Ashkenazi Jewish Women Research Articles

Cost effectiveness of population based BRCA1 founder mutation testing in Sephardi Jewish women

Population-based BRCA1/BRCA2 founder-mutation testing has been demonstrated as cost effective compared with family history based testing in Ashkenazi Jewish women. However, only 1 of the 3 Ashkenazi Jewish BRCA1/BRCA2 founder mutations (185delAG[c.68_69delAG]), 5382insC[c.5266dupC]), and 6174delT[c.5946delT]) is found in the Sephardi Jewish population (185delAG[c.68_69delAG]), and the overall prevalence of BRCA mutations in the Sephardi Jewish population is accordingly lower (0.7% compared with 2.5% in the Ashkenazi Jewish population). Cost-effectiveness analyses of BRCA testing have not previously been performed at these lower BRCA prevalence levels seen in the Sephardi Jewish population. Here we present a cost-effectiveness analysis for UK and US populations comparing population testing with clinical criteria/family history-based testing in Sephardi Jewish women. A Markov model was built comparing the lifetime costs and effects of population-based BRCA1 testing, with testing using family history-based clinical criteria in Sephardi Jewish women aged ≥30 years. BRCA1 carriers identified were offered magnetic resonance imaging/mammograms and risk-reducing surgery. Costs are reported at 2015 prices. Outcomes include breast cancer, ovarian cancer, and excess deaths from heart disease. All costs and outcomes are discounted at 3.5%. The time horizon is lifetime, and perspective is payer. The incremental cost-effectiveness ratio per quality-adjusted life-year was calculated. Parameter uncertainty was evaluated through 1-way and probabilistic sensitivity analysis. Population testing resulted in gain in life expectancy of 12 months (quality-adjusted life-year= 1.00). The baseline discounted incremental cost-effectiveness ratio for UK population-based testing was £67.04/quality-adjusted life-year and for US population was $308.42/quality-adjusted life-year. Results were robust in the 1-way sensitivity analysis. The probabilistic sensitivity analysis showed 100% of simulations were cost effective at £20,000/quality-adjusted life-year UK and the $100,000/quality-adjusted life-year US willingness-to-pay thresholds. Scenario analysis showed that population testing remains cost effective in UK and US populations, even if premenopausal oophorectomy does not reduce breast cancer risk or if hormone replacement therapy compliance is nil. Population-based BRCA1 testing is highly cost effective compared with clinical criteria-driven approach in Sephardi Jewish women. This supports changing the paradigm to population-based BRCA testing in the Jewish population, regardless of Ashkenazi/Sephardi ancestry.

Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women

ImportanceAmong Ashkenazi Jewish women, 3 mutations in BRCA1 and BRCA2 severely increase the risk of breast and ovarian cancer. However, among Ashkenazi Jewish patients with breast cancer who do not carry one of these founder mutations, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene is not known. This information would be valuable to the patient and family for cancer prevention and treatment.ObjectiveTo determine the frequency of cancer-predisposing mutations other than the BRCA1 and BRCA2 founder alleles among patients of Ashkenazi Jewish ancestry with breast cancer.Design, Setting, and ParticipantsIn this cohort study, genomic DNA of women from 12 major cancer centers with a first diagnosis of invasive breast cancer who identified themselves and all 4 grandparents as Ashkenazi Jewish and participated in the New York Breast Cancer Study (NYBCS) from 1996 to 2000 was sequenced for known and candidate breast cancer genes. Data analysis was performed from July 10, 2014, to March 10, 2017.Main Outcomes and MeasuresGenomic DNA from all 1007 NYBCS probands was sequenced for 23 known and candidate breast cancer genes using BROCA, a targeted multiplexed gene panel.ResultsOf the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN). Of all inherited predispositions to breast cancer in the NYBCS, 73.8% (104 of 142) were due to a BRCA1 or BRCA2 founder allele, 4.9% (7 of 142) to another BRCA1 or BRCA2 mutation, and 21.8% (31 of 142) to a mutation in another gene. Overall, 14.1% (142 of 1007) of Ashkenazi Jewish patients with breast cancer in the NYBCS carried a germline mutation responsible for their disease: 11.0% (111 of 1007) in BRCA1 or BRCA2, and 3.1% (31 of 1007) in CHEK2 or another breast cancer gene. Of the 111 patients with BRCA1 or BRCA2 mutations, 57 (51.4%) had a mother or sister with breast or ovarian cancer and 54 patients (48.6%) did not.Conclusions and RelevanceComprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer.

Cost-effectiveness of population based BRCA testing with varying Ashkenazi Jewish ancestry

Population-based BRCA1/BRCA2 testing has been found to be cost-effective compared with family history-based testing in Ashkenazi-Jewish women were >30 years old with 4 Ashkenazi-Jewish grandparents. However, individuals may have 1, 2, or 3 Ashkenazi-Jewish grandparents, and cost-effectiveness data are lacking at these lower BRCA prevalence estimates. We present an updated cost-effectiveness analysis of population BRCA1/BRCA2 testing for women with 1, 2, and 3 Ashkenazi-Jewish grandparents. Decision analysis model. Lifetime costs and effects of population and family history-based testing were compared with the use of a decision analysis model. 56% BRCA carriers are missed by family history criteria alone. Analyses were conducted for United Kingdom and United States populations. Model parameters were obtained from the Genetic Cancer Prediction through Population Screening trial and published literature. Model parameters and BRCA population prevalence for individuals with 3, 2, or 1 Ashkenazi-Jewish grandparent were adjusted for the relative frequency of BRCA mutations in the Ashkenazi-Jewish and general populations. Incremental cost-effectiveness ratios were calculated for all Ashkenazi-Jewish grandparent scenarios. Costs, along with outcomes, were discounted at 3.5%. The time horizon of the analysis is "life-time," and perspective is "payer." Probabilistic sensitivity analysis evaluated model uncertainty. Population testing for BRCA mutations is cost-saving in Ashkenazi-Jewish women with 2, 3, or 4 grandparents (22-33 days life-gained) in the United Kingdom and 1, 2, 3, or 4 grandparents (12-26 days life-gained) in the United States populations, respectively. It is also extremely cost-effective in women in the United Kingdom with just 1 Ashkenazi-Jewish grandparent with an incremental cost-effectiveness ratio of £863 per quality-adjusted life-years and 15 days life gained. Results show that population-testing remains cost-effective at the £20,000-30000 per quality-adjusted life-years and $100,000 per quality-adjusted life-years willingness-to-pay thresholds for all 4 Ashkenazi-Jewish grandparent scenarios, with ≥95% simulations found to be cost-effective on probabilistic sensitivity analysis. Population-testing remains cost-effective in the absence of reduction in breast cancer risk from oophorectomy and at lower risk-reducing mastectomy (13%) or risk-reducing salpingo-oophorectomy (20%) rates. Population testing for BRCA mutations with varying levels of Ashkenazi-Jewish ancestry is cost-effective in the United Kingdom and the United States. These results support population testing in Ashkenazi-Jewish women with 1-4 Ashkenazi-Jewish grandparent ancestry.

Young Women's Perceptions Regarding Communication with Healthcare Providers About Breast Cancer, Risk, and Prevention.

Women younger than 45 years old have lower rates of breast cancer, but higher risk of recurrence and mortality after a cancer diagnosis. African American women are at risk for early onset and increased mortality; Ashkenazi Jewish women are at risk for genetic mutations leading to breast and ovarian cancer. Although younger women are encouraged to talk to doctors about their family history, little is known about these discussions. In 2015, 167 women aged 18-44 years participated in 20 focus groups segmented by geographic location, age, race/ethnicity, and family history of breast and ovarian cancer. Transcript data were analyzed using NVivo 10 software. Although the majority of women talked to their doctor about breast and ovarian cancer, these conversations were brief and unsatisfying due to a lack of detail. Topics included family history, breast cancer screening, and breast self-examination. Some women with and without family history reported that healthcare providers offered screening and early detection advice based on their inquiries. However, few women took action or changed lifestyle behaviors with the intent to reduce risk as a result of the conversations. Conversations with young women revealed missed opportunities to: enhance patient-provider communication and increase knowledge about breast cancer screening and surveillance for higher risk patients. Physicians, allied health professionals, and the public health community can better assist women in getting accurate and timely information about breast and ovarian cancer, understanding their family history to determine risk, and increasing healthy behaviors.

Abstract P3-08-02: Multi-gene panel testing for hereditary cancer predisposition in unsolved high risk breast and ovarian cancer patients

Abstract Background Among women with an elevated risk of hereditary breast and ovarian cancer who previously tested negative for pathogenic mutations in BRCA1 and BRCA2, a subset remain at increased risk of having hereditary breast, ovarian or other cancers, and should be offered multi-gene panel testing. We tested three groups of women who were enrolled in the UCSF Cancer Genetics and Prevention Program: (i) 97 women with a personal history of bilateral breast cancer, (ii) 104 women with a personal history of breast cancer and a first-degree or second-degree relative with ovarian cancer, and (iii) 99 women with a personal history of ovarian, fallopian tube, or primary peritoneal cancer. All women previously tested negative for pathogenic BRCA1 and BRCA2 mutations by either limited or comprehensive testing. Methods We performed comprehensive next-generation sequencing using a panel of 19 genes developed by Color Genomics (a CLIA-certified laboratory) covering ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. Results Across the groups tested, 9% had pathogenic mutations in one or more of the genes analyzed (8% in genes other than BRCA1 and BRCA2). Among these women, Ashkenazi Jewish and Hispanic women had elevated mutation rates compared to those of other ethnicities. In addition, we identified two women with pathogenic mutations in two cancer susceptibility genes, which has significant implications for family testing. These results demonstrate the importance of genetic testing of genes other than BRCA1 and BRCA2. Conclusions Among women with an elevated risk of hereditary breast and ovarian cancer who have previously tested negative for BRCA1 and BRCA2 mutations, we propose that women with characteristics of any of the three groups above be considered for subsequent multi-gene panel testing. Additionally, ethnicity and the possibility of multiple mutations may be indications for additional testing in these women and in family members of carriers. Citation Format: Crawford BB, Adams SB, Sittler T, Van den Akker J, Chan SB, Leitner O, Ryan LN, Gil E, Van 't Veer LJ. Multi-gene panel testing for hereditary cancer predisposition in unsolved high risk breast and ovarian cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-02.

Abstract IS01: Brca testing in high-risk populations

Abstract The traditional family-history (FH) based approach to genetic testing for BRCA mutations misses >50% of at risk carriers. BRCA mutations (founder mutations) are more prevalent in some populations (e.g. Ashkenazi Jews). Risk models used for this purpose are moderately affective at predicting a mutation but have poor ability/NLR at ruling out a BRCA mutation. Technological advances have raised the possibility of systematic population-based genetic testing for BRCA mutations in these populations but some uncertainty has remained on whether risks outweigh the benefits. A randomised controlled trial (GCaPPS, ISRCTN73338115) of BRCA1/2 gene-mutation testing in the Ashkenazi-Jewish (AJ) population compares psychological/quality-of-life consequences of Population-Screening (PS) with testing those fulfilling standard FH-based clinical criteria alone. A decision analytic model has compared cost-effectiveness of population-based BRCA testing with the standard FH-based approach in AJ women over 30 years. Model probabilities utilise GCaPPS trial/published literature to estimate total costs, effects in terms of Quality-Adjusted-Life-Years (QALYs), cancer incidence, incremental cost-effectiveness ratio (ICER) and population impact. AJ population and BRCA-test result data (from 2000-2010) obtained through ONS and all London NHS clinical genetics laboratories provide NHS BRCA detection rates. This along with BRCA prevalence estimates were used to calculate and simulate (n=10000000) time-to-detect all FH-positive BRCA-carriers in the London AJ-population (BRCA incidence=binomial distribution; rate of detection=Poisson distribution). Impact of changes in NHS funding and BRCA prevalence were assessed assuming correlations: ρ=0.25, 0.5, 0.75. 30 BRCA-carriers were identified in 1034 Ashkenazi-Jews, giving a BRCA1/2 prevalence= 2.9%(CI:1.97,4.12): BRCA1= 1.55%(CI:0.89,2.5), BRCA2= 1.35%(CI:0.74,2.26). 18/30 (60%) were FH-negative and not identified using clinical criteria. The prevalence of FH-positive/FH-negative carriers= 1.16%/1.74%. FH-based testing has a sensitivity= 40%(CI:22.7,59.4%), specificity= 88.45%(CI:86.3,90.4%), PLR= 3.46 (CI:1.95,5.34) and NLR= 0.68 (CI:0.46,0.87). There was no significant difference between FH and PS-arms at 7-days or 3-months for a range of psychological measures of anxiety, depression, health-anxiety, distress, uncertainty and quality-of-life. Overall anxiety (p=0.0001), and uncertainty (p=0.0008) associated with genetic testing decreased, but quality-of-life and health anxiety did not change with time. The BRCA detection rate in London AJ from 2006-2010 =34.2/year, with the pattern being randomly spread (Poisson-model goodness-of-fit test (p=0.439). Modelling BRCA detection rates and BRCA prevalence estimated it would take 44.8 years (CI: 21.02, 66.76) to detect all FH-positive BRCA carriers in London. Compared to FH-based testing population-screening can save 0.090 more life-years and 0.101 more QALYs resulting in 33 days gain in life-expectancy. Population-screening is cost saving with a baseline discounted ICER of -2079£/QALY. This approach may lead to 276 fewer ovarian and 508 fewer breast cancer cases in the UK. Compared to FH-based testing, population-based genetic testing in Ashkenazi-Jews doesn't adversely affect short term psychological/quality-of-life outcomes, detects additional BRCA carriers and is highly cost effective. Efficient, acceptable and more cost-effective ways of delivering information on genetic risk on a population basis are also necessary for this. Telephone and DVD based approaches have been found to be cost efficient. This suggests the feasibility of a population based approach in some populations with a high BRCA prevalence. It could have significant policy implications for the AJ population (and potentially other similar populations) which can save lives, but will require a change in the current paradigm of a FH-based approach to genetic testing in such populations. Citation Format: Ranjit Manchanda, MD, MRCOG, PhD. Brca testing in high-risk populations [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr IS01.

Abstract P1-17-05: Formative evaluation of interventions addressing culturally relevant needs of young breast cancer survivors

Abstract Background. Young women diagnosed with breast cancer face challenges impacting their quality of life, psychosocial functioning, and reproductive health outcomes. Ashkenazi Jewish women experience a disproportionately high prevalence of genetic mutations in the BRCA1/2 genes linked to a higher incidence of hereditary breast and ovarian cancer, and have unique needs based on genetic risk and cultural factors. Sharsheret, a national not-for-profit organization with an expertise in supporting Jewish young breast cancer survivors (YBCS), developed two interventions, the Peer Support Network (PSN) and Genetics for Life® (GFL), to address the culturally specific needs of Jewish YBCS. In 2011, Sharsheret conducted a formative evaluation to strengthen its existing PSN and GFL interventions. Methods. Four focus groups were conducted with 27 YBCS having participated in the PSN or GFL. The groups investigated the information and support needs of YBCS of Jewish descent and YBCS perceptions of PSN and GFL content, materials and delivery channels. Two groups (online and in-person) investigated the needs of YBCS, PSN and GFL program content, and PSN and GFL program delivery related to the psychosocial health of YBCS. Two groups (online and in-person) explored YBCS needs, PSN and GFL program content, and PSN and GFL program delivery related to the reproductive health of YBCS. Participants were recruited using in-person methods, email blasts, social media and via Sharsheret website postings. Qualitative data were analyzed using a notes-based thematic analysis. Results. Across groups, respondents identified the primary information needs for YBCS included resources addressing genetics, side effects and consequences of treatment (e.g., effects on fertility, intimacy and premature menopause) rather than treatment itself. Respondents identified that their support needs included culturally relevant peer support and genetic resources at the time of diagnosis, treatment and after treatment, as well as support for partners, family members and friends. Participants preferred to receive information and support through diverse modalities, including health care providers, the internet, peer supporters, support groups, symposia and teleconferences and mass media. Respondents recommended outreach efforts for the PSN and GFL interventions in locations that attract young people, including pediatricians’ offices, schools, salons, and college campuses, and to clergy, school principals, local Jewish organizations and health care providers. Participants also suggested potential technology-based modifications to PSN and GFL intervention delivery, including online intake forms, a LiveChat option, video testimonials, interactive expert column, online pedigrees and family conference calls with a genetic counselor or clinical staff member. Conclusion. YBCS identified the PSN and GFL interventions as critical resources attentive to their culturally specific information and support needs. Focus group participants provided strategies to enhance intervention content and reach. Healthcare professionals serving YBCS of diverse backgrounds can utilize the data gleaned from this evaluation to shape culturally relevant interventions and materials to address the unique needs of YBCS. Citation Format: Rochelle Shoretz, Adina Fleischmann, Elana Silber, Mary Ann Hall, Ashani Johnson-Turbes. Formative evaluation of interventions addressing culturally relevant needs of young breast cancer survivors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-17-05.

Genotype-Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers.

The genotype-phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi-ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi-Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0-12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation-specific counseling and be more aggressively managed for risk reduction.

Genetic counseling content: How does it impact health behavior?

Women with hereditary breast-ovarian cancer face decisions about screening (transvaginal ultrasound, CA125, mammography, breast exams) and proactive (before cancer) or reactive (after cancer) surgery (oophorectomy, mastectomy). The content of genetic counseling and its relation to these key health behaviors is largely unexamined. Ashkenazi Jewish women (n=78) were surveyed through the process of genetic testing and had audiorecorded counseling sessions available for Linguistic Inquiry and Word Count analysis. Proportions for participant and counselor cognitive and affective content during sessions were used as primary predictor variables in linear mixed models for change in intentions for screening and treatment and in self-reported screening. Cognitive and affective content were important predictors of behavior. Counselor cognitive content was associated with ovarian screening. An interaction effect also emerged for CA-125, such that counselor cognitive content plus participant cognitive content or counselor affective content were associated with more screening. Teasing out the factors in risk communication that impact decision-making are critical, and affect from a risk communicator can spur action, such as cancer screening.

Expanded screening for Ashkenazi Jewish women worth it in UK

Expanded screening for Ashkenazi Jewish women worth it in UK

PR26 Population screening of BRCA-1 and BRCA-2 mutations in Jewish Ashkenazi women

PR26 Population screening of BRCA-1 and BRCA-2 mutations in Jewish Ashkenazi women

Looking Jewish: The Embodiment of Gender, Class, and Ethnicity among Ashkenazi Jewish Women in Montreal, 1945-1980

Le présent article porte sur la façon dont l’identité juive canadienne s’est inscrite et négociée à même le corps des juives ashkénazes (d’Europe de l’Est) à Montréal au cours des années 1950, 1960 et 1970. Prises au sein d’une culture nordaméricaine de la beauté idéalisant des traits physiques précis, ces femmes ont souvent entretenu une relation difficile avec leur propre corps et eu de la difficulté à trouver leur place dans le modèle canadien. Mettant largement à contribution des entretiens personnels ainsi que divers livres de recettes et magazines féminins, l’auteure explore comment ces femmes ont à la fois dissimulé et révélé leur singularité et leur ressemblance, et comment le fait d’être juive ou d’être blanche s’est traduit, codifié et projeté sur leur corps.

Cultural Aspects of Healthy BRCA Carriers From Two Ethnocultural Groups

We explored the experiences of Ashkenazi Jewish and French Canadian women and meanings attributed to their hereditary breast and ovarian cancer (HBOC) risk. We purposively sampled 40 BRCA1 or BRCA2 (BRCA) mutation carriers and conducted theoretically driven semistructured interviews. According to content analysis, participants from these two ethnocultural groups held divergent meanings associated with being a BRCA carrier and different views pertaining to the illness experience and risk awareness. All participants identified a genetic basis; however, the French Canadian women also expressed other causes. The French Canadian women reported not knowing other carriers in their social environment, whereas the Ashkenazi Jewish women emphasized a strong sense of community contributing to their ethnic risk awareness. Based on these findings, we suggest that French Canadian women could benefit from greater awareness of the HBOC genetic risk and that health care providers should consider ethnically related and individual-based experiences and meanings during counseling.

Surgically treated ovarian endometriosis association with BRCA1 and BRCA2 mutations

Endometriosis is associated with an increased risk of ovarian cancer. Few studies have also shown increased risk of breast cancer. BRCA1/2 mutations are linked to an increased risk of breast and ovarian cancers but their relation to endometriosis is unknown.The objective of this study was to examine the mutation rate of BRCA1/2 among women with surgically treated ovarian endometriosis.We collected 126 specimens from Jewish Ashkenazi women with endometriotic (76) and control non-endometriotic (50) ovarian cysts, reviewed the pathological diagnoses and extracted DNA from all samples. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), samples were examined for the founder germline mutations of BRCA1/2, most common among Ashkenazi Jews. The rate of mutations in each group was calculated and compared.BRCA1/2 mutation rate was 1/76 (1.3%) in the endometriotic cyst study group and 1/50 (2%) in the control non-endometriotic cysts, showing no statistically significant difference between the groups (p=0.84). BRCA1/2 mutation rate was similar to the previously reported rate among Jewish Ashkenazi women.BRCA1/2 mutation rates in patients with endometriotic ovarian cysts and with non-endometriotic ovarian cysts are similar. A larger cohort is required to completely exclude the possibility of an association between BRCA1/2 mutations and surgically treated endometriosis.

FMR1 CGG allele length in Israeli BRCA1/BRCA2 mutation carriers and the general population display distinct distribution patterns.

Premature ovarian failure and diminished ovarian reserve have been noted both in female BRCA1/BRCA2 mutation carriers and in carriers of the Fragile X syndrome FMR1 gene CGG repeat size premutation. Based on the observation that BRCA mutation carriers do not harbour long CGG repeats in the FMR1 gene, it was hypothesized that BRCA-associated premature ovarian failure is mediated via FMR1. To test this notion, we evaluated the distribution of constitutional FMR1 genotypes in 188 BRCA1/BRCA2 mutation-positive Jewish Ashkenazi women and 15 708 female, mostly Ashkenazi controls in Israel. BRCA1/BRCA2 mutation carriers displayed a unique distribution of FMR1 genotypes compared with controls (p = 0·018) with a prominence of the shorter CGG alleles (<26 repeats). There was no allele size distribution differences within BRCA carriers when comparing cancer free (n = 95) and breast cancer affected women (n = 93) (p = 0·43). In conclusion, BRCA mutation carriers exhibit a distinct CGG FMR1 repeat size pattern compared with the general population, but it is unlikely to account for the reported diminished ovarian reserve or act as a modifier breast cancer gene in BRCA mutation carriers.

Abstract P3-07-05: Frequent BRCA1 and BRCA2 mutations are found in Mexican and Mexican-American women with breast cancer

Abstract Background: The Arizona Cancer Registry has shown that in Pima County, AZ, breast cancer diagnosed in young Latinas increased 40% from 2004-2008, compared to 1999-2003, and Latinas more likely to die of their cancer. This study seeks to characterize genetic variation in women of Mexican ancestry with breast cancer using next generation sequencing, with the goal of providing prevalence information to help guide screening and cancer prevention efforts. Methods: The ELLA Binational Breast Cancer Study enrolled women of Mexican ancestry living in either U.S. or Mexico within 24 months of breast cancer diagnosis. Mexican women from the state of Jalisco were collected through collaboration with the Universidad de Guadalajara and women of Mexican ancestry were recruited from Tucson and Phoenix, AZ. Genomic DNA from 92 ELLA study participants (49 from the U.S. and 43 from Mexico) was enriched for breast cancer influencing gene sequence using the BROCA panel with standard techniques. Samples were sequenced with next generation sequencing and variants identified. Results: Sequencing of breast cancer risk genes in 92 Mexican and Mexican-American women with breast cancer revealed the presence of deleterious mutations in 15% of women (14/92). Five carry mutations in BRCA1, 5 in BRCA2, 2 in CHEK2, 1 in PALB2 and 1 in RAD51C. An additional 9% of participants (8/92) carry rare mutations of unknown functional consequence in the same genes. Four carry mutations in BRCA1 or BRCA2 at sites predicted to alter splice enhancers and four carry missense mutations in CHEK2 that are predicted to damage to kinase function. None of these variants appear in public databases or are characterized functionally in gene-specific databases. Dozens of women carry VUS or novel variants. Women carrying BRCA1 mutations are significantly more likely to have had triple negative pathology. Women carrying other mutations known or thought to be deleterious are also more likely to have been younger at diagnosis, to have more aggressive breast cancer or to report a family history of breast cancer. Table 1. Deleterious MutationsGeneEffectTotalBRCA1185delAG1BRCA12569delC2BRCA1Del Complete Gene1BRCA1Del Exons 9-121BRCA2c.658delGT1BRCA2c.3264insT2BRCA2c.5195delT1BRCA2c.6024insG1CHEK2R160G2PALB2S779 Stop1RAD51CDel Exons 4-91 Conclusion: Deleterious BRCA1 and BRCA2 gene mutations are common among women of Mexican ancestry diagnosed with breast cancer. Within this cohort, the prevalence of BRCA1/2 mutations is 11%, and 4% of women carry mutations in other genes increasing breast cancer risk. This is higher than the 10% mutation prevalence estimated for Ashkenazi Jewish women with breast cancer. An additional 9% of women carry variants likely to disrupt gene function and dozens of VUS and novel variants are found in these women. Further analysis of samples from the remaining 942 women using genetic sequencing will help further elucidate the role of genetic risk factors in women of Mexican ancestry with breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-05.

When is the Use of Race/Ethnicity Appropriate in Risk Assessment Tools for Preconceptual or Antenatal Genetic Screening and How Should it be Used?

In the UK a ‘Family Origin Questionnaire’ (FOQ) has been introduced as a decision-making tool primarily to identify partners of high risk status in ‘low prevalence’ areas in antenatal screening for haemoglobin variants. A ‘family origins’ laboratory form for Down’s syndrome antenatal screening has followed, with active consideration of Tay Sachs Disease antenatal/ pre-conception carrier screening for Ashkenazi Jewish women. Similar screening developments for the haemoglobinopathies and cystic fibrosis are occurring in other countries. It is timely to ask when and how categories based on family origin concepts should be operationalised and used to assess genetic risk, given the methodological uncertainties and potential risk of offence, essentialisation, discrimination and/or stigmatisation. The potential limitations of these tools are examined, including generic concepts, social sensitivities of language, issues of testing, implementation, and training, and time-limitedness of the categories, to assess where the balance lies between the benefits and disadvantages of such usage.

A comparison of the detection of BRCA mutation carriers through the provision of Jewish population-based genetic testing compared with clinic-based genetic testing

Background:Guidelines for genetic testing for BRCA1 or BRCA2 stipulate that a personal or family history of cancer is necessary to be eligible for testing. Approximately 2% of Ashkenazi Jewish women carry a mutation, but to date population-based testing has not been advocated. Little is known about the relative yield of a conventional genetic testing programme versus a programme of widespread testing in a population with common founder mutations.Methods:We provided both referral-based and Jewish population-based testing between 2008 and 2012. We compared the numbers of BRCA mutation carriers identified through the two streams and estimated the number of genetic counselling hours devoted to each programme.Results:From 2008 to 2012, 38 female carriers were identified through 487 referrals to our genetics centre (29 unaffected with cancer). During the same time, 6179 Jewish women were tested through our population-based programme and 93 mutation carriers were identified (92 unaffected with cancer). Fewer counsellor hours were devoted to the population-based than to the clinical referral-based testing programme.Conclusion:Genetic testing of all Jewish women above the age of 25 years will greatly expand the number of BRCA mutation carriers identified without a commensurate increase in the number of hours required for counselling.

Dealing with the unexpected: consumer responses to direct-accessBRCAmutation testing

Background. Inherited BRCA gene mutations convey a high risk for breast and ovarian cancer, but current guidelines limit BRCA mutation testing to women with early-onset cancer and relatives of mutation-positive cases. Benefits and risks of providing this information directly to consumers are unknown.Methods. To assess and quantify emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service® report of three BRCA mutations that are common in Ashkenazi Jews, we invited all 136 BRCA1 and BRCA2 mutation-positive individuals in the 23andMe customer database who had chosen to view their BRCA reports to participate in this IRB-approved study. We also invited 160 mutation-negative customers who were matched for age, sex and ancestry. Semi-structured phone interviews were completed for 32 mutation carriers, 16 women and 16 men, and 31 non-carriers. Questions addressed personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of the result, emotional responses, perception of personal cancer risk, information sharing, and actions taken or planned.Results. Eleven women and 14 men had received the unexpected result that they are carriers of a BRCA1 185delAG or 5382insC, or BRCA2 6174delT mutation. None of them reported extreme anxiety and four experienced moderate anxiety that was transitory. Remarkably, five women and six men described their response as neutral. Most carrier women sought medical advice and four underwent risk-reducing procedures after confirmatory mutation testing. Male carriers realized that their test results implied genetic risk for female relatives, and several of them felt considerably burdened by this fact. Sharing mutation information with family members led to screening of at least 30 relatives and identification of 13 additional carriers. Non-carriers did not report inappropriate actions, such as foregoing cancer screening. All but one of the 32 mutation-positive participants appreciated learning their BRCA mutation status.Conclusions. Direct access to BRCA mutation tests, considered a model for high-risk actionable genetic tests of proven clinical utility, provided clear benefits to participants. The unexpected information demonstrated a cascade effect as relatives of newly identified carriers also sought testing and more mutation carriers were identified. Given the absence of evidence for serious emotional distress or inappropriate actions in this subset of mutation-positive customers who agreed to be interviewed for this study, broader screening of Ashkenazi Jewish women for these three BRCA mutations should be considered.

Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation

The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations.