Joellen M. Schildkraut

Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality

CONTEXT Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. OBJECTIVE To estimate risk and mortality reduction stratified by mutation and prior cancer status. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. MAIN OUTCOMES MEASURES Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. RESULTS No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). CONCLUSIONS Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.

The genetic attributable risk of breast and ovarian cancer

The age‐specific proportion of breast and ovarian cancer in the general population that is likely to be due to a breast/ovarian cancer susceptibility gene(s) is estimated. In addition, the age‐specific penetrance of ovarian cancer for women predicted to be carriers of a susceptibility gene is calculated using population‐based data.

EPIDEMIOLOGY OF INTRACRANIAL MENINGIOMA

Meningiomas are the most frequently reported primary intracranial neoplasms, accounting for approximately 25% of all such lesions diagnosed in the United States. Few studies have examined the risk factors associated with a diagnosis of meningioma with two categories of exposure, hormones (both endogenous and exogenous) and radiation, most strongly associated with meningioma risk. Limited data are also available on long-term outcomes for meningioma patients, although it is clear that the disease is associated with significant morbidity and mortality. Recent legislation passed in the United States (The Benign Brain Tumor Cancer Registries Amendment Act [H.R. 5204]) mandates registration of benign brain tumors such as meningioma. This will increase the focus on this disease over the coming years as well as likely increase the reported prevalence of the disease. The increased emphasis on research dedicated to the study of brain tumors coupled with the advent of new tools in genetic and molecular epidemiology make the current era an ideal time to advance knowledge for intracranial meningioma. This review highlights current knowledge of meningioma epidemiology and new directions for research efforts in this field.

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 gonado-tropic 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.

Characterization of BRCA1 and BRCA2 Mutations in a Large United States Sample

PURPOSE An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families. METHODS We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family. RESULTS In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling. CONCLUSION The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ∼2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79–0.86, Ptrend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73–0.81, Ptrend = 4.1 × 10−21).

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort.

BackgroundData from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene.MethodsWe examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offsprings DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m2.ResultsHypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (β-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offsprings epigenome.ConclusionsWhile our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offsprings future health status.

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).

Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy

Folic acid (FA) supplementation before and during pregnancy has been associated with decreased risk of neural tube defects although recent reports suggest it may also increase the risk of other chronic diseases. We evaluated exposure to maternal FA supplementation before and during pregnancy in relation to aberrant DNA methylation at two differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) expression in infants. Aberrant methylation at these regions has been associated with IGF2 deregulation and increased susceptibility to several chronic diseases. Using a self-administered questionnaire, we assessed FA intake before and during pregnancy in 438 pregnant women. Pyrosequencing was used to measure methylation at two IGF2 DMRs in umbilical cord blood leukocytes. Mixed models were used to determine relationships between maternal FA supplementation before or during pregnancy and DNA methylation levels at birth. Average methylation at the H19 DMR was 61.2%. Compared to infants born to women reporting no FA intake before or during pregnancy, methylation levels at the H19 DMR decreased with increasing FA intake (2.8%, p=0.03, and 4.9%, p=0.04, for intake before and during pregnancy, respectively). This methylation decrease was most pronounced in male infants (p=0.01). Methylation alterations at the H19 DMR are likely an important mechanism by which FA risks and/or benefits are conferred in utero. Because stable methylation marks at DMRs regulating imprinted genes are acquired before gastrulation, they may serve as archives of early exposures with the potential to improve our understanding of developmental origins of adult disease.

Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke

Epigenetic alterations may mechanistically explain the developmental origins of adult disease, namely the hypothesis that many complex adult chronic diseases originate as a result of conditions encountered in utero. If true, epigenetically regulated imprinted genes, critical to normal growth and development, may partially mediate these outcomes. We determined the influence of in utero exposure to cigarette smoking on methylation at two differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) and H19, and how this might relate to birth weight of infants born to 418 pregnant women. Smoking status was ascertained through self-report and medical records. Bisulfite pyrosequencing was used to measure methylation in umbilical cord blood DNAs. Least squares DNA methylation means at each DMR and birth weight were compared between infants of smokers and non-smokers, using generalized linear models. While there were no significant differences at the H19 DMR, infants born to smokers had higher methylation at the IGF2 DMR than those born to never smokers or those who quit during pregnancy (49.5%, SD=8.0 versus 46.6%, SD=5.6 and 45.8%, SD=6.3, respectively; p=0.0002). The smoking-related increase in methylation was most pronounced in male offspring (p for sex interaction=0.03), for whom approximately 20% of smoking-related low birth weight was mediated by DNA methylation at the IGF2 DMR. Our findings suggest that IGF2 DMR plasticity is an important mechanism by which in utero adjustments to environmental toxicants are conferred. Larger studies to replicate these findings are required.