Age at last birth in relation to risk of endometrial cancer: pooled analysis in the epidemiology of endometrial cancer consortium.

Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (P(trend) < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.

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

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 using fixed effects models. We additionally investigated whether SNPs are predictive of plasma estradiol and estrone levels in the NHS using linear regression. RESULTS: 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.

Reproductive factors and postmenopausal hormone use in relation to endometrial cancer risk in the Nurses' Health Study cohort 1976-2004.

Endometrial cancer is a disease primarily driven by cumulative exposure to estrogen unopposed by progesterone. Reproductive factors associated with changes in endogenous hormone levels and use of exogenous hormones such as postmenopausal hormones influence the risk of disease. The authors used the Nurses' Health Study, comprised of 121,700 nurses, to assess the above associations. Over 28 years of follow-up, 778 adenocarcinoma cases were diagnosed and 1,850,078 person-years were accumulated. Cox proportional hazards models were used to estimate relative risks (RR) and 95% confidence intervals (CI). A late age at menarche decreased the risk independent of body mass index (BMI) (P-trend = 0.02). A late age at menopause increased cancer risk (P-trend = 0.0003). An advanced age at last birth reduced the risk (P-trend < 0.0001), however, an inverse association with age at first birth and parity diminished after adjustment for age at last birth. Compared with never users, an increased risk was observed among long-term (> or =5 years) users of both estrogen (E) (RR = 7.67, 95% CI: 5.57, 10.57) and combined estrogen plus progesterone (E+P) (RR = 1.52, 95% CI: 1.03, 2.23). Normal-weight (BMI < 25) women had the highest risk following E or E+P use (P-interaction-E = 0.0008, P-interaction-E+P = 0.02). The findings from this study underscore the importance of hormonal mechanisms in endometrial carcinogenesis.

A review of adult obesity prevalence, trends, risk factors, and epidemiologic methods in Kuwait.

OBJECTIVE: Kuwait is among the countries with the highest obesity rates worldwide; however, little is known about the state of obesity epidemiology research in Kuwait. In this paper, we therefore review the findings and methodology of studies on the prevalence, trends and risk factors of obesity in Kuwait. METHODS: The PubMed database was searched using the keyword combination: obesity and adults and Kuwait. Out of 111 articles, 39 remained after abstract review, and 18 were selected after full-text review. RESULTS: The studies were all cross-sectional and published in the last fifteen years (1997-2012). The sample size ranged from 177 to 38,611 individuals. Only 30% of studies used random sampling. The prevalence (BMI ≥ 30) in studies with a nationally representative sample ranged from 24% to 48% overall and in adults >50 years was greater than 52%. Rates were significantly higher in women than those in men. Studies that examined trends showed an increase in obesity prevalence between 1980 and 2009. Multiple risk factors including sociocultural factors were investigated in the studies; however, factors were only crudely assessed. CONCLUSION: There is a need for future studies, particularly surveillance surveys and prospective cohort studies utilizing advanced methods, to monitor trends and to comprehensively assess the factors contributing to the obesity epidemic in Kuwait.

Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls.

Genital powder use has been associated with risk of epithelial ovarian cancer in some, but not all, epidemiologic investigations, possibly reflecting the carcinogenic effects of talc particles found in most of these products. Whether risk increases with number of genital powder applications and for all histologic types of ovarian cancer also remains uncertain. Therefore, we estimated the association between self-reported genital powder use and epithelial ovarian cancer risk in eight population-based case-control studies. Individual data from each study were collected and harmonized. Lifetime number of genital powder applications was estimated from duration and frequency of use. Pooled ORs were calculated using conditional logistic regression matched on study and age and adjusted for potential confounders. Subtype-specific risks were estimated according to tumor behavior and histology. 8,525 cases and 9,859 controls were included in the analyses. Genital powder use was associated with a modest increased risk of epithelial ovarian cancer [OR, 1.24; 95% confidence interval (CI), 1.15-1.33] relative to women who never used powder. Risk was elevated for invasive serous (OR, 1.20; 95% CI, 1.09-1.32), endometrioid (OR, 1.22; 95% CI, 1.04-1.43), and clear cell (OR, 1.24; 95% CI, 1.01-1.52) tumors, and for borderline serous tumors (OR, 1.46; 95% CI, 1.24-1.72). Among genital powder users, we observed no significant trend (P = 0.17) in risk with increasing number of lifetime applications (assessed in quartiles). We noted no increase in risk among women who only reported nongenital powder use. In summary, genital powder use is a modifiable exposure associated with small-to-moderate increases in risk of most histologic subtypes of epithelial ovarian cancer.

GSTM1 and GSTT1 copy number variation in population-based studies of endometrial cancer risk.

BACKGROUND: Glutathione S-transferases (GST) detoxify a broad range of carcinogenic metabolites and lack of GSTM1 and GSTT1 activity due to gene deletions are prevalent. The associations of GSTM1 and GSTT1 polymorphisms with endometrial cancer risk have been inconsistent. METHODS: We investigated gene dosage effects of GSTM1 and GSTT1 copy number in 441 endometrial cancer cases and 1,237 matched controls selected from the Nurses' Health Study and Women's Health Study, as well as gene-environment interactions. RESULTS: Carriers of at least 2 GSTT1 genes had an increased risk of endometrial cancer (OR = 1.51, 95% CI = 1.04-2.19; P(trend) = 0.04) compared with women who were GSTT1 null. GSTM1 was not associated with endometrial cancer risk (OR(2/3 vs. 0 copies) = 0.82, 95% CI = 0.52-1.27; P(trend) = 0.41). We did not observe effect modification of either the GSTM1 or GSTT1 association with cancer risk by smoking status, postmenopausal hormone use, or body mass index. CONCLUSIONS: Our results suggested GSTM1 copy number does not influence endometrial cancer risk, whereas higher GSTT1 copy number may be associated with increased risk. Our findings supported that GSTT1 differs in its substrate specificity from GSTM1 and may generate intermediates more genotoxic to endometrial cells than the parent chemical. Future studies are needed to clarify this relationship. IMPACT: We hypothesized risk associated with GST enzymes may differ depending on environmental and/or occupational exposures. Our assessment of gene-environment interactions suggested GSTM1 and GSTT1 are not involved in the in vivo human metabolism of estrogen and its metabolites.

Perineal use of talcum powder and endometrial cancer risk.

BACKGROUND: Several studies have reported a positive association between perineal use of talcum powder among adult women and ovarian cancer risk. However, the relationship between talcum powder use and other gynecologic malignancies such as endometrial cancer has not been examined, and little information is available on nonhormonal risk factors for endometrial cancer. METHODS: Perineal use of talcum powder was assessed in 1982 in the Nurses' Health Study. Approximately 40% of women who responded to the questions about perineal use of talcum powder reported ever use. Cox proportional hazards models were used to estimate the incidence rate ratio of endometrial cancer and 95% confidence interval (CI), adjusted for body mass index and other potential confounders. We evaluated the relationship among all women and stratified by menopausal status. RESULTS: Our analysis included 66,028 women with 599 incident cases of invasive endometrial adenocarcinoma diagnosed between 1982 and 2004. Although no association was observed overall, the association varied by menopausal status (P interaction=0.02) and a positive association was observed among postmenopausal women; ever use of talcum powder was associated with a 21% increase in risk of endometrial cancer (95% CI, 1.02-1.44), whereas regular use (at least once a week) was associated with a 24% increase in risk (95% CI, 1.03-1.48). In addition, we observed a borderline increase in risk with increasing frequency of use (P trend=0.04). CONCLUSIONS: Our results suggest that perineal talcum powder use increases the risk of endometrial cancer, particularly among postmenopausal women. IMPACT: Future and larger studies are needed to confirm this association and investigate potential mechanisms.

Multifunctional specificity of the protein C/activated protein C Gla domain.

Activated protein C (APC) has potent anticoagulant and anti-inflammatory properties that are mediated in part by its interactions with its cofactor protein S and the endothelial cell protein C receptor (EPCR). The protein C/APC Gla domain is implicated in both interactions. We sought to identify how the protein C Gla domain enables specific protein-protein interactions in addition to its conserved role in phospholipid binding. The human prothrombin Gla domain, which cannot bind EPCR or support protein S cofactor activity, has 22/45 residues that are not shared with the human protein C Gla domain. We hypothesized that the unique protein C/APC Gla domain residues were responsible for mediating the specific interactions. To assess this, we generated 13 recombinant protein C/APC variants incorporating the prothrombin residue substitutions. Despite anticoagulant activity similar to wild-type APC in the absence of protein S, APC variants APC(PT33-39) (N33S/V34S/D35T/D36A/L38D/A39V) and APC(PT36/38/39) (D36A/L38D/A39V) were not stimulated by protein S, whereas APC(PT35/36) (D35T/D36A) exhibited reduced protein S sensitivity. Moreover, PC(PT8/10) (L8V/H10K) displayed negligible EPCR affinity, despite normal binding to anionic phospholipid vesicles and factor Va proteolysis in the presence and absence of protein S. A single residue variant, PC(PT8), also failed to bind EPCR. Factor VIIa, which also possesses Leu-8, bound soluble EPCR with similar affinity to wild-type protein C, collectively confirming Leu-8 as the critical residue for EPCR recognition. These results reveal the specific Gla domain residues responsible for mediating protein C/APC molecular recognition with both its cofactor and receptor and further illustrate the multifunctional potential of Gla domains.