Screening for Founder Mutations in BRCA1 and BRCA2 in Unselected Jewish Women

2010 ◽  
Vol 28 (3) ◽  
pp. 387-391 ◽  
Author(s):  
Kelly A. Metcalfe ◽  
Aletta Poll ◽  
Robert Royer ◽  
Marcia Llacuachaqui ◽  
Anna Tulman ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Brca Mutation ◽  
Saliva Sample ◽  
Jewish Women ◽  
Founder Mutations ◽  
Brca1 And Brca2 ◽  
Family History Questionnaire ◽  
National Newspaper ◽  
Current Guidelines

Purpose There are two mutations in BRCA1 and one mutation in BRCA2 that are present in up to 2.5% of Ashkenazi Jewish women. Current guidelines for testing stipulate that a personal or family history of cancer be present to be eligible for testing. To date, population screening in this population has not been suggested. However, this may be rational. Little is known about the appropriateness of testing guidelines for the Jewish population or the level of interest in testing. Methods Eligible subjects were women who self-identified as Jewish, who were between the ages of 25 and 80 years, and who resided in Ontario. Subjects were recruited through an article in a national newspaper. Women were asked to complete a study questionnaire and a family history questionnaire and to provide a blood or saliva sample. The risk of carrying a BRCA mutation was estimated for each woman. Results A total of 2,080 women were enrolled onto the study. The overall mutation prevalence was 1.1% (0.5% for BRCA1 and 0.6% for BRCA2). Among the 22 mutation carriers, the mean estimate of carrying a BRCA mutation was 3.9%. Ten (45%) of the 22 women met the current Ontario Ministry of Health Guidelines criteria for testing. Conclusion There is considerable interest for genetic testing among Jewish women at low risk of carrying a mutation. However, many women with mutations are ineligible for genetic testing under current guidelines. Approximately 1% of Jewish women carry a BRCA mutation, and these women should be considered to be candidates for genetic testing.

Moving Toward Personalized Medicine: Treatment-Focused Genetic Testing of Women Newly Diagnosed With Ovarian Cancer

2010 ◽  
Vol 20 (5) ◽  
pp. 704-716 ◽  
Author(s):  
Alison H. Trainer ◽  
Bettina Meiser ◽  
Kaaren Watts ◽  
Gillian Mitchell ◽  
Kathy Tucker ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Mutation Frequency ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Age At Onset ◽  
Prognostic Significance ◽  
Brca1 And Brca2 ◽  
Germline Brca Mutation

Objectives:The presence of a germline BRCA mutation defines a genotype-specific group of women whose invasive ovarian cancer is associated with an increasingly well-defined prognostic and chemosensitivity biological profile. To determine the criteria that may be used to select patients for BRCA treatment-focused genetic testing, we performed a systemic literature search of studies that assessed BRCA1 and BRCA2 mutation frequency in women with ovarian cancer unselected for family history. The results are discussed with regard to the added clinical value gained by identifying a germline BRCA mutation at the time of the ovarian cancer diagnosis.Methods:BRCA-related studies were identified in the CD-ROM databases PubMed (including MEDLINE), PsychINFO, and CINAHL and included in the review if they met the following criteria: they (a) assessed mutation frequency in women with ovarian cancer who were unselected for family history and ethnicity, (b) were published in a peer-review journal, (c) between January 1997 and October 2009, and (d) in the English language.Results:Studies investigating the prevalence of BRCA1 or BRCA2 mutations in ovarian cancer patients unselected for family history or ethnicity have found a pathological BRCA mutation rate of approximately 3% to 17%. Without a significant family history, specific features that may be used to target treatment-focused BRCA testing in the ovarian cancer setting include young age at onset (<50 years), high-grade serous tumor histology, and specific ethnicity associated with known BRCA founder mutations.Conclusions:We believe that given the growing appreciation of the prognostic significance of BRCA mutations and the differential chemosensitivity shown by these tumors, as well as the potential of novel agents such as poly(ADP-ribose) polymerase inhibitors, the identification of a germline BRCA mutation concurrent with a new diagnosis of ovarian cancer will significantly impact on tailoring personalized ovarian management in the future.

Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma

2015 ◽  
Vol 33 (28) ◽  
pp. 3124-3129 ◽  
Author(s):  
Spring Holter ◽  
Ayelet Borgida ◽  
Anna Dodd ◽  
Robert Grant ◽  
Kara Semotiuk ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Brca Mutation ◽  
Ductal Adenocarcinoma ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Cancer Family ◽  
Cancer Family History ◽  
Testing Criteria

Purpose The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. Patients and Methods Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. Results Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P = .02, P < .001, and P = .05, respectively). However, the majority of the BRCA mutation–positive patients did not actually meet these genetic testing criteria. Conclusion Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.

Cost effectiveness of in vitro fertilisation and preimplantation genetic testing to prevent transmission of BRCA1/2 mutations

2020 ◽  
Vol 35 (2) ◽  
pp. 434-445 ◽  
Author(s):  
Joseph H Lipton ◽  
Mahdi Zargar ◽  
Ellen Warner ◽  
Ellen E Greenblatt ◽  
Esther Lee ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cost Effectiveness ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Cost Effective ◽  
In Vitro Fertilisation ◽  
Brca1 And Brca2 ◽  
Preimplantation Genetic Testing ◽  
The Cost

Abstract STUDY QUESTION Is it cost-effective to use in vitro fertilisation and preimplantation genetic testing of monogenic defects (IVT/PGT-M) to prevent transmission of BRCA1/2 mutations to second-generation new births in comparison with naturally conceived births? SUMMARY ANSWER In this cost-effectiveness analysis, we found that IVF/PGT-M is cost-effective for BRCA1 and BRCA2 mutation carriers if using a willingness to pay of $50 000 per quality-adjusted life-year (QALY). WHAT IS KNOWN ALREADY Carriers of a BRCA1 or BRCA2 mutation have a significantly increased risk of several types of cancer throughout their lifetime. The cost of risk reduction, screening and treatment of cancer in this population is high. In addition, there is a 50% chance of passing on this genetic mutation to each child. One option to avoid transmission of an inherited deleterious gene to one’s offspring involves in vitro fertilisation with preimplantation genetic testing. STUDY DESIGN, SIZE, DURATION We implemented a state transition model comparing the healthcare impact of a cohort of healthy children born after IVF/PGT-M, who have a population risk of developing cancer, to a cohort of naturally conceived live-births, half of whom are carriers of the BRCA mutation. Transition probabilities are based on published sources, a lifetime horizon and a perspective of a provincial Ministry of Health in Canada. PARTICIPANTS/MATERIALS, SETTING, METHODS The target population is the second-generation new births who have at least one parent with a known BRCA1 or BRCA2 mutation. MAIN RESULTS AND THE ROLE OF CHANCE At a willingness-to-pay threshold of $50 000 per QALY, IVF/PGT-M is a cost-effective intervention for carriers of either BRCA mutation. For BRCA1, the incremental cost-effectiveness ratio (ICER) for IVF/PGT-M is $14 242/QALY. For BRCA2, the ICER of intervention is $12 893/QALY. Probabilistic sensitivity analysis results show that IVF/PGT-M has a 98.4 and 97.3% chance of being cost-effective for BRCA1 and BRCA2 mutation carriers, respectively, at the $50 000/QALY threshold. LIMITATIONS, REASONS FOR CAUTION Our model did not include the short-term negative effect of IVF/PGT-M on the woman’s quality of life; in addition, our model did not consider any ethical issues related to post-implantation genetic testing. WIDER IMPLICATIONS OF THE FINDINGS In countries in which the healthcare of a large segment of the population is covered by a single payer system such as the government, it would be cost-effective for that payer to cover the cost of IVF/PGT-M for couples in which one member has a BRCA mutation, in order to avoid the future costs and disutility of managing offspring with an inherited BRCA mutation. STUDY FUNDING/COMPETING INTEREST(S) Dr Wong’s research program was supported by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC), the Canadian Liver Foundation and an Ontario Ministry of Research, Innovation and Science Early Researcher Award. All authors declared no conflict of interests.

Unique genetic characteristics of BRCA mutation carriers in a cohort of Arab American women.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1541-1541 ◽  
Author(s):  
Seerin Viviane Shatavi ◽  
Lindsay Dohany ◽  
Mohammad Muhsin Chisti ◽  
Ishmael A. Jaiyesimi ◽  
Dana Zakalik
Keyword(s):  
Genetic Testing ◽  
Brca Mutation ◽  
Arab American ◽  
Deleterious Mutations ◽  
Brca1 And Brca2 ◽  
American Women ◽  
Mutation Carriers ◽  
Brca Mutation Carriers ◽  
Arab American Women ◽  
Exon 11

1541 Background: Worldwide ethnic variations in the distribution of BRCA1 and BRCA2 mutations of breast cancer patients have been recently recognized. This has led to investigations of the epidemiology, genetics and clinical characteristics of BRCA positive individuals within specific populations. This study aims to describe the findings of BRCA genetic testing in a cohort of Arab American women. Methods: A total of 73 women of Arab ancestry were evaluated in the Beaumont Cancer Genetics Program from Jan 2008 to Jan 2013. Criteria for genetic testing included a personal or family history suggestive of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Patients underwent comprehensive genetic counseling, followed by full sequence analysis for germline mutations in BRCA1 and BRCA2. Results: 63 women of Arab ancestry underwent genetic testing for BRCA1 and BRCA2. 13 (21%) patients were found to be mutation carriers, of whom 10 (16%) of the 63 had deleterious mutations (7 in BRCA2, and 3 in BRCA1), and 3 (5%) had variants of undetermined significance (VUS) in BRCA2. Of the 10 patients with deleterious mutations, 4 (40%) unrelated individuals had the same mutation, 5804del4, in exon 11 of BRCA2. The remaining patients had deleterious mutations in exon 2, exon 20, and exon 13 of BRCA2; one patient had a BRCA1 and BRCA2 mutation (exon 18). 7 of 10 patients with deleterious mutations had a cancer diagnosis, of which 5 had breast cancer, 1 had ovarian cancer, 1 had pancreatic cancer, and 3 were unaffected. Conclusions: This study demonstrates that BRCA mutations (predominantly in BRCA2) were seen in a significant proportion of Arab American women undergoing genetic testing for HBOC. A mutation in BRCA2, 5804del4, was seen in nearly half (4/10) of the carriers of deleterious mutations. This mutation, in exon 11, has not previously been associated with Arab ethnicity and may represent a founder mutation. Knowledge of the genetic spectrum, frequency, and clinical characteristics of BRCA mutation carriers will lead to greater understanding of hereditary cancer in Arab American women.

Mutation analysis of PALB2 in high-risk and lower-risk patients negative for BRCA1 and BRCA2 mutations.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 30-30
Author(s):  
Shelly Cummings ◽  
Jenny Peterson ◽  
Elisha Hughes ◽  
Rajesh R. Kaldate ◽  
Sonia Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Family History ◽  
High Risk ◽  
Cancer Patients ◽  
Lower Risk ◽  
Risk Group ◽  
Breast Cancer Patients ◽  
Brca1 And Brca2 ◽  
Palb2 Mutation

30 Background: PALB2 has been identified as a breast cancer susceptibility gene conferring ~ 2-4 fold increased risk of breast cancer. A number of studies have estimated the PALB2 mutation prevalence to range from 0.5% - 2.9% in populations of breast cancer patients. We performed an analysis to determine the PALB2 mutation prevalence in a large U.S. referral testing population. Methods: DNA samples were anonymized from two subsets of patients: 955 early onset breast cancer patients with severe family history, and 524 patients with later onset of breast cancer and/or less severe family history. All patients were negative for deleterious sequence mutations or large rearrangements in BRCA1 and BRCA2. Results: We identified 10 disease associated PALB2 mutations in the high risk group of 955 patients and 2 deleterious PALB2 mutations in the lower risk group of 524 patients. Identified PALB2 mutations included 8 nonsense, 3 frameshift mutations and a splice site mutation. The mutation prevalence for the high risk population was 1.05% (95% C.I., 0.5 -1.92) whereas that for the lower risk population was 0.38% (95% C.I., 0.05-1.37). The observed rate of PALB2 variants of unknown significance (VUS) identified in this study was ~5% (78 VUS were in 75 of the 1479 patients that were tested). Our variant classification program which successfully decreased the VUS rate in BRCA1 and BRCA2 is similarly expected to enhance mutation classification on an on-going basis for PALB2 genetic testing. Conclusions: Genetic testing for PALB2 may be indicated as a reflex test for breast cancer patients who test negative for BRCA1 and BRCA2.

scholarly journals An evaluation of BRCA1 and BRCA2 founder mutations penetrance estimates for breast cancer among Ashkenazi Jewish women

2005 ◽  
Vol 7 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Monica R McClain ◽  
Katherine L Nathanson ◽  
Glenn E Palomaki ◽  
James E Haddow
Keyword(s):  
Breast Cancer ◽  
Ashkenazi Jewish ◽  
Jewish Women ◽  
Founder Mutations ◽  
Brca1 And Brca2

Clinical Characteristics of Individuals With Germline Mutations in BRCA1 and BRCA2: Analysis of 10,000 Individuals

2002 ◽  
Vol 20 (6) ◽  
pp. 1480-1490 ◽  
Author(s):  
Thomas S. Frank ◽  
Amie M. Deffenbaugh ◽  
Julia E. Reid ◽  
Mark Hulick ◽  
Brian E. Ward ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Clinical Setting ◽  
Ductal Carcinoma ◽  
European Ancestry ◽  
Founder Mutations ◽  
Brca1 And Brca2 ◽  
High Risk Women ◽  
Breast Neoplasia ◽  
History Of

PURPOSE: To assess the characteristics that correlate best with the presence of mutations in BRCA1 and BRCA2 in individuals tested in a clinical setting. PATIENTS AND METHODS: The results of 10,000 consecutive gene sequence analyses performed to identify mutations anywhere in the BRCA1 and BRCA2 genes (7,461 analyses) or for three specific Ashkenazi Jewish founder mutations (2,539 analyses) were correlated with personal and family history of cancer, ancestry, invasive versus noninvasive breast neoplasia, and sex. RESULTS: Mutations were identified in 1,720 (17.2%) of the 10,000 individuals tested, including 968 (20%) of 4,843 women with breast cancer and 281 (34%) of 824 with ovarian cancer, and the prevalence of mutations was correlated with specific features of the personal and family histories of the individuals tested. Mutations were as prevalent in high-risk women of African (25 [19%] of 133) and other non-Ashkenazi ancestries as those of European ancestry (712 [16%] of 4379) and were significantly less prevalent in women diagnosed before 50 years of age with ductal carcinoma in situ than with invasive breast cancer (13% v 24%, P = .0007). Of the 74 mutations identified in individuals of Ashkenazi ancestry through full sequence analysis of both BRCA1 and BRCA2, 16 (21.6%) were nonfounder mutations, including seven in BRCA1 and nine in BRCA2. Twenty-one (28%) of 76 men with breast cancer carried mutations, of which more than one third occurred in BRCA1. CONCLUSION: Specific features of personal and family history can be used to assess the likelihood of identifying a mutation in BRCA1 or BRCA2 in individuals tested in a clinical setting.

scholarly journals BRCA Germline Mutations in Jewish Patients With Pancreatic Adenocarcinoma

2009 ◽  
Vol 27 (3) ◽  
pp. 433-438 ◽  
Author(s):  
Cristina R. Ferrone ◽  
Douglas A. Levine ◽  
Laura H. Tang ◽  
Peter J. Allen ◽  
William Jarnagin ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Founder Mutation ◽  
Statistical Tests ◽  
Brca Mutation ◽  
Prognostic Significance ◽  
Founder Mutations ◽  
Brca1 And Brca2 ◽  
Increased Risk ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations

Purpose 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. Patients and Methods 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. Results 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%). Conclusion 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.

Validation of BRCA mutation-carrier probability model, BRCAPRO, in Japanese.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e12532-e12532
Author(s):  
Masahiro Ito ◽  
Yuri Yasuda ◽  
Akihiko Furuta ◽  
Noriaki Ohuchi
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Positive Predictive Value ◽  
Mutation Carrier ◽  
Predictive Value ◽  
Brca Mutation ◽  
Brca Mutation Carrier ◽  
Mutation Probability ◽  
Sensitivity Specificity

e12532 Background: Genetic testing has not been widely performed in Japan. It is not known whether BRCA mutation-carrier model is useful for selecting eligible person of genetic testing. We studied the validation of BRCAPRO in Japanese. Methods: Twenty-six hundred sixty-five people visited to our hospital between 2011 and 2012.They were surveyed family history as a risk factor of inheriting breast cancer according to NCCN guideline. Among them, those who have a number of family history of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer were selected and in addition, genetic counselor constructed family tree. We also calculated BRCA1/2 mutation probability by BRCAPRO.Those who had more than 10% mutation probability and early onset breast cancer, triple negative breast cancer were received genetic counseling and genetic testing for applicants. We also calculated sensitivity, specificity and predictive value at 10% estimated probability. Results: One hundred five people (3.9%) were selected as a risk of inheriting breast cancer, of which sixty-three people (2.3%) were constructed family tree.The number of people who had more than 10% and 30% mutation probability by BRCAPRO was seven (0.26%) and three (0.11%).Nine people performed BRCA1/2 genetic testing (proband : eight, relative: one)Four people carried a deleterious BRCA mutation (BRCA1: three, BRCA2: one).In the cases which had more than 30% mutation probability, all of them carried a deleterious BRCA mutation. Most of their mutation site was L63X which was most frequent in Japan. Using a 10% cut-off, sensitivity was 75%, specificity was 80%,positive predictive value was 75%. When it comes to the cases which had more than 30% mutation probability, Sensitivity, specificity, positive predictive value were all 100%. Conclusions: Our findings suggest BRCAPRO is useful in Japanese, especially those who have more than 30% mutation probability.

scholarly journals Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry

2019 ◽  
Author(s):  
Ruth I. Tennen ◽  
Sarah B. Laskey ◽  
Bertram L. Koelsch ◽  
Matthew H. McIntyre ◽  
Joyce Y. Tung ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Self Report ◽  
Ashkenazi Jewish ◽  
Family History Information ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Jewish Ancestry ◽  
History Of ◽  
Current Guidelines

ABSTRACTCurrent guidelines recommend BRCA1 and BRCA2 genetic testing for individuals with a personal or family history of certain cancers. Three BRCA1/2 founder variants — 185delAG (c.68_69delAG), 5382insC (c.5266dupC), and 6174delT (c.5946delT) — are common in the Ashkenazi Jewish population. We characterized a cohort of more than 2,800 research participants in the 23andMe database who carry one or more of the three Ashkenazi Jewish founder variants, evaluating two characteristics that are typically used to recommend individuals for BRCA testing: self-reported Jewish ancestry and family history of breast, ovarian, prostate, or pancreatic cancer. Of the 1,967 carriers who provided self-reported ancestry information, 21% did not self-report any Jewish ancestry; of these individuals, more than half (62%) do have detectable Ashkenazi Jewish genetic ancestry. In addition, of the 343 carriers who provided both ancestry and family history information, 44% did not have a first-degree family history of a BRCA-related cancer and, in the absence of a personal history of cancer, would therefore be unlikely to qualify for clinical genetic testing. These findings provide support for the growing call for broader access to BRCA genetic testing.

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