BRCA1 Founder Research Articles

Screening of the Portuguese BRCA2 Founder Mutation in Breast Cancer Patients Unselected for Family History.

Abstract Background and Objective: The identification of BRCA2 c.156_157insAlu as a founder mutation of Portuguese origin and the optimization of its screening method, allows for fast genetic diagnosis in positive families. Although prevalent in Portuguese families with hereditary breast cancer risk (45% of the families with identified mutations in our Institute are positive for BRCA2 c.156_157insAlu), its prevalence in the general population of Portuguese breast cancer patients unselected for family history is unknown. Our objective was to determine the frequency of c.156_157insAlu in general Portuguese breast cancer (BC) population.Material and methods: After Ethics approval, recruitment started in April 2008.Two centres started the study: the Cancer Institute in Lisbon that observes patients from the Centre and South of the country, and the Hospital of Terceira Island in Azores (patients recruited in Terceira Island were originated from all Azorean Islands). All these patients had the diagnosis of invasive breast cancer, and after counselling a peripheral blood sample was collected and BRCA2 c.156_157insAlu screened by a three-step PCR method (Machado PM et al; J Clin Oncol 25:2027-2034, 2007). Post-test counselling was given at the Breast Cancer Risk Evaluation Clinic, where all patients had their family history analyzed. If at high risk for hereditary cancer, women were advised to enter general screening of BRCA1/2 mutations, when negative for BRCA2 c.156_157insAlu.Results: Three hundred twenty three BC patients (226 from Azores; 97 from the Continent) were recruited for this study and have already been screened. Eighty-three patients from Azores met criteria for familial breast cancer (37%). In the Continent only 10 high-risk patients have been identified so far. Average age at diagnosis was 55.8 yrs; 13 patients had bilateral BC (4%); 18 (6%) patients (all from Azores) had a second cancer diagnosis. Two women (1% of all, and 2% of the patients from the Continent) were positive for the BRCA2 c.156_157insAlu mutation: 1- breast cancer diagnosis at age 45 and a maternal aunt with breast cancer at age 60; 2- bilateral BC (ages 35 and 37), no family history for breast and/or ovarian cancer. The 10 high-risk patients BRCA2 c.156_157insAlu negative accepted to proceed with general BRCA1/2 screening.Patient recruitment is still open.Conclusions: Although we cannot conclude that c.156_157insAlu screening is relevant in the unselected population, one of the positive patients did not meet criteria for counselling outside this study. Our data also suggest that, even for familial BC, c.156_157insAlu may not be as prevalent in the Azorean population. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3061.

Two founder BRCA2 mutations predispose to breast cancer in young women

The mutation spectrum of BRCA1 and BRCA2 presents a wide range of unique mutations in breast/ovarian cancer patients but recurrent mutations with founder effects have also been described. BRCA2 5344delAATA and 9538delAA are recurrent mutations in Castilla-León (Spain) representing 10.6% of BRCA2 positive families. By genotyping eleven chromosome 13 markers (4.3 Mb) we demonstrate that each mutation shows core haplotypes of 1.66 and 0.87 Mb, respectively, supporting a common ancestor in Castilla-León. Furthermore, both mutations are associated with earlier onset of breast cancer (5344delAATA: 37.4 years, P = 0.033; 9538delAA: 39.4 years, P = 0.008). The identification of founder effects improves the genetic screening strategy to be followed and facilitates the clinical management of asymptomatic carriers.

1044 Comparative proteomics of the radioresistant phenotype in head and neck cancer: Gp96 as a novel prediction marker and radio-sensitizing target for radiotherapy

The founder mutations in BRCA (BRCA1*185delAG, BRCA1*5382insC, and BRCA2*6174delT) account for 95% of the detectable BRCA mutations in breast and ovarian cancer families of Ashkenazi Jewish ancestry. Optimal clinical management of individuals from these high-risk families relies on the identification of BRCA founder mutations in the laboratory. We have therefore developed a rapid and reliable approach using pyrosequencing, which allows for the detection of these frequent frameshift mutations on different types of specimens. We were able to correctly identify all mutants in a blinded analysis of 177 DNA samples, including 120 DNA samples extracted from paraffin tissues, 30 samples derived from blood specimens, and 27 samples derived from saliva. The mutation detection rate of pyrosequencing was 100% for all of the DNA samples tested with neither false-positive nor false-negative results. The assay also demonstrated both high accuracy and high precision for the detection of these common mutations in paraffin tissues. Furthermore, saliva collection is a noninvasive alternative for DNA isolation in both clinical and research settings. We show that pyrosequencing is a rapid and reliable method that serves as an excellent platform for BRCA founder mutation analysis, especially when only paraffin-embedded tissues are available.

Genetic variation in IGF-1 and breast cancer risk in Ashkenazi carriers and noncarriers of BRCA1/2 mutations

Earlier studies indicate that high circulating levels of insulin-like growth factor-1 (IGF-1) may be associated with premenopausal breast cancer. We studied variations in the IGF-1 gene and the growth hormone (GH1) gene in relation to risk of breast cancer in 667 Ashkenazi Jewish women (321 cases, 346 controls) from a population-based case-control study in Northern Israel, and a clinical series of 331 founder BRCA mutation carriers (161 affected, 170 unaffected). All participants were tested for six polymorphisms in the IGF-1 gene and one GH1 polymorphism. Logistic regression models were used to estimate odds ratios for haplotype-specific and genotype-specific age-adjusted risks. Two common IGF-1 haplotypes (ATTCAC, GAGTGT) were found, when compared with the most prevalent haplotype ATTCGC (32.5%), to be associated with a decreased risk of breast cancer in premenopausal noncarrier women only. Age-adjusted odds ratios were 0.5 (95% confidence interval: 0.28-0.92) for ATTCAC and 0.46 (95% confidence interval: 0.24-0.89) for GAGTGT. The GH1 polymorphism did not influence the risk of breast cancer in our study population. The IGF-1 gene seems to be associated with breast cancer risk in premenopausal Ashkenazi Jewish women who are not carriers of mutations in BRCA1/2 genes.

A Rapid and Reliable Test for BRCA1 and BRCA2 Founder Mutation Analysis in Paraffin Tissue Using Pyrosequencing

The founder mutations in BRCA (BRCA1*185delAG, BRCA1*5382insC, and BRCA2*6174delT) account for 95% of the detectable BRCA mutations in breast and ovarian cancer families of Ashkenazi Jewish ancestry. Optimal clinical management of individuals from these high-risk families relies on the identification of BRCA founder mutations in the laboratory. We have therefore developed a rapid and reliable approach using pyrosequencing, which allows for the detection of these frequent frameshift mutations on different types of specimens. We were able to correctly identify all mutants in a blinded analysis of 177 DNA samples, including 120 DNA samples extracted from paraffin tissues, 30 samples derived from blood specimens, and 27 samples derived from saliva. The mutation detection rate of pyrosequencing was 100% for all of the DNA samples tested with neither false-positive nor false-negative results. The assay also demonstrated both high accuracy and high precision for the detection of these common mutations in paraffin tissues. Furthermore, saliva collection is a noninvasive alternative for DNA isolation in both clinical and research settings. We show that pyrosequencing is a rapid and reliable method that serves as an excellent platform for BRCA founder mutation analysis, especially when only paraffin-embedded tissues are available.

A BRCA2 founder mutation and seven novel deleterious BRCA mutations in southern Chinese women with breast and ovarian cancer

A BRCA2 founder mutation and seven novel deleterious BRCA mutations in southern Chinese women with breast and ovarian cancer

Potential Excess Mortality in BRCA1/2 Mutation Carriers beyond Breast, Ovarian, Prostate, and Pancreatic Cancers, and Melanoma

BackgroundAlthough the increase in risk of developing breast, ovarian, and prostate cancer in BRCA1 and BRCA2 mutation carriers has been studied extensively, its impact on mortality is not well quantified. Further, possible effect of BRCA mutations on non-cancer mortality risk has not been examined.Methodology/Principal FindingsUsing mortality data from the relatives of 5,287 genotyped participants, of whom 120 carried a BRCA Ashkenazi Jewish founder mutation, in a community-based study of the Ashkenazi Jewish population in the Washington D.C area, we examined the association between the three Ashkenazi BRCA founder mutations and risk of overall and non-cancer mortality. To examine risks beyond the established effects of these mutations, we analyzed the data excluding both deaths and follow-up times after reported diagnosis of melanoma and cancer of the breast, ovary, prostate, and pancreas. Using an extension of the kin-cohort method that accounts for informative censoring, we estimated that, in the absence of breast, ovarian, and pancreatic cancers, and melanoma, female carriers had a life expectancy that was 6.8 years lower (95% CI: 1.2–10.5) than non-carriers. In male mutation carriers, the reduction in life expectancy, in the absence of prostate and pancreatic cancers and melanoma, was 3.7 (95% CI: −0.4, 6.8) years. When deaths and follow-up times after any cancer diagnosis were excluded, the difference in life expectancy was 5.7 years for women (95% CI: −0.1, 10.4) and 3.7 years for men (95% CI: −0.4, 6.9). An overall test of association for men and women together showed a statistically significant association between BRCA1/2 mutations and increased non-cancer mortality (p = 0.024).Conclusions/SignificanceThese findings suggest that there may be unknown effects of BRCA1/2 mutations on non-neoplastic diseases that cause death at older ages.

Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations.

Protein-truncating mutations in BRCA1 and in particular BRCA2 genes have been associated with prostate cancer. However, there is still uncertainty about the magnitude of association particularly with Gleason score, and family history of prostate, breast, and ovary cancers. To further examine associations between three founder mutations located in BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) genes and prostate cancer, we conducted a study of 979 prostate cancer cases and 1,251 controls among Ashkenazi Jewish men. Detailed information was obtained on prostate cancer pathology, age at diagnosis, and family history of all cancers. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression models. Prostate cancer risk was increased (OR, 1.9; 95% CI 0.9-4.1) for BRCA2 mutation carriers but not for BRCA1 mutation carriers. BRCA2 mutation carriers had an OR of 3.2 (95% CI, 1.4-7.3) for Gleason score of 7 to 10, but no association was observed for Gleason score of < 7. Carriers of BRCA1-185delAG mutation also had an OR of 3.5 (95% CI, 1.2-10.3) for Gleason score of > or =7 tumors; however, the association of either BRCA1-185delAG or 5382insC mutation was not statistically significant. Associations between founder mutations and prostate cancer were stronger in men with no first-degree family history of breast and/or ovarian cancers but were unaffected by family history of prostate cancer. These results indicate that the BRCA2 founder mutation confers a 3-fold elevated risk of high-grade prostate cancer. Although BRCA1 mutations were not associated with prostate cancer, the BRCA1-185delAG was associated with high Gleason score tumors. These findings should be carefully considered in genetic counseling and/or evaluating therapeutic options.

BRCA Germline Mutations in Jewish Patients With Pancreatic Adenocarcinoma

The prognostic significance of germline BRCA1 and BRCA2 mutations in Jewish patients with pancreatic adenocarcinoma (PAC) is unknown. Our objective was to define the prevalence of BRCA1 and BRCA2 in an unselected group of Jewish patients and to compare the clinical characteristics and overall survival (OS) of patients with resected BRCA mutation-associated PAC to PAC patients without mutations. Jewish patients with PAC resected between January 1986 and January 2004 were identified. DNA was extracted from the archived material, anonymized, and genotyped for founder mutations in BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT). Standard two-sided statistical tests were utilized. Of the 187 Jewish patients who underwent resection for PAC, tissue was available for 145 patients. Eight subjects (5.5%) had a BRCA founder mutation (two with BRCA1 [1.3%], six with BRCA2 [4.1%]). The BRCA2 founder mutation was identified in 4.1% of patients with pancreatic adenocarcinoma compared with only 1.1% of cancer-free Washington, DC,-area controls (4.1% v 1.1%; P = .007; odds ratio, 3.85; 95% CI, 2.1 to 10.8). Patients with and without BRCA1 or BRCA2 mutations did not differ in age (mean, 66 v 73 years; P = .6) or other clinicopathologic features. OS was not significantly different (median, 6 v 16 months; P = .35). A previous cancer was reported by 24% (35 of 145) of patients with the most common sites being breast cancer (9 of 35; 74%) and prostate cancer (8 of 35; 23%). Founder mutations for BRCA1 and BRCA2 were identified in 5.5% of Ashkenazi patients operated on for PAC. BRCA2 mutations were more prevalent than documented by population studies. Consistent with previous reports, BRCA2 mutations are associated with an increased risk of PAC.

Should lifestyle modifications be promoted to prevent breast cancer?

Should lifestyle modifications be promoted to prevent breast cancer?

Molecular diagnosis of the Portuguese founder mutation BRCA2 c.156_157insAlu

We wish to reply to the Letter to the Editor written by Machado and Vaz [1] concerning our recently published article on the c.156_157insAlu BRCA2 founder mutation [2], first discovered by Teugels et al. [3] in a Portuguese patient living in Belgium. That letter has several misstatements about our and others’ work that must not remain unchallenged. Machado and Vaz suggest in their letter [1] that we diagnose the c.156_157insAlu BRCA2 mutation by subjective evaluation of band intensities after RT-PCR. We think that it is clear in our paper [2], under the subheading ‘‘Screening for the c.156_157insAlu BRCA2 mutation’’, that we screen for this mutation by using two independent PCRs, one for exon 3 amplification and another specific for the Alu rearrangement. Using this strategy, in positive cases we expect two bands in the first PCR (one band if negative) and one band in the second PCR (none if negative). The second PCR helps to control the first PCR for eventual problems with preferential amplification of the shorter fragment (the normal), whereas the first PCR controls for eventual absence of amplification in the second PCR. This strategy of two independent PCRs (which differs from the nested PCR approach used by Machado et al. [4]), followed by sequencing of the genomic fragments in positive cases, allows the unambiguous detection of the c.156_157insAlu BRCA2 mutation. In the Results section of our article [2], the molecular diagnosis of families with the c.156_157insAlu BRCA2 mutation is also described under the separate subheading ‘‘Detection of the c.156_157insAlu BRCA2 mutation’’, whereas any mention to RT-PCR data appears under the subheading ‘‘Analysis of RNA transcripts’’. Therefore, the reason why we performed RT-PCR with primers located in exons 1 and 6 was not to confirm the mutation, but to deliberately be able to compare the physiologic alternative splice lacking exon 3 in controls with the effect of the exon 3 Alu insertion in carriers. Taking advantage of a known polymorphism in BRCA2 exon 2 (previously reported as c.-25G[A [2, 5, 6], but described as c.-26G[A according to the recommendations of the Human Genome Variation Society [7], we clearly demonstrated in Fig. 1 of our paper [2] the preferential production of the transcript without exon 3 by the allele with the Alu insertion and its (presumably residual) production by both alleles in non-carriers. Machado and Vaz [1] state that RT-PCR must be used to confirm the c.156_157insAlu BRCA2 mutation in each patient and that a reliable confirmation of this rearrangement must be done using the primers in exons 2 and 10 first described by Nordling et al. [8]. Both these claims are unfounded for the following reasons. First, it is not necessary to confirm one given mutation at the RNA level in every new patient once its pathogenic nature is well established, as it is now the case for this BRCA2 rearrangement. Second, Machado and Vaz claim [1] that these primers amplify specifically the transcript produced from the allele with the Alu insertion, and not the ubiquitous alternative splice transcript, allegedly because only the former transcript includes at least the first part of BRCA2 exon 10 [1]. They present no data to support this assumption nor do they exist in the literature. In fact, Zou et al. [9] have shown that the full length transcript and the ubiquitous alternative splice differ only by the lack of exon 3 in the latter, so exon 10 does not distinguish them. Additionally, the forward primer described by Nordling A. Peixoto C. Santos P. Rocha P. Pinto S. Bizarro M. R. Teixeira (&) Department of Genetics, Portuguese Oncology Institute, Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal e-mail: manuel.teixeira@ipoporto.min-saude.pt

Population Approach in Breast Cancer Research Based on Integration of Genetic, Clinicopathological and Genealogical Clues

Like other cancer types, breast cancer is considered to be a genetic disease. While the majority of genetic changes are somatic, a minority are in germline. About 10-20% of breast cancer is thought to be due to a germline mutation in high-penetrance genes, where the major focus has been on BRCA1 and BRCA2. Some of these mutations are defined as founder mutations. Studies on founder mutations yield important information, mainly due to a large number of available carriers with the same mutation, regarding penetrance, expression, genetic modifiers or low-penetrant genes and influence from the environment. Population studies are also valuable due the possibilities for evaluating clinicopathological data in a group of patients who have the same mutation. In Iceland a rare founder mutation has been detected in BRCA1, and a frequent founder mutation has been detected in BRCA2. In addition to population-based studies on genetics and clinicopathology, an extensive analysis of somatic changes in tumours of BRCA2 founder mutation carriers has been made.

Absence of founder BRCA1 and BRCA2 mutations in coetaneous malignant melanoma patients of Ashkenazi origin

Several epidemiologic studies have provided suggestive evidence of a link between coetaneous malignant melanoma (CMM) and breast cancer. The Breast Cancer Linkage Consortium (BCLC) reported approximately 2.6-fold increase in the risk for CMM among BRCA2 carrier families. To evaluate the role of BRCA1/2 mutations in CMM, we screened 92 Jewish patients of Ashkenazi origin diagnosed with CMM for the three Ashkenazi founder mutations: 185delAG and 5382insC in the BRCA1 and 6174delT in the BRCA2 gene. Information about personal demography, family history of cancer, and occupational and lifestyle history was collected. Thirty-seven of 92 (40.2%) CMM patients reported a family history of cancer in a first-degree relative. In 14 patients, history of breast cancer (BC) was recorded; however, no family had features associated with BRCA carrier status (i.e., young age at BC onset, history of several BC cases or ovarian cancer in the family). None of the patients were found to carry any of these three mutations. Our results suggest a limited role for the three Ashkenazi BRCA founder mutations in CMM risk among the Ashkenazi Jewish population. Therefore, screening patients with CMM for these BRCA1/2 mutations is not warranted.

Spectrum and characterisation of BRCA1 and BRCA2deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer

BackgroundThe incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic) during 1999–2006.MethodsThe complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing.ResultsIn 294 unrelated families (29.1% of the 1,010 probands) pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly) and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2) represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A) and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G) were demonstrated to result in aberrant transcripts and are considered as deleterious mutations.ConclusionThis study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.

Prevalence of BRCA1 and BRCA2 founder mutations in Brazilian hereditary breast and ovarian cancer families

22108 Background: Breast cancer (BC) is a significant health care problem in Brazil and only a few studies have been conducted to verify the contribution of founder mutations in BRCA genes to the occurrence of these tumors, especially in high risk families. Two recent studies in the State of Rio de Janeiro described a higher than expected prevalence of the BRCA founder mutations usually seen in individuals of Ashkenazi Jewish origin in non-Jewish breast cancer-affected women. The largest of these studies, conducted by Gomes et al., described a prevalence of 2.3% of the BRCA1 mutation 5382insC these patients were unselected for family history of the disease. Methods: Patients affected with breast cancer or other tumors of the HBOC spectrum, whose familiy histories fulfilled the ASCO criteria for HBOC and/or who had a prior probability of carryng a BRCA mutation ≥30% (using the Myriad prevalence tables and/or the Penn II model) were recruited from high risk genetics clinics in the cities of Rio de Janeiro and São Paulo. All patients denied Ashkenazi Jewish ancestry. Mutation detection was performed by PCR-amplification of the regions of interest in BRCA1 and BRCA2 followed by DNA sequencing. All mutations were confirmed in an independent sample. Results: A total of 145 unrelated patients were tested. None of them carried the 185delAG or 6174delT mutations in BRCA1 and BRCA2, respectively. Five (5) patients carried the BRCA1 mutation 5382insC in the germline, resulting in a prevalence of 3.44% for this mutation in the HBOC families studied. Conclusions: Testing for the three common BRCA founder mutations in non-Ashkenazi Brazilian women is probably not justified, especially not for the 185delAG and 6174delT mutations; the BRCA1 mutation 5382insC however, was relatively frequent. Additional haplotyping studies will be necessary to determine if these mutants share a common haplotype with those identified in individuals of Ashkenazi origin. No significant financial relationships to disclose.

Differences in outcome of young breast cancer patients according to BRCA1 mutation status

A few founder BRCA1 mutations (5382insC, 4154delA, 185delAG) account for up to 15% of high-risk (young-onset or familial or bilateral) breast cancer (BC) cases in Russia. The impact of non-founder BRCA1 mutations in this country is less studied; in particular, there are no reports analyzing gross rearrangements of this gene in the Russian patient series. We selected for the study 95 founder mutation negative high-risk BC cases. Combination of high-resolution melting (HRM) and sequencing revealed six presumably BC-associated alleles (2080delA, 4808C > G, 5214C > T, 5236G > A, 5460G > T, 5622C > T) and one variant of an unknown significance (4885G > A). The pathogenic role of the 5236G > A mutation leading to G1706E substitution was further confirmed by the loss of heterozygosity analysis of the corresponding tumor tissue. Multiplex ligation-dependent probe amplification (MLPA) revealed two additional BRCA1 heterozygotes, which carried BRCA1 deletions involving exons 1–2 and 3–7, respectively. Based on the results of this investigation and the review of prior Russian studies, three BRCA1 mutations (2080delA, 3819del5, 3875del4) were considered with respect to their possible founder effect and tested in the additional series of 210 high-risk BC patients; two BRCA heterozygotes (2080delA and 3819del5) were revealed. We conclude that the non-founder mutations constitute the minority of BRCA1 defects in Russia.

Rapid detection of carriers with BRCA1 and BRCA2mutations using high resolution melting analysis

BackgroundGermline inactivating mutations in BRCA1 and BRCA2 underlie a major proportion of the inherited predisposition to breast and ovarian cancer. These mutations are usually detected by DNA sequencing. Cost-effective and rapid methods to screen for these mutations would enable the extension of mutation testing to a broader population. High resolution melting (HRM) analysis is a rapid screening methodology with very low false negative rates. We therefore evaluated the use of HRM as a mutation scanning tool using, as a proof of principle, the three recurrent BRCA1 and BRCA2 founder mutations in the Ashkenazi Jewish population in addition to other mutations that occur in the same regions.MethodsWe designed PCR amplicons for HRM scanning of BRCA1 exons 2 and 20 (carrying the founder mutations185delAG and 5382insC respectively) and the part of the BRCA2 exon 11 carrying the 6174delT founder mutation. The analysis was performed on an HRM-enabled real time PCR machine.ResultsWe tested DNA from the peripheral blood of 29 individuals heterozygous for known mutations. All the Ashkenazi founder mutations were readily identified. Other mutations in each region that were also readily detected included the recently identified Greek founder mutation 5331G>A in exon 20 of BRCA1. Each mutation had a reproducible melting profile.ConclusionHRM is a simple and rapid scanning method for known and unknown BRCA1 and BRCA2 germline mutations that can dramatically reduce the amount of sequencing required and reduce the turnaround time for mutation screening and testing. In some cases, such as tracking mutations through pedigrees, sequencing may only be necessary to confirm positive results. This methodology will allow for the economical screening of founder mutations not only in people of Ashkenazi Jewish ancestry but also in other populations with founder mutations such as Central and Eastern Europeans (BRCA1 5382insC) and Greek Europeans (BRCA1 5331G>A).

Similar prevalence of founder BRCA1 and BRCA2 mutations among Ashkenazi and non-Ashkenazi men with breast cancer: Evidence from 261 cases in Israel, 1976–1999

To evaluate the potential contribution of mutations in the BRCA1 and BRCA2 genes to male breast cancer (MBC), we expanded a previous study to screen a total of 261 Israeli men diagnosed with breast carcinoma. A total of 21 BRCA2 6174delT and 8 BRCA1 185delAG mutations were found. Similar frequencies of BRCA1 and BRCA2 mutation carriers were found among Ashkenazi (12.8%) and non-Ashkenazi Jews (9.1%). The combined prevalence of BRCA1/ BRCA2 founder mutations among Ashkenazi Jewish men is slightly higher than for women, due to a higher frequency of BRCA2 mutations.

Clinical Outcomes of Breast Cancer in Carriers ofBRCA1andBRCA2Mutations

Some features of breast cancer in women with a BRCA1 mutation suggest that hereditary breast cancer has a poor outcome. We conducted a national population-based study of Israeli women to determine the influence, if any, of a BRCA1 or a BRCA2 mutation on the prognosis in breast cancer. We obtained data on all incident cases of invasive breast cancer that were diagnosed from January 1, 1987, to December 31, 1988, and recorded in the Israel National Cancer Registry. We requested a paraffin-embedded tumor block or an unstained slide and the corresponding pathological and clinical records for all such cases. DNA extracted from the tumor specimens was analyzed for the three founder mutations in BRCA1 and BRCA2. For each subject, available pathological and oncologic records were reviewed. We were able to retrieve a pathological sample from 1794 of 2514 subjects (71%). Among those women, we obtained medical records for 1545 (86%). A BRCA1 or BRCA2 mutation was identified in 10% of the women who were of Ashkenazi Jewish ancestry. The adjusted hazard ratios for death from breast cancer were not significantly different among mutation carriers and noncarriers (hazard ratio among BRCA1 carriers, 0.76; 95% confidence interval [CI], 0.45 to 1.30; P=0.31; hazard ratio among BRCA2 carriers, 1.31; 95% CI, 0.80 to 2.15; P=0.28). Among women who were treated with chemotherapy, the hazard ratio for death among BRCA1 carriers was 0.48 (95% CI, 0.19 to 1.21; P=0.12). Breast cancer-specific rates of death among Israeli women are similar for carriers of a BRCA founder mutation and noncarriers.

Survival in advanced-stage ovarian cancer patients with non-Ashkenazi Jewish BRCA mutations

5514 Background: Previous studies have shown a survival advantage in ovarian cancer patients with Ashkenazi-Jewish BRCA founder mutations compared to sporadic ovarian cancer patients. The purpose of this study is to determine if this association exists in ovarian cancer patients with non- Ashkenazi Jewish (non-AJ) BRCA1 or BRCA2 mutations. Methods: Patients with stage III or IV ovarian, fallopian tube, or primary peritoneal cancer and a BRCA1 or BRCA2 mutation, seen for genetic testing between January 1996 and October 2006, were identified from the institutional and genetics databases. Medical records were reviewed for clinical factors including response to initial chemotherapy. Response is defined as no clinical evidence of disease with normalization of serum CA-125 and no radiographic evidence of disease or a negative second-look surgery. Patients with sporadic ovarian cancer, without a family history of breast or ovarian cancer, were compared to similar cases, matched by age, stage, and year of diagnosis. Progression-free and overall survival were calculated by the method of Kaplan-Meier. Chi-square tests and univariate logistic regression were also used in the data analysis. Results: Thirty-nine advanced-stage ovarian cancer patients with non-AJ BRCA mutations and 47 matched, advanced-stage sporadic ovarian cancer patients have been analyzed. Compared to patients with sporadic ovarian cancer, non-AJ BRCA mutation carriers had a longer progression-free survival (PFS, 32.4 mos. vs. 22.1 mos., p = 0.0303) and overall survival (OS, 101.4 mos. vs. 51.3 mos., p &lt; 0.001). Similarly, 72% of the non-AJ BRCA mutation carriers had a complete response to initial treatment, compared to 45% of the sporadic ovarian cancer patients (p = 0.01). The odds of complete response to initial treatment were 3.2 times greater in the non-AJ BRCA group than in the sporadic group (OR 3.2; 95% CI 1.27 - 8.15). Conclusions: This study demonstrates a significant survival advantage in advanced-stage ovarian cancer patients with non-AJ BRCA mutations when compared to similar patients with sporadic ovarian cancer. Response to initial treatment appears to impact this improved survival. No significant financial relationships to disclose.