Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

https://www.cell.com/ajhg/pdf/S0002-9297(07)60640-5.pdf

Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies

Maternal hemorrhage, defined as a cumulative blood loss of greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process, remains the leading cause of maternal mortality worldwide (1). Additional important secondary sequelae from hemorrhage exist and include adult respiratory distress syndrome, shock, disseminated intravascular coagulation, acute renal failure, loss of fertility, and pituitary necrosis (Sheehan syndrome).Hemorrhage that leads to blood transfusion is the leading cause of severe maternal morbidity in the United States closely followed by disseminated intravascular coagulation (2). In the United States, the rate of postpartum hemorrhage increased 26% between 1994 and 2006 primarily because of increased rates of atony (3). In contrast, maternal mortality from postpartum obstetric hemorrhage has decreased since the late 1980s and accounted for slightly more than 10% of maternal mortalities (approximately 1.7 deaths per 100,000 live births) in 2009 (2, 4). This observed decrease in mortality is associated with increasing rates of transfusion and peripartum hysterectomy (2-4).The purpose of this Practice Bulletin is to discuss the risk factors for postpartum hemorrhage as well as its evaluation, prevention, and management. In addition, this document will encourage obstetrician-gynecologists and other obstetric care providers to play key roles in implementing standardized bundles of care (eg, policies, guidelines, and algorithms) for the management of postpartum hemorrhage.

ACOG practice bulletin: Clinical management guidelines for obstetrician-gynecologists

Background: Germline BRCA1 mutations confer a substantial lifetime risk of breast and ovarian cancer, but whether cancer at other sites is increased is less clear To evaluate the risks of other cancers in BRCA1 mutation carriers, we conducted a cohort study of 11 847 individuals from 699 families segregating a BRCA1 mutation that were ascertained in 30 centers across Europe and North America Methods: The observed cancer incidence was compared with the expected cancer incidence based on population cancer rates Relative risks (RRs) of each cancer type in BRCA1 carriers relative to risks for the general population were estimated by weighting individuals according to their estimated probability of being a mutation carrier All statistical tests were two-sided Results: BRCA1 mutation carriers were at a statistically significantly increased risk for several cancers, including pancreatic cancer (RR = 226, 95% confidence interval [CI] = 126 to 406, P = 004) and cancer of the uterine body and cervix (uterine body RR = 265, 95% CI = 169 to 416, P<001; cervix RR = 372, 95% CI = 226 to 610, P<001) There was some evidence of an elevated risk of prostate cancer in mutation carriers younger than 65 years old (RR = 182, 95% CI = 101 to 329, P = 05) but not in those 65 years old or older (RR = 084, 95% CI = 053 to 133, P = 45) Overall, increases in the risk for cancer at sites other than the breast or ovary were small and evident in women (RR = 230, 95% CI = 193 to 275, P = 001) but not in men (RR = 095, 95% CI = 081 to 112, P = 58) Conclusions: In carriers of BRCA1 mutations, the overall increased risk of cancer at sites other than breast and ovary is small and is observed in women but generally not in men BRCA1 mutations may confer increased risks of other abdominal cancers in women and increased risks of pancreatic cancer in men and women

/pdf/cancer-incidence-in-brca1-mutation-carriers-1v1psor2r1.pdf

Cancer Incidence in BRCA1 Mutation Carriers

A population-based series of 649 unselected incident cases of ovarian cancer diagnosed in Ontario, Canada, during 1995–96 was screened for germline mutations in BRCA1 and BRCA2. We specifically tested for 11 of the most commonly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradient gel electrophoresis for the remainder of BRCA1, and with PTT for exons 10 and 11 of BRCA2. No mutations were found in all 134 women with tumors of borderline histology. Among the 515 women with invasive cancers, we identified 60 mutations, 39 in BRCA1 and 21 in BRCA2. The total mutation frequency among women with invasive cancers, 11.7% (95% confidence interval [95%CI] 9.2%–14.8%), is higher than previous estimates. Hereditary ovarian cancers diagnosed at age 60 years were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. Risks of ovarian, breast, and stomach cancers and leukemias/lymphomas were increased nine-, five-, six- and threefold, respectively, among first-degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of cases carrying BRCA2 mutations. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast-cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5′ fifth, but 8.8-fold increased risk for mutations in the 3′ fifth (95%CI 3.6–22.0), corresponding to a carrier penetrance of essentially 100%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer–cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Past studies may have underestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has focused more on early-onset disease. If confirmed in future studies, the trend in breast-cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a greater cause of cancer in male carriers than previously has been thought.

Prevalence and Penetrance of Germline BRCA1 and BRCA2 Mutations in a Population Series of 649 Women with Ovarian Cancer

Background: Increasing numbers of BRCA1 mutation carriers are being identified in cancer risk evaluation programs. However, no estimates of cancer risk specific to a clinic-based population of mutation carriers are available. These data are clinically relevant, because estimates based on families ascertained for linkage studies may overestimate cancer risk in mutation carriers, and population-based series may underestimate it. Wide variation in risk estimates from these disparate ascertainment groups makes counseling in risk evaluation programs difficult. The purpose of this study was to estimate BRCA1-related cancer risks for individuals ascertained in a breast cancer risk evaluation clinic. Methods: Cumulative observed and age-adjusted cancer risk estimates were determined by analyzing 483 BRCA1 mutation carriers in 147 families identified in two academic breast and ovarian cancer risk evaluation clinics. Cancer risks were computed from the proportion of individuals diagnosed with cancer during a 10-year age interval from among the total number of individuals alive and cancer-free at the beginning of that interval. Age-of-diagnosis comparisons were made using two-sided Student's t tests. Results: By age 70, female breast cancer risk was 72.8% (95% confidence interval [CI] = 67.9% to 77.7%) and ovarian cancer risk was 40.7% (95% CI = 35.7% to 45.6%). The risk for a second primary breast cancer by age 70 was 40.5% (95% CI = 34.1% to 47.0%). We also identified an increased risk of cancer of the colon (twofold), pancreas (threefold), stomach (fourfold), and fallopian tube (120-fold) in BRCA1 mutation carriers as compared with Surveillance, Epidemiology, and End Results (SEER) Program population-based estimates. Conclusion: The estimates for breast and ovarian cancer risk in BRCA1 mutation carriers is higher than population-based estimates but lower than estimates based on families ascertained for linkage studies. These cancer risk estimates may most closely approximate those faced by BRCA1 mutation carriers identified in risk evaluation clinics.

/pdf/cancer-risk-estimates-for-brca1-mutation-carriers-identified-14589mjwwh.pdf

Cancer Risk Estimates for BRCA1 Mutation Carriers Identified in a Risk Evaluation Program

We investigated risk models for the inherited susceptibility of breast and ovarian cancer, using data from both high-risk families and a population based series of ovarian cancer. The first data set consisted of 112 families containing two or more relatives with epithelial ovarian cancer. BRCA1 and BRCA2 germline mutations were detected in 50% of these families. The second study involved 374 ovarian cancer cases, unselected for family history, who had DNA samples analyzed for BRCA1 mutations. Twelve women were found to be carriers. We constructed genetic models for ovarian and breast cancer using the computer program MENDEL. In the first study, we modeled the effects of BRCA1 and BRCA2 simultaneously and allowed for a third gene predisposing to ovarian cancer. None of the models fitted gave significant evidence for a third gene. Population frequencies of BRCA1 and BRCA2 mutations were estimated to be 0.00128 and 0.00172, respectively. Our results suggest that BRCA1 and BRCA2 may be sufficient to explain the majority of familial ovarian cancer and that families without mutations can be explained by sensitivity of mutation testing and chance clusters of sporadic cases. Using data on the families of the 12 mutation carriers in the second study, we estimated age-specific ovarian and breast cancer risks for BRCA1 mutation carriers. Under the best-fitting model, the cumulative ovarian cancer risk was 66% by age 70, and the corresponding breast cancer risk was 45%. The high penetrance estimate for ovarian cancer, compared with other studies, suggests that modifying genetic or environmental factors may be important determinants of risk. Genet. Epidemiol. 18:173–190, 2000. © 2000 Wiley-Liss, Inc.

Risk models for familial ovarian and breast cancer.

We conducted a population-based study to determine the contribution of germline mutations in known candidate genes to ovarian cancer diagnosed at age <30 years. Women with epithelial ovarian cancer were identified through cancer registries. DNA samples were analyzed for mutations in BRCA1, the "ovarian cancer-cluster region" (nucleotides 3139-7069) of BRCA2, and the mismatch-repair genes hMSH2 and hMLH1. Probable germline mutations in hMLH1 were identified in 2 (2%; 95% confidence interval 1%-8%) of 101 women with invasive ovarian cancer diagnosed at age <30 years. No germline mutations were identified in any of the other genes analyzed. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or hereditary nonpolyposis colorectal cancer (HNPCC). There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk [RR] = 1.6, P=.01) but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had increased risks of ovarian cancer (RR = 4.8, P=.03), myeloma (RR = 10, P=.01), and non-Hodgkin lymphoma (RR = 7, P=.004). Germline mutations in BRCA1, BRCA2, msh2, and mlh1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Our data suggest that early-onset ovarian cancer is not associated with a greatly increased risk of cancer in close relatives.

The Genetic Epidemiology of Early-Onset Epithelial Ovarian Cancer: A Population-Based Study

Prevalence and penetrance of mutations in BRCA1 and BRCA2 in a population based series of breast cancer cases

Risk Models for Familial Breast and Ovarian Cancer. A. C. ANTONIOU\", D. F. EASTON\", S. A.GAYTHER#, J. F.STRATTON#andB. J.PONDER#. \"CRCGeneticEpidemiologyUnit, Institute of Public Health and #CRC Human Cancer Genetics Research Group, University of Cambridge, UK. We investigated risk models for the inherited susceptibility of breast and ovarian cancer, using data from both high-risk families and a population based series of ovarian cancer. The first data set consisted of 112 families containing 2 or more relatives with epithelial ovarian cancer. BRCA1 and BRCA2 germline mutations were detected in 50% of these families. The second study involved 374 ovarian cancer cases, collected at the Royal Marsden Hospital, London, who had DNA samples analysed for BRCA1 mutations. 12 women were found to be carriers. We constructed genetic models for ovarian and breast cancer using the computer program MENDEL. In the first study we modelled the effects of BRCA1 and BRCA2 simultaneously and allowed for a third gene predisposing to ovarian cancer. None of the models fitted gave significant evidence for a third gene. Population frequencies of BRCA1 and BRCA2 mutations were estimated to be 0±13% and 0±17% respectively. Our results suggest that BRCA1 and BRCA2 may be sufficient to explain the majority of familial ovarian cancer and that families without mutations can be explained by sensitivity of the mutation testing and chance clusters of sporadic cases. Using data on the families of the 12 mutation carriers in the second study, we estimated age specific ovarian and breast cancer risks for BRCA1 mutation carriers. Under the best fitting model the cumulative ovarian cancer risk was 66% by age 70, and the corresponding breast cancer risk was 45%. The differences in penetrance estimates among studies suggest that modifying genetic or environmental factors may be important determinants of

Risk Models for Familial Breast and Ovarian Cancer

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Risk models for familial ovarian and breast cancer.

The Genetic Epidemiology of Early-Onset Epithelial Ovarian Cancer: A Population-Based Study

Prevalence and penetrance of mutations in BRCA1 and BRCA2 in a population based series of breast cancer cases

Risk Models for Familial Breast and Ovarian Cancer