Genetic carrier screening for spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 in an isolated population in Israel

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by progressive muscle weakness. It is caused by a mutation in the survival motor neuron gene 1 (SMN1) gene. SMA with respiratory distress 1 (SMARD1), an uncommon variant of infantile SMA also inherited in an autosomal recessive manner, is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene. We carried out genetic carrier screening among the residents of an isolated Israeli Arab village with a high frequency of SMA in order to identify carriers of SMA type I and SMARD1. During 2006, 168 women were tested for SMA, of whom 13.1% were found to be carriers. Of 111 women tested for SMARD1, 9.9% were found to be carriers. Prenatal diagnosis was performed in one couple where both spouses were carriers of SMARD1; the fetus was found to be affected, and the pregnancy was terminated. To the best of our knowledge, this is the first example of the establishment of a large-scale carrier-screening program for SMA and SMARD1 in an isolated population. SMA has a carrier frequency of 1:33-1:60 in most populations and should be considered for inclusion in a population-based genetic-screening program.     

Increased risk of breast cancer in women with false-positive test: The role of misclassification

IntroductionStudies have shown that women with a false-positive result from mammography screening have an excess risk for breast cancer compared with women who only have negative results. We aimed to assess the excess risk of cancer after a false-positive result excluding cases of misclassification, i.e. women who were actually false-negatives instead of false-positives.MethodWe used data from the Copenhagen Mammography Screening Programme, Denmark. The study population was the 295 women, out of 4743 recalled women from a total of 58,003 participants, with a false-positive test during the screening period 1991–2005 and who later developed breast cancer. Cancers that developed in the same location as the finding that initially caused the recall was studied in-depth in order to establish whether there had been misclassification.ResultsSeventy-two cases were found to be misclassified. When the women with misclassified tests had been excluded, there was an excess risk of breast cancer of 27% (RR = 1.27, 95% confidence interval (CI), 1.11–1.46) among the women with a false-positive test compared to women with only negative tests. Women with a false-positive test determined at assessment had an excess risk of 27%, while false-positives determined at surgery had an excess risk of 30%.ConclusionsThe results indicate that the increased risk is not explained only by misclassification. The excess risk remains for false-positives determined at assessment as well as at surgery, which favours some biological susceptibility. Further research into the true excess risk of false positives is warranted.     

Apropas phenomenon of women predominance among carriers of reciprocal translocations during disturbances in reproduction

The predominance of females among reciprocal (rec) translocation carriers, which have problems with reproduction in the anamnesis, is well established and usually accounts for the sterility of male carriers of this type of translocations. However, no careful comparative studies have been performed. Meta-analysis of the data on the examined pairs with reproduction problems shows that, among patients with infertility, the frequency of rec carriers was observed in 0.48% (74/15304) of men and in 0.41% (64/15454) of women; the sex ratio (SR) was 1.17, which does not differ significantly from the population value, 1.06 (p = 0.36). Robertsonian translocations (rob) were observed in 0.58% of men and in 0.11% of women; SR = 5.3 (p = 5 × 10^–13) in this group. Inversions (inv) were more often detected in women than in men, 0.14 and 0.27%, SR = 0.59 (p = 0.020). Among patients with habitual miscarriages, the frequencies of rec carriers were significantly higher than in patients with infertility: in 0.78% (151/19353) of men and in 1.42% (281/19737) of women, GR = 0.55 (p = 10^–9). Carriers of rob were found in 0.33% of men and 0.60% of women, SR = 0.55 (p = 9.7 × 10^–5). The frequency of inv was 0.17 and 0.20%, respectively. The results supports the notion that the predominance of women among fertile carriers of rob is caused by the sterility of male carriers of such rearrangements. However, the predominance of women among fertile carriers of rec cannot be due to this reason. The first reason is because there is no significant prevalence of men over women among infertile carriers of such type translocations. The second reason is because the frequency of rec male carriers among patients with infertility is significantly lower than their frequency among fertile carriers. It is likely that the reason for the observed phenomenon is the inherent oogenesis factors which affect segregation of the aberrant chromosomes.     

Angiotensinogen gene M235T variant and pre-eclampsia in Romanian pregnant women

Background. Association between the human angiotensinogen gene and essential hypertension has been confirmed in recent studies. Pre-eclampsia is a complication of pregnancy characterised by increased vascular resistance, high blood pressure, proteinuria and oedema, that appears in the second and third trimester of pregnancy. The aim of our study was the analysis of M235T mutation in the gene encoding angiotensinogen in Romanian women with different forms of hypertension during pregnancy. Methods. Fourteen women with obstetric complications were tested for M235T angiotensinogen gene mutation. Indications for testing were: severe or mild pre-eclampsia and pre-eclampsia associated with chronic hypertension. We also tested for control 6 healthy women. The M235T angiotensinogen gene mutation was analysed by polymerase chain reaction followed by enzymatic digestion with Tth 111I restriction endonuclease enzyme and agarose gel electrophoresis of the products. Results. Eleven (78.57%) of the 14 women with complications of pregnancy had M235T mutation: 9 (64.28%) were found to be heterozygous carriers of the M235T variant of the angiotensinogen gene and 2(14.28%) were found to be homozygous carriers. In the group of women with normal pregnancy, 3 (50%) of the 6 women had M235T mutation: 2 (33.33%) were found to be heterozygous carriers of the M235T variant of the angiotensinogen gene and 1 (16.66%) was found to be homozygous carrier. Conclusions. Our study shows that the M235T variant in the gene encoding angiotensinogen could be a risk factor in mild and severe pre-eclampsia.     

Clinical and radiological features of breast tumors according to history of false-positive results in mammography screening

BackgroundWomen with a false-positive result after a screening mammogram have an increased risk of cancer detection in subsequent participations, especially after assessments involving cytology or biopsy. We aimed to compare women's personal characteristics, tumoral features and the radiological appearance of cancers with and without a previous false-positive result generated by additional imaging or invasive procedures.MethodsFrom 1996 to 2007, 111,098 women aged 45–69 years participated in four population-based breast cancer screening programs in Spain, and 1281 cancers were detected. We included all cancers detected in subsequent screenings (n = 703) and explored the occurrence of previous false-positive results. We identified false-positives requiring additional imaging or invasive procedures. Differences on tumoral features (invasiveness, tumor size, and lymph node status) and radiological appearance were assessed by Chi-square test, and agreement between the location of cancer and prior suspicious by Cohen's kappa coefficient. A multivariate analysis was preformed to evaluate the effect of previous screening results and age on the odds of presenting an in situ carcinoma.ResultsAmong the 703 cancers detected in subsequent screenings, 148 women (21.1%) had a previous false-positive result. Of these, 105 were by additional imaging and 43 by invasive procedures. Women with prior false-positive result requiring invasive assessment, compared to women with negative tests, and women with prior false-positive requiring additional imaging, had a higher proportion of in situ carcinomas (31.7%, 15.3%, 12.9%, respectively; p = 0.014) and microcalcifications (37.2%, 20.2%, 9.5%, respectively; p = 0.003). The proportion of in situ carcinomas was even higher in women over 60 years (39.2%, 12.5%, 13.0%, respectively; p = 0.001). Ipsilateral cancer was observed in 65.7% of cases with prior cytology or biopsy (k = 0.479; 95%CI: 0.330–0.794).ConclusionA large number of in situ malignancies and calcification patterns were found among women with prior false-positive result in mammography screening requiring cytology or biopsies, suggesting progression from a previously benign lesion.     

Haemochromatosis gene (HFE) mutations in viral-associated neoplasia: Linkage to cervical cancer

The present study examines the frequency of the two main HFE mutations (C282Y and H63D) in a randomly selected population of 346 individuals including 201 DNA samples from women with cervical neoplasia (including high-grade squamous intraepithelial lesions and invasive squamous cell carcinoma) and a control population of 146 women from the same geographical area. We found a significantly lower risk of development of cervical neoplasia in H63D carriers (OR = 0.56; 95% CI 0.35-0.92; p = 0.01). Multivariate logistic regression analysis confirms this observation (OR = 0.55; 95% CI 0.35-0.88, p = 0.01). Regarding the C282Y mutation no association was found (OR = 1.32; 95% CI 0.53-3.33; p = 0.52). In addition, a significant difference between H63D carrier and non-carrier women on the time-to-onset of cervical lesions was observed (log-rank test: p = 0.0012). These results indicate that HFE could be considered a candidate modifier gene of viral-related neoplasia such as cervical carcinoma possibly by a dual role on iron metabolism and immunological system.     

Fragile-X Carrier Screening and the Prevalence of Premutation and Full-Mutation Carriers in Israel

Fragile-X syndrome is caused by an unstable CGG trinucleotide repeat in the FMR1 gene at Xq27. Intermediate alleles (51-200 repeats) can undergo expansion to the full mutation on transmission from mother to offspring. To evaluate the effectiveness of a fragile-X carrier-screening program, we tested 14,334 Israeli women of child-bearing age for fragile-X carrier status between 1992 and 2000. These women were either preconceptional or pregnant and had no family history of mental retardation. All those found to be carriers of premutation or full-mutation alleles were offered genetic counseling and also prenatal diagnosis, if applicable. We identified 207 carriers of an allele with >50 repeats, representing a prevalence of 1:69. There were 127 carriers with >54 repeats, representing a prevalence of 1:113. Three asymptomatic women carried the fully mutated allele. Among the premutation and full-mutation carriers, 177 prenatal diagnoses were performed. Expansion occurred in 30 fetuses, 5 of which had an expansion to the full mutation. On the basis of these results, the expected number of avoided patients born to women identified as carriers, the cost of the test in this study (U.S. $100), and the cost of lifetime care for a mentally retarded person (>$350,000), screening was calculated to be cost-effective. Because of the high prevalence of fragile-X premutation or full-mutation alleles, even in the general population, and because of the cost-effectiveness of the program, we recommend that screening to identify female carriers should be carried out on a wide scale.     

Prevalence of carriers of premutation-size alleles of the FMRI gene--and implications for the population genetics of the fragile X syndrome.

The fragile X syndrome is the second leading cause of mental retardation after Down syndrome. Fragile X premutations are not associated with any clinical phenotype but are at high risk of expanding to full mutations causing the disease when they are transmitted by a carrier woman. There is no reliable estimate of the prevalence of women who are carriers of fragile X premutations. We have screened 10,624 unselected women by Southern blot for the presence of FMR1 premutation alleles and have confirmed their size by PCR analysis. We found 41 carriers of alleles with 55-101 CGG repeats, a prevalence of 1/259 women (95% confidence interval 1/373-1/198). Thirty percent of these alleles carry an inferred haplotype that corresponds to the most frequent haplotype found in fragile X males and may indeed constitute premutations associated with a significant risk of expansion on transmission by carrier women. We identified another inferred haplotype that is rare in both normal and fragile X chromosomes but that is present on 13 (57%) of 23 chromosomes carrying FMR1 alleles with 53-64 CGG repeats. This suggests either (1) that this haplotype may be stable or (2) that the associated premutation-size alleles have not yet reached equilibrium in this population and that the incidence of fragile X syndrome may increase in the future.     

Success of a program of routine prenatal screening for hepatitis B surface antigen: the first 2 years.

Prenatal screening for hepatitis B surface antigen (HBsAg) restricted to women with defined risk factors for chronic hepatitis B virus (HBV) infection fails to identify many carriers. A centralized program of routine HBsAg screening for all pregnant women in Alberta was introduced in 1985. We collected and analysed data for the first 2 years of the program in Edmonton to determine the frequency of risk factors for HBsAg positivity, the proportion of multiparous HBsAg-positive women not identified in previous pregnancies, the efficiency and cost-effectiveness of providing immunoprophylaxis to infants at risk of HBV infection and the degree of success in inducing adequate protection. A total of 149 women (158 pregnancies) were found to be HBsAg positive. Risk factors were readily ascertainable for 85% of the women; the remaining 15% would not have been identified through risk-selective screening. The most common risk factors were Oriental ethnic origin, history of hepatitis, jaundice or multiple transfusions of blood or blood products, and occupational exposure to blood. Although 86% of the multiparous HBsAg-positive women had risk factors, only 7% had been identified in previous pregnancies. The Alberta program appears to be cost-effective. We conclude that only routine prenatal screening will identify all infants at risk of perinatal HBV infection and that a comprehensive public health program involving central laboratories, private physicians and public health staff can be highly effective and efficient in protecting infants against hepatitis B.     

Early detection of ovarian cancer: background, rationale, and structure of the Yale Early Detection Program.

Ovarian cancer has received national attention as a highly virulent disease. Its lack of early warning symptoms and the failure to develop highly sensitive screening tests have led some physicians to recommend prophylactic oophorectomies to women with relatives who have had ovarian cancer. Others have recommended routine screening of otherwise normal women for CA 125, a circulating tumor marker, and ultrasound examinations. Each of these techniques is associated with substantial false-positive rates that could lead to unnecessary surgery. A review of epidemiologic data suggests that familial ovarian cancer kindreds are rare, but women with first-degree relatives who have had ovarian cancer have a significant risk themselves for developing ovarian cancer. In addition, women with a great number of ovulatory cycles are at an increased risk for the disease. Circulating tumor markers are frequently elevated in women with advanced ovarian cancer, but their value in early detection of ovarian cancer has yet to be established. Advances in endovaginal ultrasound and color Doppler flow technology have significantly improved our ability to assess pelvic organs. This article presents the background, rationale, and structure of the Yale Early Detection Program for ovarian cancer, whose goals are to identify the best techniques for diagnosing ovarian cancer in an early stage, to determine the frequency with which such tests should be employed, to assess false-positive results, and to identify women who might benefit from prophylactic oophorectomies.     

Regional distribution of heterozygous 657del5 mutation carriers of theNBS1 gene in Wielkopolska province (Poland)

The homozygous 657del5 mutation, called Slavic mutation, of the NBS1 gene, causes the Nijmegen Breakage Syndrome (NBS). This syndrome is connected with a high incidence of malignancies in early childhood. A high frequency of NBS heterozygotes was found among patients with melanoma, breast, ovary and prostate cancer. The aim of our research was to determine the frequency of 657del5 mutation of the NBS1 gene in the population of Wielkopolska province. For this purpose, we analysed blood samples from anonymous Guthrie cards. In a group of 2090 newborns from the whole province, we found 16 heterozygous mutation carriers. The frequency of 1/131 is higher than 1/190 reported for populations from other regions in Poland. We observed differential regional distribution of heterozygous 657del5 mutation carriers within the province: among 464 samples from the eastern part of Wielkopolska we found 6 carriers (1/77), in contrast to the southern part without any carrier among 625 samples analysed. The high mean frequency of heterozygous 657del5 mutation (1/131) in Wielkopolska province may be associated with cancer incidence in this region.     

Rapid clearance of fetal DNA from maternal plasma.

Fetal DNA has been detected in maternal plasma during pregnancy. We investigated the clearance of circulating fetal DNA after delivery, using quantitative PCR analysis of the sex-determining region Y gene as a marker for male fetuses. We analyzed plasma samples from 12 women 1-42 d after delivery of male babies and found that circulating fetal DNA was undetectable by day 1 after delivery. To obtain a higher time-resolution picture of fetal DNA clearance, we performed serial sampling of eight women, which indicated that most women (seven) had undetectable levels of circulating fetal DNA by 2 h postpartum. The mean half-life for circulating fetal DNA was 16.3 min (range 4-30 min). Plasma nucleases were found to account for only part of the clearance of plasma fetal DNA. The rapid turnover of circulating DNA suggests that plasma DNA analysis may be less susceptible to false-positive results, which result from carryover from previous pregnancies, than is the detection of fetal cells in maternal blood; also, rapid turnover may be useful for the monitoring of feto-maternal events with rapid dynamics. These results also may have implications for the study of other types of nonhost DNA in plasma, such as circulating tumor-derived and graft-derived DNA in oncology and transplant patients, respectively.     

Peptide-to-protein distribution versus a competition for significance to estimate error rate in blood protein identification

The simplest model—that authentic tandem mass spectrometry (MS/MS) spectra are no different from noise, random spectra, or false-positive results—may be directly examined by chi-square comparison of the peptide-to-protein distribution. The peptide-to-protein distribution of a set of 4151 redundant blood proteins identified by X!TANDEM indicated that there is a low probability that the authentic data were the same as noise, random spectra, or false-positive correlations (P < 0.0001). In contrast, a competition for significance failed to distinguish approximately 90% of authentic blood proteins from those of noise, random spectra, or false-positive results (P < 0.01) and apparently incurred a large type II error (false negative). The chi-square test of peptide-to-protein frequency distributions was found to be an efficient means to distinguish authentic data from false-positive results. Frequency-based statistics unambiguously demonstrated that proteins can be identified by liquid chromatography–electrospray ionization-MS/MS from human blood with acceptable confidence. Thus, the chi-square fit of the peptide-to-protein distribution could distinguish authentic data from random or false-positive data, but the score distribution method could not separate real results from false results.     

Cystic fibrosis heterozygote screening in 5,161 pregnant women.

A screening program for cystic fibrosis (CF) heterozygotes was conducted in a large HMO prenatal population, to evaluate the level of interest among eligible patients, the effectiveness of prescreening education, attitudes toward the screening process, psychological effects, and utilization of prenatal diagnosis and its outcomes. The heterozygote identification rate and frequency of specific CFTR mutations were also assessed. Identified carriers were offered genetic counseling and testing of male partners. Prenatal diagnosis was offered if both parents were identified as carriers. A total of 5,161 women underwent carrier testing; 947 others completed survey instruments only. The acceptance rate of screening was high (78%), and pretest education by videotape was generally effective. Adverse psychological effects were not reported. Participants generally found screening to be desirable and useful. Screening identified 142 female heterozygotes, 109 couples in which the male partner was not a carrier, and 7 high-risk couples. The incidence of R117H mutations was much higher than expected. The number of identified carriers was much lower in Hispanics than in Caucasians. We conclude that large-scale prenatal screening for CF heterozygotes in the absence of a family history of CF is an acceptable method for identifying couples at risk for affected fetuses. Sufficient pretest education can be accomplished efficiently, test insensitivity is well accepted, adverse psychological events are not observed, and general patient satisfaction is high.     

Similar Mechanisms Underlie the Detection of Horizontal and Vertical Disparity Corrugations

Our aim was to compare sensitivity for horizontal and vertical disparity corrugations and to resolve whether these stimuli are processed by similar or radically different underlying mechanisms. We measure global disparity sensitivity as a function of carrier spatial frequency for equi-detectable carriers and found a similar optimal carrier relationship for vertical and horizontal stimuli. Sensitivity as a function of corrugation spatial frequency for stimuli of comparable spatial summation and composed of optimal, equi-detectable narrowband carriers did not significantly differ for vertical and horizontal stimuli. A small anisotropy was revealed when fixed, high contrast broadband carriers were used. In a separate discrimination-at-threshold experiment, multiple mechanisms of similar tuning were revealed to underlie the detection of both vertical and horizontal disparity corrugations. We conclude that the processing of the horizontal and vertical disparity corrugations occurs along similar lines.     

Abnormalities of the Electrocardiogram in Female Carriers of Duchenne Muscular Dystrophy

The algebraic sum of the R and S waves (R-S) in the V₁ lead of the electrocardiogram has been found to be significantly greater in female carriers of X-linked Duchenne muscular dystrophy (but not in women with limb-girdle muscular dystrophy) compared with normal women of comparable age. A similar E.C.G. abnormality is found in affected boys, and possibly certain carriers have a latent cardiomyopathy and may even be predisposed to cardiac failure.     

Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.     

The use of fructose 1-phosphate to detect Hunter heterozygotes in fibroblast cultures from high-risk carriers

Summary Fibroblast cultures from 49 possible Hunter disease carriers were collected. These cultures were analysed for the incorporation of ³⁵S-sulphate into acid mucopolysaccharides in the presence and the absence of fructose 1-phosphate. For 10 of these women more than one abnormal result was observed, when two or three cultures from each individual were tested. For six additional women only one abnormal result was found, when three cultures for each of these females were analysed. The implication that just one abnormal result indicates carriership stems from the observation that 24 out of 25 obligate carriers have been confirmed by this criterion (Tønnesen et al. 1983). By mean of the same criterion we have thus established carriership for 16 possible carriers. From genetic inference three additional carriers were found among the females showing normal results in the fibroblast cultures. As a test of the reliability of the method, analyses of the tested informative female offspring of Hunter carriers showed 20 of 38 informative females to be carriers.     

Massively parallel sequencing of the mouse exome to accurately identify rare, induced mutations: an immediate source for thousands of new mouse models

Accurate identification of sparse heterozygous single-nucleotide variants (SNVs) is a critical challenge for identifying the causative mutations in mouse genetic screens, human genetic diseases and cancer. When seeking to identify causal DNA variants that occur at such low rates, they are overwhelmed by false-positive calls that arise from a range of technical and biological sources. We describe a strategy using whole-exome capture, massively parallel DNA sequencing and computational analysis, which identifies with a low false-positive rate the majority of heterozygous and homozygous SNVs arising de novo with a frequency of one nucleotide substitution per megabase in progeny of N-ethyl-N-nitrosourea (ENU)-mutated C57BL/6j mice. We found that by applying a strategy of filtering raw SNV calls against known and platform-specific variants we could call true SNVs with a false-positive rate of 19.4 per cent and an estimated false-negative rate of 21.3 per cent. These error rates are small enough to enable calling a causative mutation from both homozygous and heterozygous candidate mutation lists with little or no further experimental validation. The efficacy of this approach is demonstrated by identifying the causative mutation in the Ptprc gene in a lymphocyte-deficient strain and in 11 other strains with immune disorders or obesity, without the need for meiotic mapping. Exome sequencing of first-generation mutant mice revealed hundreds of unphenotyped protein-changing mutations, 52 per cent of which are predicted to be deleterious, which now become available for breeding and experimental analysis. We show that exome sequencing data alone are sufficient to identify induced mutations. This approach transforms genetic screens in mice, establishes a general strategy for analysing rare DNA variants and opens up a large new source for experimental models of human disease.     

Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U.S. population-based case-control studies of ovarian cancer.

We investigate the familial risks of cancers of the breast and ovary, using data pooled from three population-based case-control studies of ovarian cancer that were conducted in the United States. We base estimates of the frequency of mutations of BRCA1 (and possibly other genes) on the reported occurrence of breast cancer and ovarian cancer in the mothers and sisters of 922 women with incident ovarian cancer (cases) and in 922 women with no history of ovarian cancer (controls). Segregation analysis and goodness-of-fit testing of genetic models suggest that rare mutations (frequency .0014; 95% confidence interval .0002-.011) account for all the observed aggregation of breast cancer and ovarian cancer in these families. The estimated risk of breast cancer by age 80 years is 73.5% in mutation carriers and 6.8% in noncarriers. The corresponding estimates for ovarian cancer are 27.8% in carriers and 1.8% in noncarriers. For cancer risk in carriers, these estimates are lower than those obtained from families selected for high cancer prevalence. The estimated proportion of all U.S. cancer diagnoses, by age 80 years, that are due to germ-line BRCA1 mutations is 3.0% for breast cancer and 4.4% for ovarian cancer. Aggregation of breast cancer and ovarian cancer was less evident in the families of 169 cases with borderline ovarian cancers than in the families of cases with invasive cancers. Familial aggregation did not differ by the ethnicity of the probands, although the number of non-White and Hispanic cases (N = 99) was sparse.