Maternal vitamin D, DNA methylation at imprint regulatory regions and offspring weight at birth, 1 year and 3 years.

BACKGROUND/OBJECTIVE: Vitamin D deficiency during pregnancy is associated with poor birth outcomes in some studies, but few have examined weight beyond birth. In addition, little is known about how vitamin D influences DNA methylation of regulatory regions known to be involved in growth, as possible mediators to weight status in offspring. SUBJECTS/METHODS: We conducted linear regressions to assess maternal plasma 25-hydroxyvitamin D (25(OH)D) by quartile and birth weight for gestational age z-score, 1-year weight-for-length z-score and 3-year body mass index (BMI) z-score among 476 mother/infant dyads from a prospective cohort. We assessed maternal 25(OH)D and infant DNA methylation at nine differentially methylated regions (DMRs) of genomically imprinted genes with known functions in fetal growth, including H19, IGF2, MEG3, MEG3-IG, MEST, NNAT, PEG3, PLAGL1 and SGCE/PEG10. RESULTS: Mean (standard deviation, s.d.) maternal 25(OH)D was 41.1 (14.2) nmol l-m at a mean (s.d.) of 13.2 (5.5) weeks gestation. After adjustment for potential confounders, the first (Q1) and second (Q2) quartiles of 25(OH)D, compared to the fourth (Q4), were associated with lower birth weight for gestational age z-scores (-0.43 units; CI: -0.79, -0.07; P=0.02 for Q1 and -0.56 units; CI: -0.89, -0.23; P=0.001 for Q2). Q1 compared to Q4 was associated with higher 1-year weight-for-length z-scores (0.78 units; 0.08, 1.54; P=0.04) and higher 3-year BMI z-scores (0.83 units; 0.11, 0.93; P=0.02). We did not observe associations between maternal 25(OH)D and methylation for any of the nine DMRs after correcting for multiple testing. CONCLUSIONS: Reduced maternal 25(OH)D was associated with lower birth weight for gestational age z-scores but higher 1-year weight-for-length and 3-year BMI z-scores in offspring. However, 25(OH)D does not appear to be operating through the regulatory sequences of the genomically imprinted genes we examined.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Newborns of obese parents have altered DNA methylation patterns at imprinted genes.

BACKGROUND: Several epidemiologic studies have demonstrated associations between periconceptional environmental exposures and health status of the offspring in later life. Although these environmentally related effects have been attributed to epigenetic changes, such as DNA methylation shifts at imprinted genes, little is known about the potential effects of maternal and paternal preconceptional overnutrition or obesity. OBJECTIVE: We examined parental preconceptional obesity in relation to DNA methylation profiles at multiple human imprinted genes important in normal growth and development, such as: maternally expressed gene 3 (MEG3), mesoderm-specific transcript (MEST), paternally expressed gene 3 (PEG3), pleiomorphic adenoma gene-like 1 (PLAGL1), epsilon sarcoglycan and paternally expressed gene 10 (SGCE/PEG10) and neuronatin (NNAT). METHODS: We measured methylation percentages at the differentially methylated regions (DMRs) by bisulfite pyrosequencing in DNA extracted from umbilical cord blood leukocytes of 92 newborns. Preconceptional obesity, defined as BMI ⩾30 kg m(-2), was ascertained through standardized questionnaires. RESULTS: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST (ß=-2.57; s.e.=0.95; P=0.008), PEG3 (ß=-1.71; s.e.=0.61; P=0.005) and NNAT (ß=-3.59; s.e.=1.76; P=0.04) DMRs. Changes related to maternal obesity detected at other loci were as follows: ß-coefficient was +2.58 (s.e.=1.00; P=0.01) at the PLAGL1 DMR and -3.42 (s.e.=1.69; P=0.04) at the MEG3 DMR. CONCLUSION: We found altered methylation outcomes at multiple imprint regulatory regions in children born to obese parents, compared with children born to non-obese parents. In spite of the small sample size, our data suggest a preconceptional influence of parental life-style or overnutrition on the (re)programming of imprint marks during gametogenesis and early development. More specifically, the significant and independent association between paternal obesity and the offspring's methylation status suggests the susceptibility of the developing sperm for environmental insults. The acquired imprint instability may be carried onto the next generation and increase the risk for chronic diseases in adulthood.

Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring.

OBJECTIVES: Low birth weight (LBW) has been associated with common adult-onset chronic diseases, including obesity, cardiovascular disease, type II diabetes and some cancers. The etiology of LBW is multi-factorial. However, recent evidence suggests exposure to antibiotics may also increase the risk of LBW. The mechanisms underlying this association are unknown, although epigenetic mechanisms are hypothesized. In this study, we evaluated the association between maternal antibiotic use and LBW and examined the potential role of altered DNA methylation that controls growth regulatory imprinted genes in these associations. METHODS: Between 2009-2011, 397 pregnant women were enrolled and followed until delivery. Prenatal antibiotic use was ascertained through maternal self-report. Imprinted genes methylation levels were measured at differentially methylated regions (DMRs) using bisulfite pyrosequencing. Generalized linear models were used to examine associations among antibiotic use, birth weight and DMR methylation fractions. RESULTS: After adjusting for infant gender, race/ethnicity, maternal body mass index, delivery route, gestational weight gain, gestational age at delivery, folic acid intake, physical activity, maternal smoking and parity, antibiotic use during pregnancy was associated with 138 g lower birth weight compared with non-antibiotic use (ß-coefficient=-132.99, s.e.=50.70, P=0.008). These associations were strongest in newborns of women who reported antibiotic use other than penicillins (ß-coefficient=-135.57, s.e.=57.38, P=0.02). Methylation at five DMRs, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) and PEG3 (P=0.08), was associated with maternal antibiotic use; among these, only methylation at the PLAGL1 DMR was also associated with birth weight. CONCLUSION: We report an inverse association between in utero exposure to antibiotics and lower infant birth weight and provide the first empirical evidence supporting imprinted gene plasticity in these associations.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Factors associated with African Americans' enrollment in a national cancer genetics registry.

This study explored whether reactions to the Cancer Genetics Network (CGN) or CGN enrollment differed by receipt of a standard informational brochure versus a targeted version addressing factors previously associated with African Americans' health behavior decisions and research participation. The 262 participants, identified through tumor registries or clinic contacts, were mailed brochures and completed phone interviews. When asked whether - based on the brochure - they were or were not 'leaning toward' CGN enrollment, about 75% of both standard and targeted groups reported leaning toward. When given the opportunity at the end of the interview, 68% enrolled in the CGN. Trust was strongly related to enrollment. Less education, less satisfaction with cancer care, and individualistic rather than collective orientation were associated with lower trust. Education was also bivariately associated with enrollment, but mediation analysis indicated that the operational mechanism of education's influence on enrollment was through trust.

Relationship between lifetime ovulatory cycles and overexpression of mutant p53 in epithelial ovarian cancer.

BACKGROUND: Several lines of evidence have suggested a relationship between a woman's number of ovulatory cycles and the development of ovarian epithelial cancer. Repair of the ovarian surface after ovulation requires cellular proliferation, and spontaneous mutations arising during the DNA synthesis that accompanies this proliferation may play a role in carcinogenesis. PURPOSE: We conducted a molecular epidemiologic study to test the hypothesis that a greater number of ovulatory cycles increases the risk of ovarian cancer by inducing proliferation-associated DNA damage. In particular, we examined the association between the lifetime number of ovulatory cycles and mutation of the p53 tumor-suppressor gene (also known as TP53) in ovarian tumors. METHODS: Case-case and case-control analyses involving participants in the Cancer and Steroid Hormone study were used to examine the association between p53 gene mutation in ovarian tumors and the lifetime number of ovulatory cycles. The women in our study were 20-54 years of age and included 197 case patients with invasive ovarian epithelial cancer and 3363 control subjects. Mutation of the p53 gene was indicated by overexpression of p53 protein (i.e., cellular accumulation of mutant p53 protein) in paraffin-embedded ovarian cancer tissue blocks; the mutant protein was detected by means of standard immunohistochemical techniques. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by employing multivariate analyses, with the use of logistic regression. Reported P values are two-sided. RESULTS: Women whose cancers overexpressed p53 protein (p53 positive) had a greater mean number of lifetime ovulatory cycles (388 +/- 77.4 cycles [mean +/- standard deviation]) than women whose cancers did not overexpress p53 protein (p53 negative) (342 +/- 119.0 cycles) (P = .0025). Furthermore, women with p53-positive tumors were more likely to have had moderate (i.e., 235-375) or high (i.e., 376-533) numbers of ovulatory cycles than women with p53-negative tumors (age-adjusted ORs = 7.0 [95% CI = 1.6-30.5] and 7.7 [95% CI = 1.4-41.2], respectively) (< or = 234 cycles was the referent category). After controlling for age, menopausal status, and nulliparity, women with p53-positive tumors were found to be significantly more likely to have had moderate or high numbers of ovulatory cycles than control subjects (ORs = 4.3 [95% CI = 1.4-13.0] and 9.1 [95% CI = 2.7-30.9], respectively); the corresponding ORs for women with p53-negative tumors compared with control subjects were 0.6 (95% CI = 0.3-1.4) and 1.3 (95% CI = 0.5-3.2), respectively. CONCLUSIONS AND IMPLICATIONS: A higher number of ovulatory cycles may be associated with increased amounts of proliferation-associated DNA damage and increased risk of developing p53-positive but not p53-negative epithelial ovarian cancer. Our results are consistent with more than one developmental pathway in the pathogenesis of this type of cancer.

Environmental contaminants and body fat distribution.

The effect of body mass index (BMI) and waist:hip ratio (WHR) on plasma levels of organochlorines [i.e., 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE)] was investigated in a sample of black and white women drawn from a population-based study in North Carolina. Organochlorine levels were determined in plasma samples from 99 women selected on the basis of race (black versus white) and quartile of the WHR (1st versus 4th). Of a panel of 20 organochlorine compounds tested, only DDE was detectable in most study subjects. Measurements of height, weight, and waist and hip circumferences were taken during an in-person interview. Information was elicited regarding dietary, residential, and breast-feeding histories. Results of multiple regression analyses indicate that black women had significantly higher plasma levels of DDE than white women. These levels were independent of BMI and WHR. BMI but not WHR was also found to be an independent predictor of DDE plasma level. These results suggest that black/white differences should be considered in studies that explore the relationship between environmental contaminants and various disease outcomes, such as breast cancer risk. In addition, BMI may affect circulating levels of contaminants and should also be considered a potentially important modifying factor for exposure to lipophilic substances.

Early onset baldness and prostate cancer risk.

Prostatic carcinoma is the leading cancer among American men, yet few risk factors have been established. Although increased androgen levels have long been associated with both prostatic carcinoma and baldness, to date no studies have shown an association between hair patterning and prostate cancer risk. A lack of standardized instruments to assess baldness or the assessment of hair patterning during uninformative periods of time may have precluded the ability of previous studies to detect an association. We hypothesized that baldness, specifically vertex baldness, should be assessed using standardized instruments and during early adulthood if an association with prostate cancer risk is to be found. To test this hypothesis, we included identical items related to hair patterning in surveys that were administered in two distinct prostate cancer case-control studies (Duke-based study, n = 149; 78 cases; 71 controls and community-based study, n = 130; 56 cases; 74 controls). In each, participants were provided with an illustration of the Hamilton Scale of Baldness and asked to select the diagrams that best represented their hair patterning at age 30 and again at age 40. From these data, the following five categories were created and compared: not bald (referent group); vertex bald early onset (by age 30); vertex bald later onset (by age 40); frontal bald early onset (by age 30); frontal bald later onset (by age 40); and frontal (at age 30) to vertex bald (at age 40). Separate analyses of the two studies are consistent and suggest an association between vertex baldness and prostate cancer [vertex bald early onset odds ratios, 2.44 [confidence interval (CI), 0.57-10.46)] and 2.11 (CI, 0.66-6.73), respectively; vertex bald later onset odds ratios, 2.10 (CI, 0.63-7.00) and 1.37 (CI, 0.47-4.06), respectively]. Although statistical significance was not achieved in either one of these studies, the concordance between the data suggests a need for future studies to determine whether early onset vertex baldness serves as a novel biomarker for prostate cancer and whether androgen production, metabolism, or receptor status differs among these men when compared to those who exhibit other types of hair patterning.

Coronary risk associated with age and sex of parental heart disease in the Framingham Study.

Data from the Framingham Study, a population-based prospective study of 5,209 persons, were analyzed to determine whether a parental history of death by coronary artery disease (CAD) before or after 65 years of age was an independent risk factor for CAD of early onset (age younger than 60 years) or late onset (age 60 years or older) among the men and women in the cohort. Death due to CAD in parents was associated with a 30% increase in the risk of CAD. The effect was apparently stronger for an early CAD outcome, with adjusted relative risks of 1.5 for early and 1.2 for late outcome CAD. The effect of parental CAD death on risk was not mediated by other shared risk factors for CAD. These findings were similar for those with either a mother or a father with CAD, if CAD onset in the offspring occurred before the age of 60 years. For persons with CAD at age 60 years or older, maternal CAD death was a stronger predictor of CAD than paternal CAD death. The association with parental history of CAD was similar among men and women in the cohort, with adjusted relative risks of 1.3 and 1.2, respectively. However, early age of parental CAD death may account for the association among women (RR = 1.6), whereas late age of CAD death for either parent was associated with the risk of CAD among men (RR = 1.4).

Family history of gynaecological cancers: relationships to the incidence of breast cancer prior to age 55.

As part of a multi-centre epidemiological study of cancer in women between the ages of 20 and 54, data were collected concerning family history of gynaecological cancers in the female relatives of 4730 women with newly diagnosed breast cancer and the relatives of 4688 women from the general population. Women who were diagnosed with breast cancer prior to age 45 were more likely than controls to have a mother or sister with ovarian cancer (odds ratio (OR): 1.50), endometrial cancer (1.29), and cervical cancer (1.53), although none of these elevations achieved statistical significance. The corresponding odds ratios for women diagnosed with breast cancer between the ages of 45 and 54 were 1.88, 0.84 and 0.93. The association with ovarian cancer was statistically significant in this group (95% confidence interval (CI): 1.11-3.19). In this latter group, having a first degree relative with ovarian cancer was associated approximately as strongly with breast cancer as was having a first degree relative with breast cancer. The results suggest that there may be a shared genetic basis for some cancers of the breast and ovary. From a clinical perspective, the results indicate that in setting appropriate levels of screening for breast cancer and in establishing an appropriate age at which to begin such screening for a particular woman, her family history of ovarian cancer should be considered in addition to her family history of breast cancer.

No association between alpha 1-antichymotrypsin and familial Alzheimer's disease.

Alzheimer's disease (AD) is the most common mid to late age-of-onset neurodegenerative disorder. AD has a strong and complex genetic etiology, and multiple genes, acting independently and/or interacting, likely affect the risk of developing AD. Several genes involved with AD already have been described, but only the APOE gene on chromosome 19q has been shown to affect the risk of the most common form of AD, occurring with onset over the age of 65. Because a substantial portion of late-onset AD is not explained by APOE, other genes affecting late-onset AD likely occur. These could act either independently or perhaps interact with APOE. alpha 1-Antichymotrypsin (ACT) is a major component of the amyloid plaques found in the brains of AD patients and may play a role in the pathophysiology of AD. It has been proposed that a specific polymorphism within the ACT gene interacts with APOE to increase the risk of developing AD. Our results do not confirm this finding.

Oral contraceptives and breast cancer: a case-control study with hospital and community controls.

Several recent reports have noted an increase risk of breast cancer associated with the use of oral contraceptives (OCs) among various subgroups of young women. These reports spurred us to analyze data from a case-control study in North Carolina of 158 breast cancer patients, 326 hospital controls, and 1140 community controls less than 60 years of age. A logistic regression model was used to calculate odds ratios and 95% confidence intervals and to control for potential confounders. No association between ever-use of OCs and the risk of breast cancer was found for cases compared with either control group. No increased risk was observed for OC use before age 25 or before first full-term pregnancy, or in relation to duration of use, recency of use, or time since first use. Analysis of the subgroup of women less than 45 years of age also showed no relationship between OC use and breast cancer risk. However, an elevated risk of breast cancer was observed among nulliparous women with 5 or more years of OC use in comparisons with hospital controls (odds ratio 7.8) and community controls (odds ratio 2.3). This analysis was based on small numbers of subjects and the 95% confidence intervals touched or overlapped with 1. An unexpected association between duration of OC use and breast cancer risk was found among older premenopausal women in comparisons of cases with both control groups. For these women, a trend was evident in the odds ratio by duration of OC use, and the comparison between cases and community controls was statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Epithelial ovarian cancer risk among women with polycystic ovary syndrome.

OBJECTIVE: To investigate the relationship between polycystic ovary syndrome (PCOS) and ovarian cancer, and to present three hypotheses regarding hormonal factors and the risk of ovarian cancer in women. METHODS: Data were analyzed from a population-based, case-control study, the Cancer and Steroid Hormone Study, to test the hypotheses. Four hundred seventy-six subjects with histologically confirmed epithelial ovarian cancer were identified from eight tumor registries of the Surveillance Epidemiology and End Results program. The study included 4081 controls ascertained via random-digit telephone dialing. All subjects and controls were aged 20-54 years. RESULTS: Seven subjects with ovarian cancer and 24 controls reported that they had been diagnosed with PCOS before the study period. Ovarian cancer risk was found to increase 2.5-fold (95% confidence interval [CI] 1.1-5.9) among women with PCOS. This association is found to be stronger among women who never used oral contraceptives (odds ratio [OR] 10.5, 95% CI 2.5-44.2) and women who were in the first quartile of body mass index (13.3-18.5 kg/m2) at age 18 (OR 15.6, 95% CI 3.4-71.0). CONCLUSION: The data suggest that the hormonal status of women with PCOS featuring abnormal patterns of gonadotropic secretion (enhanced levels of LH) in lean women may be a mitigating factor for the observed association between PCOS and ovarian cancer. We hope that our preliminary data stimulate further investigation of the testable hypotheses.

Prognostic factors in early-onset epithelial ovarian cancer: a population-based study.

OBJECTIVE: To investigate the clinical prognostic factors that influence ovarian cancer survival in women with early-onset epithelial ovarian cancer using population-based data. METHODS: Subjects in the current study were from a population-based series of 197 patients with invasive ovarian cancer and 60 patients with ovarian cancer of low malignant potential who were identified from the Cancer and Steroid Hormone study. All subjects were between 20 and 54 years of age at diagnosis for ovarian cancer. Epidemiologic data were obtained from each participant. Immunohistochemical staining was performed to assess p53 expression in paraffin-embedded ovarian cancers. Univariate and multivariate analyses for survival were conducted using the proportional hazards model to test the prognostic significance of several clinicopathologic factors among subjects. RESULTS: Among women with invasive tumors, the proportional hazards model revealed that advanced stage at diagnosis [hazard ratio = 4.1, 95% confidence interval (CI) = 2.5, 6.6], age at diagnosis 46-54 (hazard ratio = 2.0, 95% CI = 1.3, 3.0), and overexpression of p53 (hazard ratio = 1.5, 95% CI = 1.1, 2.3) were significantly associated with decreased survival. CONCLUSION: These results provide evidence that stage, age, and p53 overexpression are independent predictors of decreased survival in women with invasive ovarian cancer diagnosed younger than age 55. Further investigation of the effect of age at diagnosis on the relationship between p53 overexpression and ovarian cancer survival is warranted.

Cigarette smoking and epithelial ovarian cancer by histologic type.

OBJECTIVE: To examine cigarette smoking as a risk factor for different types of epithelial ovarian cancer. METHODS: We used data from the Cancer and Steroid Hormone Study, a multicenter, population-based, case control investigation. Cases were 447 women aged 20-54 years with diagnoses of epithelial ovarian cancer. Controls were 3868 women selected by random-digit dialing. Conditional logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) as estimators of the relative risk of ovarian cancer. With age and study site as conditioning variables, OR point estimates were additionally adjusted for parity and use of oral contraceptives. RESULTS: The OR of mucinous epithelial ovarian cancer for women who had ever smoked was 2.3 (95% CI 1.4, 3.9) and for current smokers was 2.9 (95% CI 1.7, 4.9). The OR of mucinous tumors for current smokers was significantly elevated regardless of years since first cigarette or age at which women first smoked. The OR of mucinous tumors for current smokers increased slightly as cumulative pack-years of smoking increased, although the trend was not significant. Similar patterns of elevated risk were not observed among serous, endometrioid, or other histologic types. Odds ratio point estimates for former smokers were not significantly elevated for any histologic type. CONCLUSION: Current cigarette smoking was a risk factor for mucinous epithelial ovarian cancer, but not other histologic types.

Age at natural menopause and the risk of epithelial ovarian cancer.

OBJECTIVE: To investigate the relationship between age at natural menopause and risk of developing epithelial ovarian cancer. METHODS: Using data from six population-based, case-control studies conducted in the United States, age at natural menopause among 1411 women with epithelial ovarian cancer and 6380 control subjects were analyzed using survival analysis methods, including Kaplan-Meier and proportional hazards models. Subjects ranged from 20 to 81 years of age. RESULTS: The median age at natural menopause was 50 years among cases compared with 51 years among controls, a difference of borderline statistical significance (P =.06). The hazard ratio for the relationship between case-control status and age at natural menopause was 1.09 (95% confidence interval 0.99, 1.20). Controlling for potential confounders including parity, oral contraceptive use, tubal ligation, smoking, and body mass index did not appreciably change this association. There was little evidence of an association between early age at natural menopause and early onset ovarian cancer (diagnosis age under 48 years). CONCLUSION: We observed a weak association between ovarian cancer risk and age at natural menopause and, among women with early onset disease, there was little evidence to suggest that early menopause is related to ovarian cancer. Thus, there seems little need for increased surveillance or screening for ovarian cancer among women with early natural menopause.

Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk.

OBJECTIVE: Using data from a case-control study of endometrial cancer, we investigated the relationship between the progestin and estrogen potency in combination oral contraceptives (OCs) and the risk of developing endometrial cancer. METHODS: Subjects included 434 endometrial cancer cases and 2,557 controls identified from the Cancer and Steroid Hormone (CASH) study. OCs were classified into four categories according to the individual potencies of each hormonal constituent (high versus low estrogen or progestin potency). Logistic regression was used to evaluate associations between endometrial cancer risk and combination OC formulations. RESULTS: With non-users as the referent group, use of OCs with either high potency progestin [odds ratio for endometrial cancer (OR)=0.21, 95% confidence interval (CI)=0.10 to 0.43] or with low potency progestin (OR=0.39, 95% CI=0.25 to 0.60) were both associated with a decreased risk of endometrial cancer. Overall high progestin potency OCs did not confer significantly more protection than low progestin potency OCs (OR=0.52, 95% CI=0.24 to 1.14). However, among women with a body mass index of 22.1 kg/m2 or higher, those who used high progestin potency oral contraceptives had a lower risk of endometrial cancer than those who used low progestin potency oral contraceptives (OR=0.31, 95% CI=0.11 to 0.92) while those with a BMI below 22.1 kg/m2 did not (OR=1.36, 95% CI=0.39 to 4.70). CONCLUSION: The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. Higher progestin-potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus.

Relationship of epithelial ovarian cancer to other malignancies within families.

The relationship of family history of cancer of the breast, colon/rectum, cervix, endometrium, lung, and thyroid to the risk of epithelial ovarian cancer was investigated in a large population-based case-control study. The data consisted of family histories from 493 epithelial ovarian cancer cases and 2,465 controls aged 20-54 years. After controlling for potential confounders, risk for epithelial ovarian cancer was found to be significantly elevated among women reporting breast cancer and colo/rectal cancer in a first-degree relative. Adjusted odds ratios were 1.5 (95% CI = 1.1-2.1) and 1.9 (95% CI = 1.1-3.3), respectively. None of the remaining four types of cancer was found to be statistically associated with the risk of epithelial ovarian cancer. However, when histologic subtypes of epithelial ovarian cancer were considered, a family history of breast cancer was found to be associated with an elevated risk of endometrioid ovarian cancer (odds ratio = 2.3; 95% CI = 1.1-4.7), as was a family history of endometrial cancer (odds ratio = 2.7; 95% CI = 1.0-6.9). The results are considered in the context of other studies of familial patterns of cancer and are compared with published findings concerning the occurrence of multiple primary cancers in the same individual. The findings indicate that further study is warranted regarding possible genetic relationships between epithelial ovarian cancer and cancers arising in other organs.