TY - JOUR
T1 - Endometrial biomarkers in premenopausal women with obesity
T2 - an at-risk cohort
AU - Dottino, Joseph A.
AU - Zhang, Qian
AU - Loose, David S.
AU - Fellman, Bryan
AU - Melendez, Brenda D.
AU - Borthwick, Mikayla S.
AU - McKenzie, Laurie J.
AU - Yuan, Ying
AU - Yang, Richard K.
AU - Broaddus, Russell
AU - Lu, Karen H.
AU - Soliman, Pamela T.
AU - Yates, Melinda S.
N1 - Funding Information:
This study was supported in part by the MD Anderson Uterine Cancer Specialized Program of Research Excellence (P50CA098258 to R.R.B. and K.H.L.) and the MD Anderson Cancer Center Support Grant (CA016672), which supports the Biostatistics Resource Group. J.A.D. was supported by a T32 training grant for gynecologic oncology (CA101642). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under grant number R24HD102061.
Funding Information:
Y.Y. reports serving as a consultant for Boehringer Ingelheim Pharmaceuticals, Servier Pharmaceuticals, Amgen Inc, Deciphera Pharmaceuticals, Ono Pharmaceuticals, Citius Pharmaceuticals, and Midas Medical Technologies outside the submitted work. P.T.S. reports receiving unrelated research trial support from Novartis and Incyte and serving on the advisory board for Tesaro. The remaining authors report no conflict of interest.This study was supported in part by the MD Anderson Uterine Cancer Specialized Program of Research Excellence (P50CA098258 to R.R.B. and K.H.L.) and the MD Anderson Cancer Center Support Grant (CA016672), which supports the Biostatistics Resource Group. J.A.D. was supported by a T32 training grant for gynecologic oncology (CA101642). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under grant number R24HD102061.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/3
Y1 - 2021/3
N2 - Background: Obesity is a well-known risk factor for endometrial cancer, but the mechanisms of obesity-related carcinogenesis are not well defined, particularly for premenopausal women. With the continuing obesity epidemic, increases in the incidence of endometrial cancer and a younger age of diagnosis are often attributed to a hyperestrogenic state created by hormone production in adipose tissue, but significant knowledge gaps remain. The balance of estrogen-responsive signals has not been defined in the endometrium of premenopausal women with obesity, where obesity may not create hyperestrogenism in the context of ovaries being the primary source of estrogen production. Obesity is associated with a state of low-grade, chronic inflammation that can promote tumorigenesis, and it is also known that hormonal changes alter the immune microenvironment of the endometrium. However, limited research has been conducted on endometrial immune-response changes in women who have an increased risk for cancer due to obesity. Objective: Endometrial estrogen-regulated biomarkers, previously shown to be dysregulated in endometrial cancer, were evaluated in a cohort of premenopausal women to determine if obesity is associated with differences in the biomarker expression levels, which might reflect an altered risk of developing cancer. The expression of a multiplexed panel of immune-related genes was also evaluated for expression differences related to obesity. Study Design: Premenopausal women with a body mass index of ≥30 kg/m2 (n=97) or a body mass index of ≤25 kg/m2 (n=33) were prospectively enrolled in this cross-sectional study, which included the assessment of serum metabolic markers and a timed endometrial biopsy for pathologic evaluation, hormone-regulated biomarker analysis, and immune response gene expression analysis. Medical and gynecologic histories were obtained. Endometrial gene expression markers were also compared across the body mass index groups in a previous cohort of premenopausal women with an inherited cancer risk (Lynch syndrome). Results: In addition to known systemic metabolic differences, histologically normal endometria from women with obesity showed a decrease in gene expression of progesterone receptor (P=.0027) and the estrogen-induced genes retinaldehyde dehydrogenase 2 (P=.008), insulin-like growth factor 1 (P=.016), and survivin (P=.042) when compared with women without obesity. The endometrial biomarkers insulin-like growth factor 1, survivin, and progesterone receptor remained statistically significant in multivariate linear regression models. In contrast, women with obesity and Lynch syndrome had an increased expression of insulin-like growth factor 1 (P=.017). There were no differences in endometrial proliferation, and limited endometrial immune differences were observed. Conclusion: When comparing premenopausal women with and without obesity in the absence of endometrial pathology or an inherited cancer risk, the expression of the endometrial biomarkers does not reflect a local hyperestrogenic environment, but it instead reflects a decreased cancer risk profile that may be indicative of a compensated state. In describing premenopausal endometrial cancer risk, it may be insufficient to attribute a high-risk state to obesity alone; further studies are warranted to evaluate individualized biomarker profiles for differences in the hormone-responsive signals or immune response. In patients with Lynch syndrome, the endometrial biomarker profile suggests that obesity further increases the risk of developing cancer.
AB - Background: Obesity is a well-known risk factor for endometrial cancer, but the mechanisms of obesity-related carcinogenesis are not well defined, particularly for premenopausal women. With the continuing obesity epidemic, increases in the incidence of endometrial cancer and a younger age of diagnosis are often attributed to a hyperestrogenic state created by hormone production in adipose tissue, but significant knowledge gaps remain. The balance of estrogen-responsive signals has not been defined in the endometrium of premenopausal women with obesity, where obesity may not create hyperestrogenism in the context of ovaries being the primary source of estrogen production. Obesity is associated with a state of low-grade, chronic inflammation that can promote tumorigenesis, and it is also known that hormonal changes alter the immune microenvironment of the endometrium. However, limited research has been conducted on endometrial immune-response changes in women who have an increased risk for cancer due to obesity. Objective: Endometrial estrogen-regulated biomarkers, previously shown to be dysregulated in endometrial cancer, were evaluated in a cohort of premenopausal women to determine if obesity is associated with differences in the biomarker expression levels, which might reflect an altered risk of developing cancer. The expression of a multiplexed panel of immune-related genes was also evaluated for expression differences related to obesity. Study Design: Premenopausal women with a body mass index of ≥30 kg/m2 (n=97) or a body mass index of ≤25 kg/m2 (n=33) were prospectively enrolled in this cross-sectional study, which included the assessment of serum metabolic markers and a timed endometrial biopsy for pathologic evaluation, hormone-regulated biomarker analysis, and immune response gene expression analysis. Medical and gynecologic histories were obtained. Endometrial gene expression markers were also compared across the body mass index groups in a previous cohort of premenopausal women with an inherited cancer risk (Lynch syndrome). Results: In addition to known systemic metabolic differences, histologically normal endometria from women with obesity showed a decrease in gene expression of progesterone receptor (P=.0027) and the estrogen-induced genes retinaldehyde dehydrogenase 2 (P=.008), insulin-like growth factor 1 (P=.016), and survivin (P=.042) when compared with women without obesity. The endometrial biomarkers insulin-like growth factor 1, survivin, and progesterone receptor remained statistically significant in multivariate linear regression models. In contrast, women with obesity and Lynch syndrome had an increased expression of insulin-like growth factor 1 (P=.017). There were no differences in endometrial proliferation, and limited endometrial immune differences were observed. Conclusion: When comparing premenopausal women with and without obesity in the absence of endometrial pathology or an inherited cancer risk, the expression of the endometrial biomarkers does not reflect a local hyperestrogenic environment, but it instead reflects a decreased cancer risk profile that may be indicative of a compensated state. In describing premenopausal endometrial cancer risk, it may be insufficient to attribute a high-risk state to obesity alone; further studies are warranted to evaluate individualized biomarker profiles for differences in the hormone-responsive signals or immune response. In patients with Lynch syndrome, the endometrial biomarker profile suggests that obesity further increases the risk of developing cancer.
KW - Lynch syndrome
KW - endometrial cancer
KW - obesity
KW - premenopausal
KW - prevention
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U2 - 10.1016/j.ajog.2020.08.053
DO - 10.1016/j.ajog.2020.08.053
M3 - Article
C2 - 32835719
AN - SCOPUS:85093702466
SN - 0002-9378
VL - 224
SP - 278.e1-278.e14
JO - American journal of obstetrics and gynecology
JF - American journal of obstetrics and gynecology
IS - 3
ER -