with a correlation of at least 0.80. Forty-eight SNPs were genotyped in the case-control studies nested within the Nurses' Health Study (NHS) (cases=544, controls=1296) and the Women's Health Study (WHS) (cases=130, controls=389). The associations with endometrial cancer were examined using conditional logistic regression to estimate odds ratio and 95% confidence intervals adjusted for known risk factors. Results from the two studies were pooled using fixed effects models. We additionally investigated Correspondence to: Stalo Karageorgi, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. Fax: +617-432-1722, skarageo@hsph.harvard.edu. Conflict of interest statementThe authors declare that there are no conflicts of interest. Author contributionsAll authors contributed to this study and approved the enclosed final manuscript. S.K. performed all analyses, assisted with study design, and prepared the manuscript; M.McG. assisted with study design, data analysis, and manuscript editing; and I.L., J.B, P.K, and I.DV. were involved in all stages of this project, including obtaining funding, study design, data collection, statistical support, and manuscript editing.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. whether SNPs are predictive of plasma estradiol and estrone levels in the NHS using linear regression. NIH Public AccessResults-Four intronic SNPs were significantly associated with endometrial cancer risk (p-value <0.05). After adjustment for multiple testing, we did not observe any significant associations between SNPs and endometrial cancer risk or plasma hormone levels.Conclusions-This is the first study to comprehensively evaluate variation in HSD17b2 and HSD17b4 in relation to endometrial cancer risk. Our findings suggest that variation in HSD17b2 and HSD17b4 does not substantially influence the risk of endometrial cancer in Caucasians.

Variations in sex hormone metabolism genes, postmenopausal hormone therapy and risk of endometrial cancer

“…Consistent with our observation of no association, Setiawan et al found no overall association between HSD17B1 SNPs or haplotypes and endometrial cancer risk in a nested case control study within the NHS 44. Our findings on HSD17B2 were consistent with a recent study by Karageorgi et al45 and Low et al,31 which found no significant association between HSD17B2 variations and endometrial cancer.…”

Gene regulatory network inference: evaluation and application to ovarian cancer allows the prioritization of drug targets

“…The mechanism of regulation for this enzyme is not known. Previous studies have shown abnormally elevated levels of estradiol in cancer tissue, causing cell proliferation and tumor growth [65]. …”

Environmental Chemical Exposure May Contribute to Uterine Cancer Development

“…Another way by which TBBPA may enhance estrogen activity in rats is suggested by the finding that TBBPA inhibits hydroxysteroid-dehydrogenase-17β (HSD17β) in in vitro assays (NIH Molecular Libraries Screening Center Network, 2014 (accessed)). HSD17β converts active estradiol to less active estrone (Blom et al , 2001, Karageorgi et al , 2011), and, thus, a TBBPA-induced inhibition of HSD17β could increase estrogen activity. Elevated or prolonged estrogen levels in the uterus, could result in increased levels of mutagenic estrogen metabolites, such as catechols, capable of forming DNA adducts (Liehr, 2000) and elevating the risk for genetic damage (Cavalieri and Rogan, 2014).…”

“…In humans, formation of estrogen sulfoconjugates results in loss of binding to the estrogen receptor as well as increased renal excretion of estrogen (Raftogianis et al 2000). By competing with estrogen for sulfotransferase, TBBPA exposure could decrease estrogen excretion, resulting in elevated levels of the hormone in the uterus, and, thus, increase the carcinogenic risk at this site (Karageorgi et al 2011). TBBPA-induced uterine tumors were not seen in mice, and this may be because estrogen homeostasis is less affected in mice than in rats due to differences in the capacity and/or capability of conjugating enzymes (Burka, Sanders, and Matthews 1996).…”