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.

Survival in women with ovarian cancer with and without microsatellite instability.

PURPOSE OF INVESTIGATION: Microsatellite instability (MSI) is a hallmark of defective mismatch repair and is present in approximately 20% of ovarian cancers. It is not known if the presence of MSI predicts survival in women with epithelial ovarian cancer. MATERIALS AND METHODS: Cases of epithelial ovarian cancer were ascertained from a population-based study in Ontario and tumour samples were tested for MSI, using five MSI markers. Patients were divided into MSI-high and MSI-low/normal, according to National Cancer Institute criteria. The authors compared the prevalence of specific prognostic factors in the two subgroups, including age, grade, stage, and histology. They estimated the hazard ratio for death from ovarian cancer associated with MSI-high and with other prognostic factors using a multi-variate analysis. RESULTS: A total of 418 ovarian cancer patients were included. One hundred and twenty-seven (19.7%) cancers were MSI- high. Subgroup analyses did not reveal any statistically significant differences for pathologic features associated with MSI status. No survival difference was seen according to MSI status. CONCLUSIONS: The presence of MSI in ovarian cancer is not associated with survival.

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.

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

BACKGROUND: Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer. METHODS: The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women. RESULTS: Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers. CONCLUSIONS: Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.

Level-set segmentation of pulmonary nodules in megavolt electronic portal images using a CT prior.

PURPOSE: Pulmonary nodules present unique problems during radiation treatment due to nodule position uncertainty that is caused by respiration. The radiation field has to be enlarged to account for nodule motion during treatment. The purpose of this work is to provide a method of locating a pulmonary nodule in a megavolt portal image that can be used to reduce the internal target volume (ITV) during radiation therapy. A reduction in the ITV would result in a decrease in radiation toxicity to healthy tissue. METHODS: Eight patients with nonsmall cell lung cancer were used in this study. CT scans that include the pulmonary nodule were captured with a GE Healthcare LightSpeed RT 16 scanner. Megavolt portal images were acquired with a Varian Trilogy unit equipped with an AS1000 electronic portal imaging device. The nodule localization method uses grayscale morphological filtering and level-set segmentation with a prior. The treatment-time portion of the algorithm is implemented on a graphical processing unit. RESULTS: The method was retrospectively tested on eight cases that include a total of 151 megavolt portal image frames. The method reduced the nodule position uncertainty by an average of 40% for seven out of the eight cases. The treatment phase portion of the method has a subsecond execution time that makes it suitable for near-real-time nodule localization. CONCLUSIONS: A method was developed to localize a pulmonary nodule in a megavolt portal image. The method uses the characteristics of the nodule in a prior CT scan to enhance the nodule in the portal image and to identify the nodule region by level-set segmentation. In a retrospective study, the method reduced the nodule position uncertainty by an average of 40% for seven out of the eight cases studied.

Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis.

BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay. RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations. CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted.

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.

Biogenic amines and emotion.

The studies discussed here have shown a fairly consistent relationship between the effects of drugs on biogenic amines, particularly norepinephrine, and affective or behavioral states. Those drugs which cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioral stimulation or excitement and generally have an antidepressant effect in man (Table 1). From these findings, a number of investigators have formulated the concept, designated the catecholamine hypothesis of affective disorders (6), that some, if not all, depressions may be associated with a relative deficiency of norepinephrine at functionally important adrenergic receptor sites in the brain, whereas elations may be associated with an excess of such amines. It is not possible either to confirm or to reject this hypothesis on the basis of currently available clinical data. Although there does appear to be a fairly consistent relationship between the effects of pharmacological agents on norepinephrine metabolism and on affective state, a rigorous extrapolation from pharmacological studies to pathophysiology cannot be made. Confirmation of this hypothesis must ultimately depend upon direct demonstration of the biochemical abnormality in the naturally occurring illness. It should be emphasized, however, that the demonstration of such a biochemical abnormality would not necessarily imply a genetic or constitutional, rather than an environmental or psychological, etiology of depression. Whereas specific genetic factors may be of importance in the etiology of some, and possibly all, depressions, it is equally conceivable that early experiences of the infant or child may cause enduring biochemical changes and that these may predispose some individuals to depressions in adulthood. It is not likely that changes in the metabolism of the biogenic amines alone will account for the complex phenomena of normal or pathological affect. Whereas the effects of these amines at particular sites in the brain may be of crucial importance in the regulation of affect, any comprehensive formulation of the physiology of affective state will have to include many other concomitant biochemical, physiological, and psychological factors. Although in this review of the relationship of biogenic amines to affective state relatively little has been said concerning the intricate set of environmental and psychological determinants of emotion, the importance of these factors must be stressed. The normally occurring alterations in affective state induced by environmental events is well known to all, from personal experience. The interactions between such environmental determinants of affect, various physiological factors, and the complexity of psychological determinants, including cognitive factors derived from the individual's remote and immediate past experiences, have received only limited study under adequately controlled conditions. It may be anticipated, however, that this will prove to be a particularly fruitful area for future research, for only within such a multifactorial framework may one expect to understand fully the relationship of the biogenic amines to emotional state.

Norepinephrine turnover and metabolism in rat brain after long-term administration of imipramine.

The rate of disappearance of intracisternally administered tritiated norepinephrine from rat brain is decreased after a single dose of the tricyclic antidepressant imipramine. During long-term administration of imipramine, however, the rate of disappearance of tritiated norepinephrine from brain gradually increases, and there is a concurrent decrease in the content of endogenous norepinephrine in brain. These findings may help to explain why antidepressant effects are observed clinically only after long-termn treatment with imipramine.

MHPG excretion in depressive disorders: relation to clinical subtypes and desynchronized sleep.

The urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was significantly lower in patients with manic-depressive depressions than in patients with chronic characterological depressions. There was an inverse relationship between MHPG excretion and the amount of time spent in desynchronized sleep, particularly in the manic-depressive disorders. Excretion of MHPG was not related to the degree of retardation, agitation, or anxiety in these patients.

Norepinephrine pools in rat brain: differences in turnover rates and pathways of metabolism.

The rate of disappearance of intracisternally administered [(3)H]norepinephrine from rat brain gradually declines as a multiphasic exponential function of time. Conversion to [(3)H]normetanephrine accounts for a larger fraction of the [(3)H]norepinephrine released in the brain shortly after its intracisternal injection than that released at later times. Pools of norepinephrine in the brain thus appear to differ in their turnover rates and pathways of metabolism. The pool of norepinephrine with a rapid rate of turnover and an appreciable conversion to normetanephrine, identified by the techniques reported here, may correspond to a pool of newly synthesized norepinephrine in the brain.

X-ray standing waves: a molecular yardstick for biological membranes.

Structural information on an atomic scale has been obtained for a Langmuir-Blodgett (LB) trilayer system by means of long-period x-ray standing waves. The LB trilayer of zinc and cadmium arachidate was deposited on a layered synthetic microstructure (LSM) consisting of 200 tungsten/silicon layer pairs with a 25 A period. A 30 A thermally induced inward collapse of the zinc atom layer that was initially located in the LB trilayer at 53 A above the LSM surface has been observed. The mean position and width of the zinc atom layer was determined with a precision of +/- 0.3 A.

Alterations in brain norepinephrine metabolism induced by environmental stimuli previously paired with inescapable shock.

Footshock stress produced an immediate increase in brain concentrations of 3-methoxy-4-hydroxyphenylglycol sulfate (MHPG-SO4), a major metabolite of the neurotransmitter norepinephrine, in the rat brain. Twenty-four hours after footshock stress, when concentrations had returned to baseline, increases in MHPG-SO4 and emotional behavior could be elicited by previously neutral environmental stimuli that had been paired with the stress.

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.

Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history.

BACKGROUND: Heritable mutations of the breast cancer gene BRCA1 are rare, occurring in fewer than 1% of women in the general population, and therefore account for a small proportion of cases of breast and ovarian cancers. Nevertheless, the presence of such mutations is highly predictive of the development of these cancers. PURPOSE: We developed and applied a mathematic model for calculating the probability that a woman with a family history of breast and/or ovarian cancer carries a mutation of BRCA1. METHODS AND RESULTS: As a basis for the model, we use Mendelian genetics and apply Bayes' theorem to information on the family history of these diseases. Of importance are the exact relationships of all family members, including both affected and unaffected members, and ages at diagnosis of the affected members and current ages of the unaffected members. We used available estimates of BRCA1 mutation frequencies in the general population and age-specific incidence rates of breast and ovarian cancers in carriers and noncarriers of mutations to estimate the probability that a particular member of the family carries a mutation. This probability is based on cancer statuses of all first- and second-degree relatives. We first describe the model by considering single individuals: a woman diagnosed with breast and/or ovarian cancer and also a woman free of cancer. We next considered two artificial and two actual family histories and addressed the sensitivity of our calculations to various assumptions. Particular relationships of family members with and without cancer can have a substantial impact on the probability of carrying a susceptibility gene. Ages at diagnosis of affected family members and their types of cancer are also important. A woman with two primary cancers can have a probability of carrying a mutation in excess of 80%, even with no other information about family history. The number and relationships of unaffected members, along with their current ages or ages at death, are critical determinants of one's carrier probability. An affected woman with several cancers in her family can have a probability of carrying a mutation that ranges from close to 100% to less than 5%. CONCLUSION: Our model gives informative and specific probabilities that a particular woman carries a mutation. IMPLICATIONS: This model focuses on mutations in BRCA1 and assumes that all other breast cancer is sporadic. With the cloning of BRCA2, we now know that this assumption is incorrect. We have adjusted the model to include BRCA2, but the use of this version must await publication of penetrance data for BRCA2, including those for male breast cancer that are apparently associated with BRCA2 but not with BRCA1. The current model is, nevertheless, appropriate and useful. Of principal importance is its potential and that of improved versions for aiding women and their health care providers in assessing the need for genetic testing.

Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history.

BACKGROUND: The discovery of BRCA1 and BRCA2 has led to a reassessment of the association between family history of breast/ovarian cancer and breast cancer risk after controlling for carrier status for mutations in the BRCA1 and BRCA2 genes. We examined whether family history of breast cancer remains a predictive risk factor for this disease after carrier status for BRCA1 and/or BRCA2 mutations is taken into consideration. METHODS: The data are from 4730 case subjects with breast cancer and 4688 control subjects enrolled in the Cancer and Steroid Hormone Study. The probability of being a BRCA1 and/or BRCA2 gene carrier was calculated for each woman. Among predicted noncarriers, logistic regression was used to assess the relationship (odds ratios and 95% confidence intervals [CIs]) between case or control status and family history of breast or ovarian cancer. Estimates of age-specific breast cancer risk are presented by predicted carrier status. RESULTS: Among predicted noncarriers, case subjects were 2.06 times (95% CI = 1.69-2.50) and 1.24 times (95% CI = 1.17-1.32) more likely to report a first-degree or second-degree family history of breast cancer, respectively, than were control subjects. Case subjects were 1.99 times (95% CI = 1.63-2.44), 1.66 times (95% CI = 1.18-2.38), and 2.23 times (95% CI = 0.21-24.65) more likely to report an affected mother, sister, or both, respectively, than were control subjects. A family history of ovarian cancer was not statistically significantly associated with breast cancer risk. Noncarriers were predicted to have a lifetime risk of 9% of developing breast cancer compared with a 63% risk for carriers. CONCLUSIONS: Among women with a moderate family history of breast cancer, i.e., predicted noncarriers of BRCA1 and/or BRCA2 mutations, family history remains a factor in predicting breast cancer risk. In families with breast and ovarian cancers, the aggregation of these two cancers appears to be explained by BRCA1/BRCA2 mutation-carrier probability.