Ashkenazi Jewish Women Research Articles

Subjective and objective risk of breast cancer in Ashkenazi Jewish individuals at risk for BRCA1/2 mutations.

The aims of the study were to (1) examine the differences between subjective and objective estimates of the risk of breast cancer in those being tested for BRCA1/2 mutations, (2) explore new ways to conceptualize risk, and (3) examine the change in subjective risk of developing breast cancer throughout the process of genetic counseling and testing. Participants were 86 Ashkenazi Jewish women with a family or personal history indicating risk for BRCA1/2 mutations. Surveys to assess subjective risk of breast cancer (percentage risk, projected age of onset, and survival time) were administered before counseling, after counseling, and after receipt of test results. Subjective percentage risk of breast cancer was compared to estimated objective risk to determine accuracy. Those with no personal history of cancer receiving positive results became more accurate from post-counseling to post-result. Those receiving positive results increased their estimate of their percentage risk, and those receiving uninformative negative results decreased their estimate of their percentage risk from post-counseling to post-result. Those without a personal history of cancer decreased in perceived risk from post-counseling to post-result. No change in projected age of onset of breast cancer or survival time with breast cancer was seen from pre- to post-counseling or from post-counseling to post-result, and no change in accuracy or in percentage risk of breast cancer was seen from pre- to post-counseling. Individuals use information from genetic counseling to form estimates of percentage risk following receipt of test results; however, projected age of onset and survival time with breast cancer, areas not targeted by genetic counseling that may be more closely linked to health behavior, do not change.

Family Environments of Women Seeking BRCA1/BRCA2 Genetic Mutation Testing: An Exploratory Analysis

Although there is some understanding of the shared characteristics and predictors of psychological distress of women participating in hereditary breast and ovarian cancer registries, these same characteristics are only beginning to be identified in research on community women seeking genetic testing for BRCA1/BRCA2 gene mutations. This study provides an initial exploration of characteristics associated with family environments for 51 community women waiting to receive such genetic testing results. Thirty-four of the 36 women classified on family environment type of the Family Environment Scale (FES) were from Personal Growth-Oriented families. Comparisons of women with and without personal cancer histories resulted in a trend for women with personal cancer histories to be classified as from Independence-Oriented families. Reported distress appears to vary for different family emphases based on family and personal cancer history. A moral-religious family emphasis consistently appeared to be associated with decreased psychological distress. Preliminary analyses comparing these community women (who were not part of a hereditary registry but were self- or physician-referred) seeking genetic testing with normal and distressed family means found that increased cohesion and expressiveness may be related to decreased conflict, indicative of potentially supportive family environments for these women. When compared with normative data, a subset consisting of the Ashkenazi Jewish women showed a trend of less cohesion than normal families, but similar cohesion levels as distressed families.

Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.

Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset.

Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a Defined personal and family history in an Ashkenazi Jewish woman (LAMBDA).

Ancestral mutations in BRCA1 and BRCA2 are common in people of Ashkenazi Jewish descent and are associated with a substantially increased risk of breast and ovarian cancer. Women considering mutation testing usually have several personal and family cancer characteristics, so predicting mutation status from one factor alone could be misleading. The aim of this study was to develop a simple algorithm to estimate the probability that an Ashkenazi Jewish woman carries an ancestral mutation, based on multiple predictive factors. We studied Ashkenazi Jewish women with a personal or family history of breast or ovarian cancer and living in Melbourne or Sydney, Australia, or with a previous diagnosis of breast or ovarian cancer and living in the UK. DNA samples were tested for the germline mutations 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. Logistic regression was used to identify, and to estimate the predictive strength of, major determinants. A mutation was detected in 64 of 424 women. An algorithm was developed by combining our findings with those from similar analyses of a large study of unaffected Jewish women in Washington. Starting with a baseline score, a multiple of 0.5 (based on the logistic regression estimates) is added for each predictive feature. The sum is the estimated log odds ratio that a woman is a carrier, and is converted to a probability by using a table. There was good internal consistency. This simple algorithm might be useful in the clinical and genetic counselling setting. Comparison and validation in other settings should be sought.

Improved survival in women with BRCA-associated ovarian carcinoma.

The objective of this study was to determine the clinical characteristics, treatment response, and frequency of p53 overexpression in Ashkenazi Jewish women with hereditary ovarian carcinoma. Seventy-one Jewish women with epithelial ovarian carcinoma (EOC) were tested for the three BRCA founder mutations using single-strand conformation polymorphism analysis, heteroduplex analysis, and protein truncation testing. Clinical and histopathologic data were reviewed retrospectively. In vitro chemoresistance was analyzed in 32 patients. Mutations of p53 were studied using immunohistochemical detection of p53 overexpression. Thirty-four of 71 Jewish patients with EOC (48%) had germline BRCA mutations (BRCA heterozygotes), including 22 BRCA1 mutations and 12 BRCA2 mutations. BRCA heterozygotes were younger compared with Jewish patients who had EOC without mutations (sporadic carcinoma; 50 years vs. 59 years, respectively; P = 0.01). BRCA1 heterozygotes were younger compared with BRCA2 heterozygotes (48 years vs. 57 years, respectively; P = 0.01). Histopathologic tumor features were similar; however, tumors with low malignant potential were seen only in women with sporadic carcinoma. Both groups had equivalent rates of surgical cytoreduction and similar median follow-up (72 months). BRCA heterozygotes had higher response rates to primary therapy compared with patients who had sporadic disease (P = 0.01). In vitro chemoresistance predicted tumor response to platinum chemotherapy correctly in BRCA heterozygotes (P = 0.0096). BRCA heterozygotes with advance-stage disease had improved survival compared with patients who had advanced stage sporadic carcinoma (91 months vs. 54 months, respectively; P = 0.046) and had a longer disease free interval (49 months vs. 19 months, respectively; P = 0.16). p53 overexpression was common in BRCA heterozygotes (80%). BRCA1 heterozygotes developed EOC at a younger age compared with BRCA2 heterozygotes and women who had sporadic ovarian carcinoma. BRCA heterozygotes had a better response to platinum chemotherapy compared with women who had sporadic disease, which may have contributed to their improved prognosis.

Unusual phenotypic expression of the DYT1 mutation

Highly variable phenotype expression has long been recognized in DYT1 carrier patients. We report here an Ashkenazi-Jewish woman who carried a DYT1 mutation and developed a predominant unilateral myoclonic-dystonia (MD) displaying a fluctuating course. The present case is the second supporting the variability of DYT1 phenotype and further illustrates its ability to mimic the MD syndrome.

A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment.

BackgroundThe prognostic significance of germline mutations in BRCA1 and BRCA2 in women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty.MethodsTwo retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n = 584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA1/BRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women.ResultsGenotyping was successful in 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse in women with BRCA1 mutations than in those without (62% at 10 years versus 86%; P < 0.0001), but not in women with the BRCA2 mutation (84% versus 86% at 10 years; P = 0.76). Germline BRCA1 mutations were an independent predictor of breast cancer mortality in multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.2–4.8; P = 0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence interval 2.0–11.7; P = 0.001). The risk for metachronous ipsilateral cancer was not greater in women with germline BRCA1/BRCA2 founder mutations than in those without mutations (P = 0.68).ConclusionBRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in Ashkenazi women undergoing breast-conserving treatment for invasive breast cancer, but the poor prognosis associated with germline BRCA1 mutations is mitigated by adjuvant chemotherapy. The risk for metachronous ipsilateral disease does not appear to be increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up.

Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma

Overexpression of p53 has been associated with poor survival following breast carcinoma. BRCA1 interacts biochemically with p53 and may also contribute to poor outcome when constitutionally mutated. The joint effect of both abnormalities has not been studied. The primary objective of this study was to assess the impact of germline BRCA1 mutations and p53 overexpression on survival after 10 years of follow-up. A historical cohort of Ashkenazi Jewish women 65 years or younger with invasive breast carcinoma was tested for BRCA1 founder mutations. p53 overexpression was assessed by immunohistochemistry. Clinicopathologic information was obtained by chart review. In total, 278 women were analyzed. On univariate analysis, p53 overexpression (n = 63) was prognostic for worse overall survival (relative risk [RR] 2.6, P = 0.001) whereas BRCA1 germline mutations (n = 30) were of borderline significance (RR 1.9, P = 0.052). In the lymph node-negative subpopulation, BRCA1 mutation status conferred a higher mortality on univariate (RR 5.6, P < 0.001) and multivariate (RR 3.5, P = 0.03) analyses. There was a trend in favor of a worse prognosis for women who carried a germline BRCA1 mutation and whose tumor overexpressed p53. When compared with noncarriers, BRCA1 mutation carriers had a worse overall survival if they did not receive adjuvant chemotherapy (RR 3.3, P= 0.01) or adjuvant hormonal therapy (RR 2.3, P = 0.02). Germline BRCA1 mutations and p53 overexpression carry a negative prognosis that is not additive to known prognostic factors. Given the experimental sensitivity of BRCA1-mutated cells to chemotherapy, the worse survival among BRCA1 mutation-carrying lymph node-negative breast carcinoma patients may be partly explained by the significantly lower proportion of lymph node-negative patients who received adjuvant chemotherapy (P < 0.001).

Jewish identity and intentions to obtain breast cancer screening.

This study explored the associations between 2 dimensions of Jewish identity (cultural identification and religious practice) and intentions to perform breast cancer screening. Ashkenazi Jewish women (N = 220) completed surveys as part of an ongoing study of breast cancer risk counseling. Multiple regressions examined the relationships between the 2 identity measures and intention to follow routine recommendations for mammography, intention to perform monthly breast self-exam, and interest in genetic testing for breast cancer susceptibility. Cultural identity positively predicted interest in testing, whereas religious identity was inversely related. Religious identity was a significant predictor of intention to adhere to mammography recommendations. Findings show that culture and religion, although correlated, may have different associations with health attitudes.

A population-based study of Ashkenazi Jewish women’s attitudes toward genetic discrimination and BRCA1/2 testing

Purpose: The Human Genome Project continues to produce an increasing number of genetic susceptibility tests. Some of these genetic tests target social or ethnic groups who are at increased risk of developing a disease. The Ashkenazi Jewish community is one ethnic group that is an ongoing subject of genetic investigation. We assessed the attitudes of a population-based sample of Ashkenazi Jewish women toward breast–ovarian cancer susceptibility testing (BRCA1/2). In particular, we assessed concerns about group discrimination, perceptions of the advantages and disadvantages of BRCA1/2 testing, and the relationship between concerns about discrimination and the potential benefits of genetic testing.Methods: A telephone survey of a population-based sample of 200 Jewish women.Results: A minority of women (17%) in this study expressed concern or discomfort with Jews being offered BRCA1/2 testing. Most women believed there were scientific reasons for testing Jews (71%), and only 5% of women felt that research that focused on Jews was bad for Jews as a group. Increased concern about genetic discrimination was associated with women who were highly educated (odds ratio 2.68). Forty percent of women surveyed were interested in BRCA1/2 testing, 40% were not interested, and 20% were uncertain about whether they would obtain BRCA1/2 testing. Increased interest in genetic testing was associated with a desire to obtain information about children’s risk of disease and valuing information for its own sake.Conclusions: The majority of a population-based sample of Jewish women did not express concerns about group discrimination resulting from genetic testing. Women who are highly educated are more concerned about genetic discrimination. There is significant variation among Jewish women’s interest in breast cancer susceptibility testing.

Impact of cancer predisposition and radiosensitivity on the population risk of radiation-induced cancers.

This paper provides a brief overview of the current evidence for cancer predisposition and for an increased sensitivity of individuals carrying such predisposing mutations to cancers induced by ionizing radiations. We also discuss the use of a Mendelian one-locus, two-allele autosomal dominant model for predicting the impact of cancer predisposition and increased radiosensitivity on the risk of radiation-induced cancers in the population and in relatives of affected individuals using breast cancer due to BRCA1 mutations as an example. The main conclusions are the following: (1) The relative risk ratio of the risks of radiation-induced cancer in a heterogeneous population which has subgroups of normal and cancer-predisposed individuals to the risks in a homogeneous population (i.e., one which does not have these subgroups) increases with increasing dose; however, the dose dependence of the RR decreases at higher doses because of the fact that at high doses, the radiation risk to a homogeneous population will already be high. (2) The attributable risk (the proportion of cancers attributable to increased cancer susceptibility and increased radiosensitivity) follows a similar pattern. (3) When the proportion of cancers due to the susceptible genotypes is small (< 10%), as is likely to be the case for breast cancers in non-Ashkenazi Jewish women, the increases in risk ratios and attributable risks are small, and become marked only when there are very large increases in cancer susceptibility (> 1000-fold) and radiosensitivity (> 100-fold) in the susceptible group. (4) When the proportion of cancers due to the susceptible genotypes is appreciable (> or = 10%), as may be the case for breast cancers in Ashkenazi Jewish women, there may be significant increases in the risk ratios and attributable risk for comparatively moderate increases in cancer susceptibility (> 10-fold) and radiosensitivity (> 100-fold) in the susceptible subpopulation. (5) The ratio of the risk of radiation-induced cancer in relatives to that in unrelated individuals in the population increases with the biological relatedness of the relative, being higher for close than for distant relatives; however, even when the mutant BRCA1 gene frequency and the proportion of breast cancers due to these mutations are high, as in Ashkenazi Jewish women, for values of predisposition strength and radiosensitivity differential < 10, the increase in breast cancer risks is only marginal, even for first-degree relatives.

Estrogen receptor transcription and transactivation: Genetic modifiers of cancer risks conferred by BRCA1 and BRCA2

Approximately 15% of all breast cancer patients have a positive family history of the disease. BRCA1 and BRCA2 are two genes that explain major proportions of families with multiple cases of early-onset breast and/or ovarian cancer. Despite the high risks of breast and ovarian cancer conferred by deleterious BRCA1 and BRCA2 mutations, a strong variability in phenotype has been observed among families segregating the same mutation. This can range from early-onset breast cancer and ovarian cancer, to late-onset breast cancer without ovarian cancer. Even within a single pedigree, ages of onset of cancer can vary substantially. These observations support the idea that disease outcome in carriers is codetermined by other factors. Different risk estimates for BRCA mutations, depending on the type of population studied, also attest to this point. Risk estimates derived from families with multiple cases of early-onset breast cancer, used for linkage analysis to detect BRCA1 and BRCA2, came out substantially higher than those from population-based studies, and risks also appear to differ between populations. Both genetic and environmental factors are thought to interact with BRCA1 and BRCA2. The influence of nongenetic factors is demonstrated by the finding that even identical carrier twins may differ in disease history. Simple chance may determine age of onset, because multiple genetic mutations are required for full tumorigenesis. Thus far we are not even sure whether modifiers of BRCA-conferred risk actually exist, but some suggestive associations have been reported, which will require independent confirmation. Rare alleles at HRAS1 were found to increase risk of ovarian cancer in BRCA1 carriers, whereas breast cancer risk has been found to be modified by rare alleles at the androgen receptor. Among Ashkenazi Jewish women, a polymorphism in the 5' UTR of the RAD51 gene increased risk of breast cancer fourfold, but only in carriers of the BRCA2-6174delT.

Breast cancer mortality among Ashkenazi Jewish women in São Paulo and Porto Alegre, Brazil.

Increased BRCA1 and BRCA2 germline mutation rates have been reported in Ashkenazi Jewish women in North America, Europe and Israel, and have been mentioned as possibly related to a higher incidence of breast and ovarian cancer among these communities. The present study was carried out with the aim of obtaining evidence on the magnitude of breast cancer as a cause of death among Ashkenazi women in Brazil. We reviewed all death certificates archived in the Jewish Burial Societies of São Paulo (1971-1997) and Porto Alegre (1948-1997), two of the main and oldest Jewish communities in Brazil. Breast cancer observed deaths were compared with expected deaths according to breast cancer mortality in the general population. The observed ratios were approximately quite close to unity, suggesting a similar breast cancer mortality pattern among the Ashkenazi population and the general population in both cities. These results maintain similar behavior regardless of whether analyzed before or after the mid-1980s, when mammography came to be increasingly performed in Brazil. Cancer proportional mortality ratios were 1.04 (0.83-1.29) in São Paulo and 1.16 (0.84-1.57) in Porto Alegre before 1985, and 1.17 (1.00-1.44) and 1.21 (0.81-1.79), respectively, between 1985 and 1997. Some evidence of the maintenance of protective risk factors such as high parity has been observed among Ashkenazi women in São Paulo. A quite similar breast cancer mortality pattern was observed between Ashkenazi Jewish women and the general population in São Paulo and Porto Alegre, Brazil. These results may suggest an environmental role on germ mutation expression reported in this ethnic group.

Pseudo-likelihood estimates of the cumulative risk of an autosomal dominant disease from a kin-cohort study.

Wacholder et al. [1998: Am J Epidemiol 148:623-629] and Struewing et al. [1997: N Engl J Med 336:1401-1408] have recently proposed a design called the kin-cohort design to estimate the probability of developing disease (penetrance) associated with an autosomal dominant gene. In this design, volunteers (probands) agree to be genotyped and one also determines the disease history (phenotype) of first-degree relatives of the proband. They used this design to estimate that the chance of developing breast cancer by age 70 in Ashkenazi Jewish women who carried mutations of the genes BRCA1 or BRCA2 was 0.56, a figure that was lower than previously estimated from highly affected families. The method that they used to estimate the cumulative risk of breast cancer, while asymptotically correct, does not necessarily produce monotone estimates in small samples. To obtain monotone, weakly parametric estimates, we consider separate piecewise exponential models for carriers and non-carriers. As the number of intervals on which constant hazards are assumed increases, however, the maximum likelihood score equations become unstable and difficult to solve. We, therefore, developed alternative pseudo-likelihood procedures that are readily solvable for piecewise exponential models with many intervals. We study these techniques through simulations and a re-analysis of a portion of the data used by Struewing et al. [1997] and discuss possible extensions.

Germline BRCA1/2 mutations and p27(Kip1) protein levels independently predict outcome after breast cancer.

Decreased levels of the cyclin-dependent kinase inhibitor p27(Kip1) in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27(Kip1) protein levels, and outcome has not been studied. Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27(Kip1) expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27(Kip1) expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P =.009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P =.003). Similar results were seen for women whose tumors expressed low levels of p27(Kip1), compared with those with high levels (5-year DDFS, 68% v 93%; P<.0001). In a multivariate analysis, both BRCA1/2 mutation and low p27(Kip1) expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P =.05; and RR, 3.9; 95% CI, 1.4 to 11.1; P =.01, respectively). In this study, we showed that BRCA1/2 mutations were associated with low levels of p27(Kip1) in breast cancer. Both BRCA1/2 and p27(Kip1) status were identified as independent prognostic factors.

Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer

Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer

Mammography behavior after receiving a negative BRCA1 mutation test result in the Ashkenazim: A Community-based study

To define the impact of a negative BRCA1 test result on subsequent breast cancer screening behavior in women. Longitudinal study of a community-based sample of Ashkenazi Jews offered testing for the 185delAG BRCA1 mutation in 1996. Of 309 participants, 118 women were mutation negative, of average risk (based on family history of cancer), unaffected with breast cancer, and provided complete data at baseline, and Year 1 and Year 2 follow-up questionnaires. Women age 50 and older had 91.7% compliance with mammography for the year prior to entry (baseline), 88.3% during Year 1, 91.7% during Year 2 (no significant change; P = 0.775). Women under age 50 demonstrated an increase in mammography (49.2% at baseline, 62.7% Year 1, and 67.1% Year 2; P = 0.035). Both groups demonstrated significant decreases in breast cancer worry and perceived risk. Logistic regression analysis on having a mammogram at Year 2 showed that age, physician recommendation, worry, and perceived risk were all significant. Receipt of negative BRCA1 test results in a cohort of Ashkenazi Jewish women did not have a negative impact on mammography behavior 2 years after genetic testing.

Postscript: a status report on hemochromatosis population screening.

testing communities. An opportunity, because with an effective treatment available, the early detection afforded by a genetic screening program will make it possible to reduce the morbidity and mortality associated with the disease. It is a challenge, as well, because the relationship between genotype and clinical phenotype is unclear at present; e.g., not everyone inheriting two mutant copies of the gene responsible for hereditary hemochromato sis (HH) will develop significant disease, and there are concerns about how best to accomplish the screening, what the screening should entail, and social and ethical issues surrounding the screening. With regard to the challenge posed by hemochromato sis screening, there are similarities to issues previously raised with screening for the breast cancer predisposition genes, BRCA1 and BRCA2. For example, not everyone inheriting a BRCA1/BRCA2 mutation will develop breast or any cancer in her or his lifetime. And concerns have been expressed about when and whom to screen, who gets the results, and what might happen with regard to insurability and employability if the results become known to others besides the subject and his/her doctor. However, there are also significant differences between HFE and BRCA1/BRCA2 testing: cancer predisposition, following inheritance of BRCA1/BRCA2 mutations, is a dominant trait, with cancers seen in successive generations; no one really disputes the appropriateness of testing women with a strong family history of early-onset breast and/or ovarian cancer, only whether one extends the screening beyond this, for example, to all Ashkenazi Jewish women. HH, on the other hand, is a recessively inherited disorder, which means that the family history, except for sibs, is likely to be negative for other affecteds, so one cannot limit any testing just to those with a family history of the disease. The mutations in HFE, the gene responsible for HH, are more frequent than are mutations for BRCA1/BRCA2 among caucasians (estimates of carrier frequencies for mutations in HFE and BRCA1/BRCA2 among caucasians are about 1:10 and 1:200, respectively). However, clinically significant disease is less frequent in HH than in heritable breast cancer, a reflection of reduced penetrance in both disorders: for HH, estimates of clinically significant iron overload disease incidence of between 1 in 500 and 1 in 2,000, in different subpopulations have been reported, whereas between 50% and 85% of BRCA1/BRCA2 mutation carriers will develop breast cancer in their lifetimes. In some respects, HH is like another common recessive disease, cystic fibrosis (CF). In HH, homozygosity for one mutation, C282Y, accounts for over 80% of HH among northern Europeans. In CF, one common mutation, D F508, accounts for 75% or more of CF alleles among carriers and affecteds of northern European origin. In CF, the frequency of D F508 is different in different European subpopulations, accounting for only about 50% of all CF mutations in southern Europeans (Italians, Spaniards, Greeks, etc.) and about 30% of total CF in Ashkenazi Jews. In HH, different frequencies for C282Y, the common mutation, have been reported in specific European subpopulations (northern Europeans vs. Italians) and in other parts of the world (see Merryweather- Clarke et al., this issue). With regard to the major questions surrounding HH population screening:

Significantly lower rates of BRCA1/ BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer

To delineate the clinical, genetic and family history attributes in Jewish Ashkenazi women with early onset (<42 years) breast cancer we genotyped such women for the three predominant Jewish Ashkenazi mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT). The study cohort was composed of 172 women diagnosed with breast cancer at or before the age of 42 years, obtained from the oncology department registry. Mutations were identified in 54 women (31%). Of 79 women with a positive family history for breast and/or ovarian cancer, and 93 with no such family history, 45 (57%) and 9 (10%), respectively, were mutation carriers (χ 2=46; P<0.001). Contralateral breast cancer occurred in 15 of 54 mutation carriers (28%) compared with 8 of 118 (7%) non-carriers (χ 2=14; P<0.001). Early onset breast cancer per se is a weak predictor of finding germ line mutation(s) in BRCA1 and BRCA2, unless associated with a positive family history and/or bilaterality.

BRCA1 and BRCA2 Mutation Analysis of 208 Ashkenazi Jewish Women with Ovarian Cancer

Ovarian cancer is a component of the autosomal-dominant hereditary breast-ovarian cancer syndrome and may be due to a mutation in either the BRCA1 or BRCA2 genes. Two mutations in BRCA1 (185delAG and 5382insC) and one mutation in BRCA2 (6174delT) are common in the Ashkenazi Jewish population. One of these three mutations is present in approximately 2% of the Jewish population. Each mutation is associated with an increased risk of ovarian cancer, and it is expected that a significant proportion of Jewish women with ovarian cancer will carry one of these mutations. To estimate the proportion of ovarian cancers attributable to founding mutations in BRCA1 and BRCA2 in the Jewish population and the familial cancer risks associated with each, we interviewed 213 Jewish women with ovarian cancer at 11 medical centers in North America and Israel and offered these women genetic testing for the three founder mutations. To establish the presence of nonfounder mutations in this population, we also completed the protein-truncation test on exon 11 of BRCA1 and exons 10 and 11 of BRCA2. We obtained a detailed family history on all women we studied who had cancer and on a control population of 386 Ashkenazi Jewish women without ovarian or breast cancer. A founder mutation was present in 41.3% of the women we studied. The cumulative incidence of ovarian cancer to age 75 years was found to be 6.3% for female first-degree relatives of the patients with ovarian cancer, compared with 2.0% for the female relatives of healthy controls (relative risk 3.2; 95% CI 1.5-6.8; P=.002). The relative risk to age 75 years for breast cancer among the female first-degree relatives was 2.0 (95% CI 1.4-3.0; P=.0001). Only one nonfounder mutation was identified (in this instance, in a woman of mixed ancestry), and the three founding mutations accounted for most of the observed excess risk of ovarian and breast cancer in relatives.