Gestational hypertension, preeclampsia, and risk of testicular cancer

Altered levels of pregnancy hormones have been suggested to initiate testicular cancer prenatally in the male fetus. The placenta is the main source of pregnancy hormones, and pregnancy hypertension and preeclampsia are associated with placental malfunction, including altered levels of hormones such as estrogen and human chorionic gonadotropin. We therefore evaluated fetal exposure to pregnancy hypertension and preeclampsia in relation to risk of testicular cancer in adolescent and adult life. We identified 293 cases of germ cell testicular cancer in the Swedish Cancer Register, and 861 controls in the Swedish Medical Birth Register. The standardized antenatal and delivery charts of the cases and controls were traced in the archives of the delivery units, and information about maternal and pregnancy characteristics such as gestational hypertension, proteinuria, anemia, and glucosuria were extracted. Odds ratios (OR) with 95% confidence intervals (CI) were calculated using conditional logistic regression. We found a strongly decreased risk of testicular cancer among subjects exposed to severe gestational hypertension (OR, 0.29; 95% CI, 0.12-0.74, compared with no hypertension), whereas the risk was increased among those exposed to mild gestational hypertension (OR, 1.62; 95% CI, 0.98-2.69) during the fetal period. The mechanism behind the association between pregnancy hypertension and testicular cancer is unclear, but our findings may reflect a potentially protective effect of the altered pregnancy hormones such as human chorionic gonadotropin that occur in severe gestational hypertension and preeclampsia.     

In utero exposure to female hormones and germ cell tumors in children

BACKGROUND: Maternal exposure to exogenous female hormones during pregnancy has been implicated as a risk factor for malignant germ cell tumors (GCTs) in the offspring in some epidemiologic studies of testicular and ovarian carcinoma in adults. METHODS: From 1996 to 2002, 278 children younger than 15 years of age with malignant GCTs and 423 healthy controls, frequency-matched for geographic location, age, and sex were enrolled in a case-control study to investigate whether in utero exposure to female hormones is associated with the risk of malignant GCT in children. Cases were recruited from 84 institutions in the U.S. and controls were enrolled through random digit dialing. Information was obtained through telephone interview with the biological mothers of the subjects and through blinded review of the mothers' medical records. RESULTS: Neither self-reported (odds ratio [OR] = 1.15; 95% confidence interval [CI], 0.63, 2.12) nor medical chart based (OR = 1.14; 95% CI, 0.75, 1.73) maternal exposure to exogenous female hormones was related to malignant GCT risk. Pregnancy-related conditions that may have altered serum levels of circulating female hormones were also unrelated to the risk of GCT in the offspring. CONCLUSION: This study failed to provide strong evidence to support the hypothesis that maternal exposure to exogenous female hormones during pregnancy increases the risk of GCT in the offspring.     

Prenatal and perinatal risk factors and testicular cancer: a hospital-based case-control study

Some evidence exists to support the hypothesis that elevated levels of circulating maternal estrogens during early pregnancy may increase risk of testicular germ cell cancer. However, the results from studies evaluating maternal factors have been mixed. We evaluated maternal factors, particularly those associated with excess estrogen levels, as risk factors for testicular cancer. We conducted a hospital-based case-control study at The University of Texas M. D. Anderson Cancer Center in Houston, Texas of 144 testicular cancer patients diagnosed between 1990 and 1996 and 86 friend controls matched to cases on age, race, and state of residence. Risk factor data about the mother, the son, and the pregnancy were obtained from the mothers by telephone interviews and from the sons by self-administered questionnaires. Extreme nausea during the first trimester of pregnancy was associated with an elevated risk of testicular cancer [odds ratio (OR) = 2.0; 95% confidence interval (CI) = 1.0-3.9]. Adjustment for potential confounders slightly lowered this risk (OR = 1.8; 95% CI = 0.9-3.8). Risks were modestly increased for other factors that are proxy measures for maternal estrogens, including preterm delivery (OR = 2.2; 95% CI = 0.4-12.9), birth weight <3000 g (OR = 2.4: 95% CI = 0.7-8.1), and birth weight >4000 g (OR = 1.7; 95% CI = 0.9-3.2), albeit nonsignificantly so. Our finding that severe nausea was associated with increased testicular cancer risk adds evidence to support the in utero estrogen exposure hypothesis because nausea early in pregnancy is related to rising levels of circulating estrogens. For other factors, which are less direct measures of maternal estrogens, the modest associations found indicate a suggestive pattern in support of the excess estrogen hypothesis.     

Menstrual and reproductive factors in relation to ovarian cancer risk

We assessed menstrual and reproductive factors in relation to ovarian cancer risk in a large, population-based, case-control study. 563 cases in Massachusetts and New Hampshire were ascertained from hospitals and statewide tumour registries; control women (n = 523) were selected through random digit dialing and matched to case women by age and telephone sampling unit. We used multivariate logistic regression to evaluate factors in relation to risk of ovarian cancer and the major tumour histologic subtypes. Ovarian cancer risk was reduced among parous women, relative to nulliparous women (OR = 0.4; 95% CI = 0.3-0.6). Among parous women, higher parity (P = 0.0006), increased age at first (P = 0.03) or last (P = 0.05) birth, and time since last birth (P = 0.04) were associated with reduced risk. Early pregnancy losses, abortions, and stillbirths were unrelated to risk, but preterm, term, and twin births were protective. Risk was lower among women who had breast-fed, relative to those who had not (OR = 0.7; 95% CI = 0.5-1.0), but the average duration of breast-feeding per child was unrelated to risk (P for trend = 0.21). Age at menarche and age at menopause were unrelated to risk overall, although increasing menarcheal age was protective among premenopausal women (P = 0.02). Menstrual cycle characteristics and symptoms were generally unrelated to risk, although cycle-related insomnia was associated with decreased risk (OR = 0.5; 95% CI = 0.3-0.8). We found no association between the type of sanitary product used during menstruation and ovarian cancer risk. In analyses by histologic subtype, reproductive and menstrual factors had most effect on risk of endometrioid/clear cell tumours, and least influential with regard to risk of mucinous tumours. Overall, our findings offer some support to current hypotheses of ovarian pathogenesis, and show aetiologic differences among the tumour subtypes.     

Reproductive factors of ovarian and endometrial cancer risk in a high fertility population in Mexico.

A case-control study was carried out in Mexico City during 1995-1997 among women with epithelial ovarian cancer (84 cases) and endometrial cancer (85 cases). The control group consisted of 668 healthy women, matched according to age categories. In a multivariate analysis, the reproductive risk factors for ovarian and endometrial cancer are similar. The risk of ovarian cancer was inversely related to the number of full-term pregnancies; the odds ratio (OR) was 0.17 and the 95% confidence interval (CI) was 0.05-0.54 when comparing nulliparous women versus those with more than seven pregnancies. For endometrial cancer, a similar association was observed (OR, 0.11; 95% CI, 0.04-0.34). The use of oral contraceptive hormones was inversely associated with both ovarian (OR, 0.36; 95% CI, 0.15-0.83) and endometrial cancer risk (OR, 0.36; 95% CI, 0.14-0.90). In women with a history of more than 8.7 years without ovulation, the risk of ovarian cancer decreased four times (OR, 0.23; 95% CI, 0.10-0.50), and that of endometrial cancer decreased more than five times (OR, 0.17; 95% CI, 0.08-0.35). These two neoplasms are clearly typified as hormone dependent, and it is possible to establish that "ovulation" and "exfoliative" mechanisms jointly determine the level of risk for both ovarian and endometrial cancer.     

Pre-natal and peri-natal exposures and risk of testicular germ-cell cancer

The present case-control study was undertaken to investigate the association between exposure to maternal hormones and risk of testicular germ-cell cancer by histologic subgroups. Cases were males, aged 16 to 59 years, diagnosed with testicular germ-cell cancer in Ontario between 1987 and 1989. Histologic review was performed on all eligible cases for the purpose of categorizing cases as seminoma or non-seminoma (the latter classified 2 ways, with and without tumors containing seminoma). Risk factor data were collected on 502 cases, 346 case mothers, 975 age-matched controls, and 522 control mothers. Exogenous hormone exposure was associated with elevated risk (OR = 4.9, 95% CI 1.7-13.9). Several additional risk factors were associated with risk of testicular cancer: bleeding and threatened miscarriage (OR = 0.6, 95% CI 0.3-1.0), maternal cigarette smoking (12+ cigarettes/day OR = 0.6, 95% CI 0. 4-1.0). pre-term birth (OR = 1.6, 95% CI 1.0-2.5), and treatment for undescended testicle (OR = 8.0, 95% CI 3.2-20.0). First births were associated with elevated risk (OR = 1.7, 95% CI 1.0-2.8) among mothers below the age of 24 years at conception. There was little evidence that risk factors differed by histologic subgroup. We found evidence that exposure to maternal hormones, particularly estrogens, is associated with testicular germ-cell cancer risk. Not only does exposure to elevated levels (exogenous hormone use, pre-term birth, and first births among young mothers) increase risk but also exposure to relatively lower levels (heavy cigarette consumption and, perhaps, bleeding and threatened miscarriage) may decrease cancer risk.     

Timing of pregnancy and the risk of epithelial ovarian cancer.

Recent animal studies suggest that progestagen-induced apoptosis of transformed ovarian surface epithelial cells may underlie the observed protective effect of pregnancy on the risk of ovarian cancer. Assuming that increasing numbers of cells are transformed with advancing age, we postulated that the benefits of pregnancy would be greater for older than younger women and tested this hypothesis in a population-based case-control study. We conducted interviews with 620 parous women, ages 18-79 years, with histologically confirmed incident ovarian cancer and 723 parous controls of the same age. Detailed information was collected on reproductive history, as well as hormonal exposures, smoking, medical history, and other factors. We estimated the relative risk of ovarian cancer associated with births at different ages through multiple logistic regression models. After adjusting for parity, older age at first and last births, and shorter time since last birth were all associated with significantly reduced risks of ovarian cancer. Age at first birth and time since last birth were not associated with ovarian cancer when adjusted for each other, whereas age at last birth remained strongly protective [odds ratio (OR), 0.57; 95% confidence interval (CI), 0.36-0.90] among women >35 years versus women less than 25 years. The effect was independent of total parity (per year of age among women with one birth: OR, 0.93; 95%CI, 0.87-1.01; among women with four or more births: OR, 0.96; 95%CI, 0.90-1.02). Our finding that ovarian cancer risk is reduced by pregnancy at older ages is further evidence that pregnancy confers a benefit beyond anovulation and is consistent with the theory that ovarian surface epithelial cell apoptosis induced by pregnancy hormones may be the underlying protective mechanism.     

Reproductive and hormonal risk factors for thyroid cancer in Los Angeles County females.

We conducted an individually matched case-control study (292 pairs) of female thyroid cancer patients to examine the role of reproductive history and exogenous hormones in this disease. Radiation treatment to the head or neck [28 cases and 2 controls exposed; odds ratio (OR), 14.0; 95% confidence interval (CI), 3.5-121.3] and certain benign thyroid diseases (including adolescent thyroid enlargement, goiter, and nodules or tumors) were strongly associated with thyroid cancer. Irregular menstruation increased risk (OR, 1.8; 95% CI, 0.9-3.7). Age at menarche and pregnancy history were not related to disease. Women with natural menopause and hysterectomized women without oophorectomy had no increase in risk, but disease risk was elevated in women with bilateral oophorectomy (OR, 6.5; 95% CI, 1.1-38.1). In general, use of oral contraceptives and other exogenous estrogens was not associated with thyroid cancer. However, risk increased with number of pregnancies in women using lactation suppressants (P = 0.03) and decreased with duration of breastfeeding (P = 0.04). These data provide only limited support for the hypothesis that reproductive and hormonal exposures are responsible for the marked excess of thyroid cancer risk in adult females.     

Family history of cancer and risk of ovarian cancer

The aim of this study was to examine the relationship between history of cancer in first-degree relatives and ovarian cancer risk. Between 1992 and 1999, we conducted a case-control study in Italy on 1031 women with epithelial ovarian cancer and 2411 women admitted to hospital for acute non-neoplastic conditions. Odds ratios (OR) were estimated using unconditional logistic regression, adjusted for age and several potential confounders. Overall, 27 cases and nine controls reported a family history of ovarian cancer (OR = 7.0; 95% confidence interval (CI) 3.1-16). The OR was 23 (95% CI 2.6-212) below age 50 years, based on 10 cases and one control only. The risk of ovarian cancer was also increased in women with a family history of cancer of the stomach (OR = 1.5; 95% CI 1.0-2.1), intestine (OR = 1.7; 95% CI 1.2-2.4), lung (OR = 1.3; 95% CI 1.0-1.8), breast (OR = 2.3; 95% CI 1.7-3.1), lymphomas (OR = 2.3; 95% CI 1.0-5.1) and all sites (OR = 1.6; 95% CI 1.4-1.9). Our results confirm the higher ovarian cancer risk in women with a family history of ovarian and breast cancer, and suggest a few associations with other sites.     

The relationship between smoking exposure and p53 overexpression in colorectal cancer.

Although epidemiological studies of the relationship between cigarette smoking and colorectal cancer risk have been equivocal, a positive association is consistently found for colorectal adenoma development. We performed an epidemiological study to determine whether p53 protein overexpression, in tumours obtained at the time of resection, is associated with cigarette exposure in colorectal cancer. A total of 163 colorectal cancer cases and 326 healthy controls responded to a standardised questionnaire on colorectal cancer risk factors including detailed information on their history of cigarette smoking. All patients'' tumours were analysed immunohistochemically for p53 overexpression using an avidin-biotin immunoperoxidase procedure and polyclonal anti-p53 antibody CM1. Comparison of colorectal cases with controls revealed an elevated risk for ex-smokers (OR = 1.34, 95% CI 0.85-2.12) and current smokers (OR = 1.13, 95% CI 0.63-2.02) when compared with non-smokers. No dose-response relationship was found for total pack-years of smoking (trend test: P = 0.19). However, a trend for total pack-years of smoking was found when p53-positive cases were compared with p53-negative cases suggesting aetiological, heterogeneity (trend test: P = 0.06). Estimating the individual relative risk of developing a p53-positive tumour relative to controls showed no associations for smoking status or total pack-years of smoking. However, when p53-negative cases were compared with controls, an elevated risk was found for ex-smokers (OR = 1.84, 95% CI 1.00-3.37) and current years of smoking (trend test: P = 0.03). Colorectal tumours developing through p53-positive dependent pathways were not associated with smoking exposure. A significant increase in risk was observed for the p53-negative independent pathway with smoking. p53 overexpression appears to be associated with smoking exposure in colorectal cancer.     

Case-control study of female thyroid cancer--menstrual, reproductive and hormonal factors.

A case-control study including 204 histologically verified female thyroid cancer patients and an equal number of hospital controls individually matched with cases by sex, age (+/- 2 years), place of residence and time of hospitalization was performed during the period 1996-2000. In the analysis of data, univariate and multivariate conditional logistic regression, methods were applied. According to multivariate analysis, out of hormonal, menstrual and reproductive characteristics, risk factors for thyroid cancer were spontaneous abortions (odds ratio: OR = 1.89, 95% confidence interval (CI) = 1.03-3.50), oral contraceptives use (OR = 2.34, 95% CI = 1.31-4.18) and thyroid enlargement during pregnancy (OR = 16.44, 95% CI = 3.81-70.80). However, none of these three factors remained independently related to thyroid cancer after adjustment for other factors, which were significantly associated with thyroid cancer in the present study (history of residence in endemic goitre area, history of goitre or thyroid nodule, history of other endocrine diseases, radioactive iodine therapy, occupational exposure to various chemicals, family history of thyroid gland diseases and malignant tumours as well as intake of cruciferous vegetables and other vegetables, and consumption of smoked meat and cheese).     

The relationship between twin births and maternal risk of breast cancer: a meta-analysis

Women who undergo a greater number of menstrual cycles may be at increased risk of breast cancer, possibly due to cumulative exposure to ovarian hormones. Pregnancy reduces the lifetime number of menstrual cycles and also influences the levels of ovarian hormones. Twin pregnancies differ from singleton pregnancies in both hormone levels and perinatal changes. To date, a meta-analysis on the effects of twin birth on the risk of maternal breast cancer has not been conducted. Among 17 relevant publications identified in a systematic search, some suggest that twin births may be associated with lower breast cancer risk but others do not; therefore, the results are inconclusive. Although our pooled results of all 17 published studies did not show a reduced maternal risk of breast cancer for twin births (HR 0.94; 95% CI = 0.87-1.02; P = 0.127), a trend toward reduced maternal risk of breast cancer was identified in a subgroup analysis of cohort studies (HR 0.91; 95% CI = 0.83-1.01; P = 0.068). The results of this meta-analysis suggest that twin pregnancy does not significantly decrease the maternal risk of breast cancer.     

Vitamin D receptor gene polymorphisms and epithelial ovarian cancer risk.

Epidemiologic and laboratory studies support a role for the vitamin D endocrine system in ovarian carcinogenesis. The association of ovarian cancer risk with polymorphisms in the vitamin D receptor (VDR) gene, including rs10735810 (FokI), rs11568820 (Cdx-2), rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI), and BsmI-ApaI-TaqI combined genotypes, was examined among 313 women with epithelial ovarian carcinoma and 574 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. The associations of VDR polymorphisms with risk were generally inconsistent across ethnic groups. Among Caucasian women (72 cases, 148 controls), heterozygous and homozygous ApaI A allele carriers were at increased ovarian carcinoma risk compared with homozygous carriers of the ApaI a allele (OR 2.8, 95% CI 1.2-7.0 and OR 3.4, 95% CI 1.3-9.1; P(trend) = 0.02). Caucasian heterozygous carriers of FokI f allele were also at increased risk of ovarian carcinoma compared with homozygous carriers of the common allele (OR 2.5, 95% CI 1.3-4.8; P(trend) = 0.04). Among Japanese women (94 cases, 173 controls), ovarian cancer risk was significantly decreased (OR 0.5, 95% CI 0.3-0.9) among Cdx-2 A allele heterozygotes compared with homozygote G allele carriers (P(trend) = 0.03). Compared with the bbaaTT BsmI-ApaI-TaqI genotype, bbaATT and BBAAtt genotypes were associated with increased ovarian cancer risk in Caucasian women (OR 4.2, 95% CI 1.3-13.1 and OR 5.2, 95% CI 1.6-17.5), but not in Japanese women (OR 1.1, 95% CI 0.6-1.9 and OR 2.3, 95% CI:0.4-12.3). This investigation provides some evidence that polymorphisms in the VDR gene might influence ovarian cancer susceptibility.     

Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt

Patients under age 40 constitute 35.6% of all colorectal cancer cases in Egypt, an unusual disease pattern to which both environmental exposures and inefficient DNA repair may contribute. While a number of polymorphisms in DNA repair genes have been recently identified, their role as cancer risk modifiers is yet to be determined. In a pilot case-control study, we tested the hypothesis that polymorphisms in the gene for the DNA repair enzyme XRCC1 are associated with increased risk of colorectal cancer among Egyptians. Using a multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, allelic variants of the XRCC1 gene at codons 194 (Arg-->Trp) (194Trp) and 399 (Arg-->Gln) (399Gln), were analyzed in DNA from lymphocytes of 48 newly-diagnosed colorectal cancer cases and 48 age- and sex-matched controls. Overall, the inheritance of 194Trp allele (Arg/Trp genotype) and 399Gln allele (combined Arg/Gln and Gln/Gln genotypes) was associated with increased colorectal cancer risk (odds ratio (OR)=2.56, 95% confidence limits (CL) 0.73-9.40, and P=0. 08 for 194Trp allele and OR=3.98, 95% CL 1.50-10.6, and P<0.001 for 399Gln allele). Interestingly, the frequencies of 194Trp and 399Gln genotypes were higher in colorectal cancer cases under age 40 than in corresponding controls, and an association between both polymorphisms and early age of disease onset was observed (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=11.90, 95% CL 2.30-51.50, and P=0.0003 for 399Gln). Analysis of the data after adjustment for place of residence indicated that the frequencies of the genotypes with the 194Trp and the 399Gln alleles were higher among urban residents (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=9.97, 95% CL 1.98-43.76, and P<0.001 for 399Gln) than among rural residents (OR=2.00, 95% CL 0.36-26.00, and P=0.30 for 194Trp and OR=1.90, 95% CL 0.50-7.53, and P=0.20 for 399Gln). These findings support our hypothesis and suggest that polymorphisms in the XRCC1 gene, in conjunction with place of residence, may modify disease risk. This first demonstration that polymorphisms in DNA repair genes may contribute to colorectal cancer susceptibility and may increase the risk of early onset of the disease opens the door for future studies in that direction.     

Double-strand break repair gene polymorphisms and risk of breast or ovarian cancer.

Deficiencies in DNA repair have been hypothesized to increase cancer risk and excess cancer incidence is a feature of inherited diseases caused by defects in DNA damage recognition and repair. We investigated, using a case-control design, whether the double-strand break repair gene polymorphisms RAD51 5' untranslated region -135 G > C, XRCC2 R188H G > A, and XRCC3 T241M C > T were associated with risk of breast or ovarian cancer in Australian women. Sample sets included 1,456 breast cancer cases and 793 age-matched controls ages under 60 years of age, 549 incident ovarian cancer cases, and 335 controls of similar age distribution. For the total sample and the subsample of Caucasian women, there were no significant differences in genotype distribution between breast cancer cases and controls or between ovarian cancer cases and combined control groups. The crude odds ratios (OR) and 95% confidence intervals (95% CI) associated with the RAD51 GC/CC genotype frequency was OR, 1.10; 95% CI, 0.80-1.41 for breast cancer and OR, 1.22; 95% CI, 0.92-1.62 for ovarian cancer. Similarly, there were no increased risks associated with the XRCC2 GA/AA genotype (OR, 0.98; 95% CI, 0.76-1.26 for breast cancer and OR, 0.93; 95% CI, 0.69-1.25 for ovarian cancer) or the XRCC3 CT/TT genotype (OR, 0.92; 95% CI, 0.77-1.10 for breast cancer and OR, 0.87; 95% CI, 0.71-1.08 for ovarian cancer). Results were little changed after adjustment for age and other measured risk factors. Although there was little statistical power to detect modest increases in risk for the homozygote variant genotypes, particularly for the rare RAD51 and XRCC2 variants, the data suggest that none of these variants play a major role in the etiology of breast or ovarian cancer.     

Infant acute leukemia and maternal exposures during pregnancy.

Infant acute leukemia (IAL) has a unique profile characterized by the high incidence of translocations involving the MLL gene located at the 11q23 region. To test the potential role of intrauterine and perinatal factors linked to the risk of IAL development, a hospital-based case-control study was conducted in different cities of Brazil. A total of 202 children (ages 0-21 months) with newly diagnosed IAL was enrolled (1999-2005), and 440 age-matched controls were selected from the same hospitals wherein IAL cases were treated. A statistically significant association between maternal use of hormones during pregnancy and IAL was observed [odds ratio (OR), 8.76; 95% confidence interval (95% CI), 2.85-26.93] in a multivariable analysis. The association of certain exposures during pregnancy (hormones, dipyrone, metronidazole, and misoprostol) and MLL gene rearrangements was tested using a case-case approach. Despite the lack of statistical significance, the magnitude of the OR for maternal exposure to dipyrone (OR, 1.45; 95% CI, 0.75-2.86), metronidazole (OR, 1.72; 95% CI, 0.64-4.58), quinolones (OR, 2.25; 95% CI, 0.70-25.70), and hormones (OR, 1.88; 95% CI, 0.50-7.01) may suggest the occurrence of interactions between such maternal exposures during pregnancy and MLL rearrangements, yielding into IAL development. The strong and statistically significant association between IAL and estrogen exposure during pregnancy observed in this study deserves further investigation to investigate its role in intrauterine leukemogenesis.     

BRCA1 mutations in ovarian cancer and borderline tumours in Norway: a nested case-control study

The aims of the present study were to find the frequency of the most common BRCA1 mutations in women with ovarian tumours identified from a population-based cancer registry and in the general population, to estimate the relative risk of ovarian tumours among the mutation carriers, and to explore the value of using CA125 as a prediagnostic test. The study was designed as a nested case-control study within a cohort mainly consisting of participants in population-based health examinations. The data files of The Cancer Registry of Norway and the Janus serum bank were linked to identify cases with ovarian cancer and borderline tumours. Hereditary BRCA1 mutations were determined using archived serum samples and capillary electrophoresis. Altogether 478 ovarian cancer patients and 190 patients with borderline tumours were identified, and 1421 and 568 matching controls were selected. Odds ratios (OR) of developing ovarian cancer and borderline tumours in the presence of BRCA1 mutations and CA125 level were derived from conditional logistic regression models. Among the 478 ovarian cancer patients, 19 BRCA1 mutations were identified (1675delA, 1135insA, 816delGT and 3347delAG), none among the patients with borderline tumours. Only two of the 1989 controls were BRCA1 mutation carriers (0.10%). The risk of ovarian cancer among the mutation carriers was strongly elevated (OR=29, 95% CI=6.6-120). CA125 was a marker for ovarian cancer, but the sensitivity was low. This study showed that BRCA1 mutation carriers have a very high risk of ovarian cancer. However, since the prevalence of BRCA1 mutations in the Norwegian population was low, the proportion of ovarian cancers due to BRCA1 mutations seemed to be low, about 4%. The sensitivity of using CA125 only as a screening test for ovarian cancer was low.     

Endometrioid and clear cell ovarian cancers: a comparative analysis of risk factors

Endometrioid and clear cell subtypes of ovarian cancer are both known to be closely associated with endometriosis and endometrial pathology, and so have often been combined in studies of causation. We have examined these ovarian cancers separately for potentially distinct risk factors in our population-based, Australia-wide case control study of 142 women with incident invasive endometrioid, 90 with clear cell ovarian cancers and 1508 population controls. Multivariate logistic regression was used to calculated odds ratios (ORs) and 95% confidence intervals (CIs). Increasing parity, and hormonal contraceptive use for > or = 5 years, strongly decreased the risks of both subtypes. Breast feeding and tubal ligation were also inversely associated, but significantly so only for the endometrioid subtype. As expected endometriosis increased the risk of both subtypes (OR 2.2, 95% CI 1.2-3.9 for endometrioid and OR 3.0, 95% CI 1.5-5.9 for clear cell). Obesity was associated only with clear cell cancers, where we observed a two-fold increased risk (OR 2.2, 95% CI 1.2-4.1). Also a significant trend of decreasing risk with increasing intensity of smoking (p trend 0.02) and education beyond high school was associated with decreased development of clear cell cancers only. Endometrioid and clear cell ovarian cancers have some shared as well as some distinct risk factors, and therefore should be considered separately in studies of ovarian cancer.     

Different risk factor profiles for mucinous and nonmucinous ovarian cancer: results from the Danish MALOVA study.

OBJECTIVES: The aim of the study was to examine the overall risk factors for epithelial ovarian cancer and according to histologic subtypes. MATERIALS AND METHODS: Ovarian cancer cases and controls were recruited from 1995 to 1999, and personal interviews were conducted. A total of 554 cases and 1,564 randomly selected controls were included. The analyses were done using multiple logistic regression models. RESULTS: The overall risk of ovarian cancer decreased with ever being pregnant [odds ratios (OR), 0.40; 95% confidence intervals (CI), 0.30-0.55], with increasing pregnancies (OR, 0.63; 95% CI, 0.45-0.87 and OR, 0.51; 95% CI, 0.37-0.69 for two and three pregnancies as compared with one), and with older age at first and last pregnancy, respectively. Increasing years of ovulation was a very strong risk factor with a 7% to 8% increase in risk for each year of ovulation. Use of oral contraceptives (OR, 0.67, 95% CI, 0.53-0.85) and longer duration of use were associated with a decreased risk of ovarian cancer. Ever use of hormone replacement therapy increased the overall risk (OR, 1.30; 95% CI, 1.05-1.61). For all those variables, the effect was present for serous tumors, endometrioid tumors, and tumors of other histologies, but not for mucinous tumors. In contrast, current smoking was a risk factor only for mucinous tumors (OR, 1.78; 95% CI, 1.01-3.15) and increasing body mass index tended to increase the risk especially for mucinous and endometrioid tumors. CONCLUSIONS: We confirmed already known risk factors for ovarian cancer, and we observed significant differences in the risk profiles between mucinous and nonmucinous tumors indicating different etiologies.     

Association study of prostate cancer susceptibility variants with risks of invasive ovarian, breast, and colorectal cancer

Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary test of association was a comparison of genotype frequencies between cases and controls, and a test for trend stratified by study where appropriate. Genotype-specific odds ratios (OR) were estimated by logistic regression. SNP rs2660753 (chromosome 3p12) showed evidence of association with ovarian cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor allele OR, 0.95; 95% CI, 0.91-0.99; P(trend) = 0.028). This association was somewhat stronger for estrogen receptor-positive tumors (OR, 0.92; 95% CI, 0.87-0.98; P = 0.011). None of these tag SNPs were associated with risk of colorectal cancer. In conclusion, loci associated with risk of prostate cancer may also be associated with ovarian and breast cancer susceptibility. However, the effects are modest and warrant replication in larger studies.