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While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Purpose: Risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study., Participants and Methods: This analysis included asymptomatic high-risk women age ≥ 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression., Results: Invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign., Conclusion: Clinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer., (© 2014 by American Society of Clinical Oncology.)

High-grade serous carcinomas of the uterine adnexa with BRCA1 deficiency (high-grade serous carcinomas-BRCA) have recently been described to demonstrate characteristic histopathological features. We hypothesize that metastatic high-grade serous carcinomas-BRCA cases exhibit characteristic morphological features as well. We studied 102 high-grade serous carcinomas with known BRCA1 and BRCA2 genotype from the archives of the Department of Pathology at Memorial Sloan-Kettering Cancer Center. The primary site morphological characteristics of these cases were reported previously; we now focus solely on tumor morphology in sites other than the uterine adnexa (ie, metastatic sites). The study group consisted of the following case types: 13 BRCA1 germline mutations; 5 BRCA1 somatic mutations; 10 BRCA1 promoter methylation; 4 BRCA2 germline mutations; 1 BRCA2 somatic mutation; 11 lacking BRCA1 or BRCA2 abnormality; 58 cases lacking BRCA1 or BRCA2 germline mutation. Two observers independently scored invasion patterns and microscopic tumor architecture while blinded to genotype. Concordance between observers and correlations between metastatic patterns and the following indices were studied: genotype, primary site tumor characteristics, and BRCA1 immunohistochemistry. Concordance between observers was excellent (κ values >0.9). All cases with BRCA1 or 2 abnormalities showed either pushing pattern metastases (76%) or infiltrative metastases composed only of micropapillae (24%). In contrast, all cases lacking BRCA1 or 2 abnormalities showed infiltrative metastases that contained combinations of papillary, glandular, and, rarely, cribriform and micropapillary architecture (P<0.0001 for comparison with pushing metastasis and P<0.001 for comparison with purely micropapillary architecture). Morphological assessment of metastatic carcinomas, a highly reproducible exercise, accurately correlated with BRCA1 status in every case, unlike morphological assessment of primary site adnexal high-grade serous carcinomas or BRCA1 immunohistochemistry. Metastatic high-grade serous carcinomas-BRCAs exhibit characteristic morphological features that appear more sensitive and specific for BRCA mutations than two other morphologically based prediction systems and should be easier to apply in practice. These findings should be validated prospectively in an independent cohort.

BRCA1/2 large rearrangement (LR) testing has been available to patients since 2006. Three existing models commonly used in cancer genetics clinical and research settings (BRCAPRO, Penn II and Myriad II) have not been assessed for their performance in predicting the presence of BRCA1/2 large genomic rearrangements in patients who do not have mutations detectable by the traditional Sanger sequencing approach. This study sought to determine if there is an optimal pre-test probability "cut off" value, calculated using these models, to optimize detection of large rearrangements (LRs). Our cohort consisted of 3,301 probands seen for genetic counseling and BRCA1/2 clinical testing from September 2006 to September 2011. A detailed personal and three-generation family history, including self-reported ethnicity, was taken as part of our standard clinical practice. We applied the BRCAPRO, Penn II, and Myriad II models to the probands with LRs. In our cohort of 3,301 probands, 150 carried a non-Ashkenazi mutation in BRCA1 or BRCA2. Seventeen unrelated probands carried a private BRCA1/2 LR (17/150, 11.3 % of all detectable non-AJ mutations). At a pre-test probability cutoff of 10 %, all three empiric risk models would have failed to identify almost 30 % of probands with LRs. Our study shows that BRCA1/2 LR testing should be offered to all women who meet criteria for BRCA1/2 sequence analysis.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Competing Interests: The authors have declared that no competing interests exist.

This study was undertaken with the hypothesis that certain common morphologic features of ovarian carcinomas are predictably associated with BRCA1 and BRCA2 deficiencies. We selected 43 high-grade serous carcinomas diagnosed at Memorial Sloan-Kettering Cancer Center that were studied as part of The Cancer Genome Atlas pilot project. In addition to 12 randomly selected nonfamilial BRCA-unassociated cases, all 31 Memorial Sloan-Kettering Cancer Center cases with BRCA1 or BRCA2 abnormality were included (n=43). Slides were examined to assess tumor architecture, mitotic index, tumor-infiltrating lymphocytes (TILs), nuclear pleomorphism, necrosis, and involvement of fallopian tube epithelium. Comparing BRCA1-associated cases (BRCA1 germline mutation, n=4, BRCA1 somatic mutation, n=6, BRCA1 promoter methylation, n=13) with unassociated cases (n=12) identified statistically significant differences in morphology. BRCA1-associated high-grade serous carcinomas had more frequent Solid, pseudoEndometrioid, and Transitional cell carcinoma-like morphology (SET features) (P=0.0045), higher mitotic indexes (P=0.012), more TILs (P=0.034), and either geographic or comedo necrosis (P=0.034). BRCA2-associated cases (germline mutation, n=4 and somatic mutation, n=4) tended to show SET features, but they were relatively deficient in TILs and necrosis. Two algorithms incorporating tumor architecture, necrosis, and either mitotic indexes or TILs separated cases that showed 2 of 3 features (BRCA1 associated) from those with 0 of 3 features (BRCA unassociated; P=0.0016 and P=0.0033). A test set comprising 9 BRCA1 germline mutants and 14 high-grade serous carcinoma controls lacking BRCA1 and BRCA2 germline mutation was used to validate the algorithms, with specific emphasis on the ability to detect cases with BRCA1 germline mutation. Best results were obtained with the algorithm that incorporated SET features, necrosis, and mitotic index (P=0.0072; sensitivity of 1.0 (95% CI, 0.66-1.0); specificity of 0.57 (95% CI, 0.29-0.82); positive predictive value of 0.60 (95% CI, 0.32-0.84) and a negative predictive value of 1.0 (95% CI, 0.63-1.0)). These preliminary data indicate potential strong associations between morphology and genotype in high-grade serous carcinomas.

Purpose of Review: This review will focus on the implications of BRCA status in the patient with high-grade serous ovarian cancer, the differences between BRCA1 and BRCA2 mutations, and the most effective risk-reducing strategies., Recent Findings: Women with BRCA-associated epithelial ovarian cancer represent a unique group who commonly are diagnosed at a younger age, have advanced high-grade serous disease, have improved sensitivity to platinum-based chemotherapy in both the upfront and recurrent setting, and have an overall improved prognosis. Promising novel therapeutic agents such as poly (ADP-ribose) polymerase inhibitors have increased activity in patients with inherited BRCA mutations and may also have a role in patients with noninherited tumors that have decreased BRCA activity. Risk-reducing salpingo-oophorectomy (RRSO) is effective in decreasing risks of both breast and gynecologic cancer in women with BRCA mutations. However, when counseling women at inherited risk, the inherent phenotypical differences between BRCA1 and BRCA2 mutations must be considered., Summary: Patients with BRCA-associated epithelial ovarian cancer have improved response to platinum-based chemotherapy, improved survival, and may be appropriate candidates for treatment with novel targeted therapies. RRSO remains the most effective risk-reduction strategy in women with BRCA mutations.

Genome-wide association studies (GWAS) have now been performed in nearly all common malignancies and have identified more than 100 common genetic risk variants that confer a modest increased risk of cancer. For most discovered germline risk variants, the per allele effect size is small (<1.5) and the biologic mechanism of the detected association remains unexplained. Exceptions are the risk variants identified in JAK2 in myeloproliferative neoplasm and in the KITLG gene in testicular cancer, which are each associated with nearly a 3-fold increased risk of disease. GWAS have provided an efficient approach to identifying common, low-penetrance risk variants, and have implicated several novel cancer susceptibility loci. However, the identified low-penetrance risk variants explain only a small fraction of the heritability of cancer and the clinical usefulness of using these variants for cancer-risk prediction is to date limited. Studies involving more heterogeneous populations, determination of the causal variants, and functional studies are now necessary to further elucidate the potential biologic and clinical significance of the observed associations., (Copyright 2010 Elsevier Inc. All rights reserved.)

A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.

Endometrial and ovarian cancer are the fourth and fifth most common malignancies in women, with approximately 40,000 new endometrial and 25,000 new ovarian cancers expected to be diagnosed in the Unites States this year. While the majority of these cancers will occur in the absence of a family history, approximately 5% of endometrial cancers and 10% of ovarian cancers will be the result of inherited defects in high-penetrance cancer susceptibility genes. With the identification and subsequent availability of clinical genetic testing for mutations in the genes associated with hereditary breast-ovarian cancer and the Lynch/hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, targeted risk-reduction using intensive screening, chemoprevention, and prophylactic surgery has become possible for women at inherited risk of gynecologic malignancies. We review the options for gynecologic cancer risk reduction in women with an inherited mutation in BRCA1, BRCA2, or one of the mismatch repair (MMR) genes associated with Lynch/HNPCC syndrome. Additionally, we outline ongoing questions and areas for future research.

Women who carry mutations in either the BRCA1 or BRCA2 genes are at risk for early-onset breast cancer and are recommended to begin screening mammography at age 25 to 30 years. Results of in vitro and animal studies suggest that BRCA1/BRCA2 mutation carriers are hypersensitive to ionizing radiation and possibly to radiation-induced breast cancer. This study was undertaken to investigate the association of low-dose radiation exposure from mammograms with breast cancer status in BRCA mutation carriers. One hundred sixty-two female mutation carriers provided information at time of genetic testing about exposure to mammograms before enrollment. Using unconditional logistic regression, breast cancer status was not associated with number of mammograms received before diagnosis (affected women) or ascertainment [unaffected women; adjusted odds ratio (OR), 0.94; P = not significant]. A larger group of 213 women provided information about lifetime number of mammograms. There was no association between mammogram exposure and risk in the group as a whole (adjusted OR, 1.04; P = not significant), although there was a modest association in BRCA1 carriers (adjusted OR, 1.08; P = 0.03). These findings indicate that screening mammography is unlikely to be associated with a large increase in breast cancer risk in this population.

Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.

Background: Women with family histories suggestive of an increased risk of ovarian carcinoma who have not had a deleterious BRCA1 or BRCA2 mutation identified are commonly suggested to consider ovarian carcinoma screening with transvaginal ultrasound and/or assessment of CA 125 levels. Limited information is available regarding the impact of this approach on either quality of life (QOL) or need for invasive follow-up in this group of women., Methods: From November 1999 to October 2002, 184 women at intermediate risk of ovarian carcinoma were enrolled in a prospective study. Participants were screened with twice yearly transvaginal ultrasound and CA 125 assessments. Impact on QOL was measured using the Mental Component Summary (MCS) score of the Medical Outcomes Studies Short Form-36. Need for invasive follow-up was determined by questionnaire and medical record review., Results: In the current study, 135 participants underwent > or = 1 follow-up assessment. During a mean of 19.8 months of follow-up, 12.9% of ultrasounds and 3.8% of CA 125 assessments were abnormal. The authors reported that 38.5% of participants had > or = 1 abnormal ovarian screen that required a short interval follow-up. Because of either abnormal bleeding or ultrasound abnormalities, 24% of participants underwent > or = 1 endometrial sampling. Controlling for a history of breast carcinoma and menopausal status, abnormal ovarian screening results were associated with a decrease in MCS score (P = 0.034), whereas the need for endometrial sampling was not (P = 0.87)., Conclusions: Ovarian carcinoma screening in women at intermediate risk was associated with a substantial rate of abnormal screen results, endometrial sampling, and in women with abnormal ovarian screening findings, a decrease in MCS scores. These findings may have important implications for women considering ovarian carcinoma screening and for the design of future ovarian carcinoma screening trials.

Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms occurring at young age. Germline mutations in the TP53 tumor suppressor gene have been identified in approximately 71 of LFS patients and 22 of Li-Fraumeni-like (LFL) patients. Mutations within the cell cycle checkpoint gene CHEK2 have also been reported in some patients with LFS, LFL, and phenotypically suggestive of LFS (PS-LFS) not carrying a TP53 mutation. In this study, we show that 7 of the 23 patients with LFS/LFL tested positive for deleterious mutations in p53. Fifteen of the remaining sixteen were not found to carry the CHEK2* 1100delCmutation. These results indicate that CHEK2*1100delC is not a common cause of LFS, LFL, or PS-LFS in North American kindreds not carrying a TP53 mutation. Of note, two patients were found to carry p53* R72P, which is of unknown clinical significance. Lack of segregation of this allele in one of these kindreds provides strong evidence that the R72P allele is not disease-causing. While mutations in p53 account for a proportion of patients with LFS/LFL, future studies are needed to determine if other genes are responsible for LFS/LFL families not carrying germline p53 mutations.

Purpose: YKL-40 is a secreted glycoprotein (chitinase family). We compared YKL-40 with two ovarian cancer serum markers, CA125 and CA15-3, for the detection of early-stage ovarian cancer., Materials and Methods: Serum YKL-40 levels were assayed by enzyme-linked immunosorbent assay for 46 healthy subjects, 61 high-risk individuals, 33 patients with benign gynecologic processes, and 50 preoperative patients subsequently diagnosed with predominantly early-stage ovarian cancer. Serum CA125 and CA15-3 values were obtained., Results: Median YKL-40 level was 28 ng/mL (range, 15 to 166 ng/mL) for healthy subjects, 36 ng/mL (range, 9 to 69 ng/mL) for high-risk individuals without prior cancer, 44.5 ng/mL (range, 5 to 133 ng/mL) for high-risk patients with prior breast cancer, and 38 ng/mL (range, 5 to 67 ng/mL) for individuals with benign gynecologic processes (P = NS). Median preoperative YKL-40 level for ovarian cancer patients was 94 ng/mL (range, 17 to 517 ng/mL; P <.0001 compared with normal and high-risk). YKL-40 was elevated (>/= 62 ng/mL) in 36 (72%) of 50 patients compared with 23 (46%) of 50 and 13 (26%) of 50 patients for CA125 and CA15-3 (P <.008). Twenty (65%) of 31 early-stage patients had elevated serum YKL-40 levels compared with 11 (35%) of 31 and four (13%) of 31 patients for CA125 and CA15-3 (P =.039). YKL-40 levels increased with stage (P <.005), regardless of grade, histology, or patient age. Patients with early-stage tumors with YKL-40 values more than 80 ng/mL had a worse prognosis (71% recurrence v no recurrence [P =.034])., Conclusion: YKL-40 may represent a novel marker for the detection of early-stage ovarian cancer. YKL-40 levels in early-stage patients may also predict disease recurrence and survival. The utility of YKL-40 in detection of early-stage ovarian cancer deserves further investigation.

Purpose: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study., Experimental Design: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age., Results: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64-7.06; P = 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87-12.25; P = 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased., Conclusions: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.

Ovarian cancer is the fourth leading cause of cancer deaths among American women. While women in both the Ashkenazi and non-Ashkenazi populations have an estimated 1.7% lifetime risk of acquiring malignancy, the proportion of hereditary ovarian cancer is much higher in the Ashkenazim. Most of this increased proportion of hereditary ovarian cancer risk is accounted for by inherited mutations in the BRCA1 and BRCA2 genes. In the Ashkenazi Jewish population, 29 to 41% of ovarian cancer is believed to be secondary to inheriting one of three founder mutations in BRCA 1 and BRCA 2, while only 10% of ovarian cancer is attributed to mutations of these genes in non-Ashkenazim. In the US population in general, it is estimated that between 1 out of 345 and 1 out of 1000 individuals carries a BRCA mutation, compared with approximately 1 in 40 individuals of Ashkenazi Jewish descent. The ovarian cancer risk up to age 70 associated with BRCA mutation carriers has been reported to be as high as 66% for BRCA1 and 27% for BRCA2 mutation carriers. Ovarian cancer in Ashkenazi kindreds has served as a model for the study of the histopathology of inherited ovarian cancers as well as for the study of risk reduction and screening among all women at inherited risk of ovarian cancer.

Purpose: Several studies to date have reported ovarian cancer risk due to inherited BRCA1 and BRCA2 mutations using familial data or population-based series of probands. Familial aggregation associated with both of these methods may result in a substantial ascertainment bias. To address this, we have used a case-control design that does not involve familial aggregation to estimate the lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations., Experimental Design: A total of 382 ovarian cancer cases self-identified as being Jewish with no prior diagnosis of breast cancer were derived from two hospital-based series. In the first series, all 197 invasive epithelial ovarian cancer cases self-identified as Jewish and without a prior history of breast cancer, diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and 2000, were identified. In the second series, 185 Jewish invasive epithelial ovarian cancer patients without prior breast cancer were identified in a study conducted at 11 centers in North America and Israel from 1995 to 1996. Controls were 3434 Jewish women without any prior history of breast or ovarian cancer from a large study of genotyped volunteers of Jewish origin in the Washington, D. C. area recruited by investigators at the National Cancer Institute. The cases and controls were genotyped for three Ashkenazi Jewish founder mutations, namely 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances were estimated using the odds ratios, mutation prevalence in the controls, and ovarian cancer incidence rates in the general American population obtained from the Surveillance, Epidemiology and End Results database adjusted for the incidence of ovarian cancer following breast cancer., Results: Mutations were identified in 147 cases and 62 controls. The estimated penetrances at age 70 years were 37% (95% confidence interval, 25-71%) for a BRCA1 mutation and 21% (95% CI, 13-41%) for a BRCA2 mutation., Conclusions: The lifetime penetrances of BRCA1 mutations are lower than estimates obtained using familial data with multiple affected members but larger than estimates from some population-based proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the range reported by some of the studies based on familial data. These results could have implications for clinical counseling, surgical interventions, and screening recommendations in women carrying these founder mutations.

Purpose: In this study, we first sought to evaluate whether individuals heterozygous for ATM mutations may have an increased susceptibility to radiation-induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next sought to determine the frequency of ATM variants in patients with Hodgkin's lymphoma, regardless of coexisting BC, compared with healthy volunteers., Experimental Design: Full sequence analysis of ATM was performed on cDNA from peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation therapy for HD and 27 comparison cases with HD and no BC treated during the same time period. The frequency of ATM variants was analyzed in the total group of 64 cases of HD and compared to allele frequencies in 128 ethnically matched controls from the same geographical region., Results: No protein-truncating ATM mutations were observed in cases with HD with or without BC. Missense mutations were more frequent in the cohort with HD compared with patients with BC following HD (P = 0.02). The median time from HD to the development of BC was 18 years in patients with ATM variants compared with 16 years in those with no ATM variants (P = 0.04). Multiple ATM variants, including one homozygous mutation, were observed in 9 HD cases., Conclusions: Heterozygous protein-truncating or missense mutations of ATM were not associated with increased radiation-associated risk of BC after HD. The observation of multiple germ-line mutations and a homozygote suggests that rare ATM variants may constitute cancer-susceptibility alleles in a subset of cases.