Jocelyn M. Weiss

Adipokines are obesity-related factors produced in adipose tissue and secreted into the circulation. Several studies have shown a clear relationship for serum levels of 2 adipokines, adiponectin and leptin, with obesity in humans. There is an inverse correlation between levels of adiponectin and obesity, whereas levels of leptin appear to be positively correlated with obesity. Data from a limited number of epidemiologic studies suggest that circulating levels of adiponectin may also be associated with risk of endometrial cancer (EC); few prospective studies have examined this possible relationship. A number of case-control studies and 1 recent prospective study have suggested a positive association between leptin levels and EC. Some epidemiologic studies have shown a positive association between serum levels of visfatin, a recently discovered adipokine, in visceral fat and several cancers; however, its association with EC risk has not been evaluated. The relationship of prediagnostic serum levels of adiponectin, leptin, and visfatin with risk of EC was investigated prospectively in this case-control study, which was nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The association of circulating estradiol and body mass index (BMI) was also evaluated. A total of 78,216 postmenopausal women enrolled in the PLCO trial were randomized to either intervention (screening for incident EC, n= 167) or a matched control (usual care, n = 327). At baseline, study subjects and controls were matched for age, race, study center, study year of diagnosis, year of blood draw, time of day of blood collection, and use of menopausal hormone therapy (MHT). Serum concentrations of adiponectin, leptin, visfatin, and estradiol were categorized into tertiles. Conditional logistic regression analysis was used to estimate the associations of adiponectin, leptin, and visfatin with EC risk, adjusting for known risk factors, including BMI and plasma estradiol levels. Data for never and former MHT users were combined; results were similar when the population was restricted to never users only. There was an inverse association between elevated adiponectin levels and risk of EC (odds ratio [OR], T3 vs T1, 0.48; 95% confidence interval [CI], 0.29–0.80; P trend = 0.004), whereas higher levels of leptin were associated with increased risk (OR, T3 vs T1, 2.77; 95% CI, 1.60–4.79; P trend < 0.001). The associations remained significant after adjustment for estradiol, but not BMI. Stronger magnitudes of association with EC for adiponectin and leptin were found among women not using MHT (adiponectin [OR, T3 vs T1, 0.13; 95% CI, 05–0.35; P trend < 0.001] and leptin [OR, T3 vs T1, 9.19; 95% CI, 3.07–27.44; P trend < 0.001]). These associations remained statistically significant after adjustment for estradiol and BMI. Changes in visfatin levels were not associated with increased risk of EC. These findings suggest that, in addition to the estradiol pathway, a nonhormonal pathway involving adipokines may play an important role in endometrial carcinogenesis in postmenopausal women, especially among non-MHT users.

Sex steroid hormones influence prostate development and maintenance through their roles in prostate cellular proliferation, differentiation and apoptosis. Although suspected to be involved in prostate carcinogenesis, an association between circulating androgens and prostate cancer has not been clearly established in epidemiologic studies. We conducted a nested case‐control study with prospectively collected samples in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to examine associations of prostate cancer with androstenedione (Δ4‐A), testosterone (T), sex hormone‐binding globulin (SHBG) and 3α‐androstanediol glucuronide (3α‐diolG). A total of 727 incident Caucasian prostate cancer cases (age ≥ 65 years, N = 396) and 889 matched controls were selected for this analysis. Overall, prostate cancer risks were unrelated to serum T, estimated free and bioavailable T, and SHBG; however, risks increased with increasing T:SHBG ratio (p_trend = 0.01), mostly related to risk in older men (≥65 years, p_trend = 0.001), particularly for aggressive disease [highest versus lowest quartile: odds ratio (OR) 2.76, 95% confidence interval (CI) 1.50–5.09]. No clear patterns were noted for Δ4‐A and 3α‐diolG. In summary, our large prospective study did not show convincing evidence of a relationship between serum sex hormones and prostate cancer. T:SHBG ratio was related to risk in this older population of men, but the significance of this ratio in steroidal biology is unclear.

IGF‐1 and IGFBP‐3 may influence risk of prostate cancer through their roles in cellular growth, metabolism and apoptosis, however, epidemiologic results have been inconsistent. The role of obesity in prostate cancer risk is not clearly understood, but hyperinsulinemia‐related increases in bioactive IGF‐1 levels, associated with obesity, could be a component of the relationship between the IGF‐axis and prostate cancer. We conducted a nested case–control study in the prospective Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to examine associations between IGF‐1 and IGFBP‐3 and risk of prostate cancer. A total of 727 incident prostate cancer cases and 887 matched controls were selected for this analysis. There was no clear overall association between IGF‐1, IGFBP‐3 and IGF‐1:IGFBP‐3 molar ratio (IGFmr) and prostate cancer risk, however, IGFmr was associated with risk in obese men (BMI > 30, p‐trend = 0.04), with a greater than 2‐fold increased risk in the highest IGFmr quartile (OR 2.34, 95% CI 1.10–5.01). Risk was specifically increased for aggressive disease in obese men (OR 2.80, 95% CI 1.11–7.08). In summary, our large prospective study showed no overall association between the insulin‐like growth factor axis and prostate cancer risk, however, IGFmr was related to risk for aggressive prostate cancer in obese men.

There is a wide range of aggressiveness of endometrial tumors, some being indolent and easily treated while others metastasize and prove fatal. The authors used data from three population-based, case-control studies to determine if etiologic factors differ for aggressive disease. Interview data were obtained from 1,304 female residents of western Washington State who were 45–74 years of age and diagnosed with endometrial cancer during 1985–1991, 1994–1995, and 1997–1999 and from 1,779 controls who were of similar ages and selected primarily by random digit dialing. As a means of gauging aggressiveness, tumor characteristics were abstracted from the population-based cancer registry that serves western Washington State. The risk of endometrial cancer among long-term users (≥8 years) of unopposed estrogens was particularly high for the least aggressive tumors (odds ratio = 18.6, 95% confidence interval: 12.2, 28.6) but was elevated for moderate and highly aggressive tumors as well (odds ratios = 6.6 and 7.1, respectively). Women who were obese, had a history of diabetes, and had fewer than two children were also at increased risk, regardless of tumor aggressiveness, while oral contraceptive users were at decreased risk of only relatively more aggressive disease. In general, a woman's risk of endometrial cancer appears to be influenced by similar risk factors regardless of disease severity.

Exposure to estrogens is a likely cause of endometrial cancer, but the means by which estrogens exert this effect are not entirely clear. One hypothesis is that certain estrogen metabolites bind to the DNA, forming bulky adducts that damage the DNA and initiate carcinogenesis. A woman's reduced capacity to repair such damage may increase her risk of endometrial cancer. We conducted a population-based case-control study in western Washington State to address the role of variation in nucleotide excision repair genes on the risk of endometrial cancer. Case women (n = 371), ages 50 to 69 years, were diagnosed with invasive endometrial cancer between 1994 and 1999. Control women (n = 420) were selected using random-digit dialing (ages 50-65 years) and by random selection from Health Care Financing Administration data files (ages 66-69 years). Genotyping assays were done for ERCC1, ERCC2 (XPD), ERCC4 (XPF), ERCC5 (XPG), XPA, and XPC. No appreciable differences between cases and controls were observed in the genotype distributions of ERCC1 (c8092a and c19007t), ERCC2 (D312N, K751Q, and c22541a), ERCC4 (R415Q and t30028c), or ERCC5 (D1104H). Carriage of at least one variant allele for XPA G23A was associated with decreased risk of endometrial cancer [odds ratio (OR), 0.70; 95% confidence interval (95% CI), 0.53-0.93]. Carriage of at least one XPC A499V variant allele was associated with a modest decrease in risk (OR, 0.79; 95% CI, 0.59-1.05). Women with variant alleles at both XPC A499V and K939Q had 58% of the risk of women with no XPC variant alleles (OR, 0.58; 95% CI, 0.35-0.96). Our data suggest that interindividual variation in XPA and XPC influences a woman's risk of endometrial cancer.