A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico

Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States.

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Mutational Landscape for Indian Hereditary Breast and Ovarian Cancer Cohort Suggests Need for Identifying Population Specific Genes and Biomarkers for Screening

Frontiers in Oncology ◽

10.3389/fonc.2020.568786 ◽

2021 ◽

Vol 10 ◽

Author(s):

Mohammed Shaad N. Kadri ◽

Komal M. Patel ◽

Poonam A. Bhargava ◽

Franky D. Shah ◽

Nutan V. Badgujar ◽

...

Keyword(s):

Ovarian Cancer ◽

Early Detection ◽

In Silico ◽

Indian Population ◽

Brca2 Gene ◽

Breast And Ovarian Cancer ◽

Prediction Tools ◽

Ovarian Cancers ◽

Brca Genes ◽

Pathogenic Mutations

BackgroundBreast and ovarian cancers are the most prevalent cancers and one of the leading causes of death in Indian women. The healthcare burden of breast and ovarian cancers and the rise in mortality rate are worrying and stress the need for early detection and treatment.MethodsWe performed amplicon sequencing of 144 cases who had breast/ovarian cancer disease (total 137 cases are patients and seven are tested for BRCA1/2 carrier) Using our custom designed gene panel consisting of 14 genes, that are associated with high to moderate risk of breast and ovarian cancers. Variants were called using Torrent Variant Caller and were annotated using ThermoFisher’s Ion Reporter software. Classification of variants and their clinical significance were identified by searching the variants against ClinVar database.ResultsFrom a total of 144 cases, we were able to detect 42 pathogenic mutations in [40/144] cases. Majority of pathogenic mutations (30/41) were detected in BRCA1 gene, while (7/41) pathogenic mutations were detected in BRCA2 gene, whereas, (2/41) pathogenic mutations were detected in TP53 gene and BRIP1, PALB2, and ATM genes respectively. So, BRCA genes contributed 88.09% of pathogenic mutations, whereas non-BRCA genes contributed 11.91% of pathogenic mutations. We were also able to detect 25 VUS which were predicted to be damaging by in silico prediction tools.ConclusionEarly detection of cancers in the Indian population can be done by genetic screening using customized multi-gene panels. Indications of our findings show that in the Indian population, apart from the common BRCA genes, there are other genes that are also responsible for the disease. High frequency mutations detected in the study and variants of uncertain significance predicted to be damaging by in silico pathogenicity prediction tools can be potential biomarkers of hereditary breast and ovarian cancer in Indian HBOC patients.

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A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient

International Journal of Molecular Sciences ◽

10.3390/ijms22020889 ◽

2021 ◽

Vol 22 (2) ◽

pp. 889

Author(s):

Ava Kwong ◽

Cecilia Y. S. Ho ◽

Vivian Y. Shin ◽

Chun Hang Au ◽

Tsun Leung Chan ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Brca1 Gene ◽

Pathogenic Mutation ◽

Compound Heterozygous ◽

Strong Family History ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations ◽

Increased Risk ◽

History Of

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.

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Primary multiple BRCA associated breast cancer and ovarian cancer (clinical case)

Medical Council ◽

10.21518/2079-701x-2020-9-248-257 ◽

2020 ◽

pp. 248-257

Author(s):

I. B. Kononenko ◽

A. V. Snegovoy ◽

Y. A. Bozhchenko ◽

D. N. Kravchenko ◽

Vladimir Yu. Selchuk ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Clinical Case ◽

Brca2 Mutation ◽

Cumulative Risk ◽

Brca2 Gene ◽

Left Breast ◽

Luminal A ◽

Uterine Tube ◽

Luminal B

Introduction. The study of mutation in BRCA1/2 genes was first initiated in the USA and Europe, and later in Russia. Statistics indicate that women with the BRCA1/BRCA2 mutation have a higher risk of breast and/or ovarian cancer than the general population. According to different authors, the average cumulative risk among BRCA1 carriers is 65% (range 44–78%) for breast cancer and 39% (range 18–54%) for ovarian cancer. For mutation carriers in the BRCA2 gene, the risk for breast cancer is 45–49%, while the risk for RNA is 11–18%. However, in patients already diagnosed with breast cancer or ovarian cancer, the risk of a second tumor persists throughout life and may remain high even in old age. Treatment of BRCA-associated breast cancer and/or ovarian cancer is almost the same as treatment for sporadic cancer, and includes surgical, radiation, and drug anticancer therapy. However, there are some features that need to be considered in clinical practice. Clinical case. In this article we present the clinical experience of the treatment of a 32-year-old patient with BRCA1-associated primary multiple synchronous breast cancer and metachronous uterine tube cancer. In July 2015, the patient was diagnosed with synchronous cancer of both breast (Luminal A right breast cancer and Luminal B left breast cancer). As part of a treatment and with the patient’s consent, a bilateral adnexectomy was performed. In the histological examination of the operating material, the uterine tube cancer was diagnosed in situ. From 16.03.2016 to the present time the patient receives adjuvant endocrinotherapy without signs of disease progression. Conclusion. This clinical case study presents the importance of a combined approach to the treatment and prevention of BRCAassociated cancer.

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Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.3.979 ◽

1998 ◽

Vol 16 (3) ◽

pp. 979-985 ◽

Cited By ~ 151

Author(s):

V R Grann ◽

K S Panageas ◽

W Whang ◽

K H Antman ◽

A I Neugut

Keyword(s):

Quality Of Life ◽

Ovarian Cancer ◽

High Risk ◽

Surgical Procedures ◽

Brca2 Gene ◽

Cost Effective ◽

Prophylactic Surgery ◽

Breast And Ovarian Cancer ◽

Prophylactic Surgical Procedures

PURPOSE Young Ashkenazi Jewish women or those from high-risk families who test positive for BRCA1 or BRCA2 mutant genes have a significant risk of developing breast or ovarian cancer by the age of 70 years. Many question whether they should have prophylactic surgical procedures, ie, bilateral mastectomy and/or oophorectomy. METHODS A Markov model was developed to determine the survival, quality of life, and cost-effectiveness of prophylactic surgical procedures. The probabilities of developing breast and ovarian cancer were based on literature review among women with the BRCA1 or BRCA2 gene and mortality rates were determined from Surveillance, Epidemiology, and End Results (SEER) data for 1973 to 1992. The costs for hospital and ambulatory care were estimated from Health Care Financing Administration (HCFA) payments in 1995, supplemented by managed care and fee-for-service data. Utility measures for quality-adjusted life-years (QALYs) were explicitly determined using the time-trade off method. Estimated risks for breast and ovarian cancer after prophylactic surgeries were obtained from the literature. RESULTS For a 30-year-old woman, according to her cancer risks, prophylactic oophorectomy improved survival by 0.4 to 2.6 years; mastectomy, by 2.8 to 3.4 years; and mastectomy and oophorectomy, by 3.3 to 6.0 years over surveillance. The QALYs saved were 0.5 for oophorectomy and 1.9 for the combined procedures in the high-risk model. Prophylactic surgeries were cost-effective compared with surveillance for years of life saved, but not for QALYs. CONCLUSION Among women who test positive for a BRCA1 or BRCA2 gene mutation, prophylactic surgery at a young age substantially improves survival, but unless genetic risk of cancer is high, provides no benefit for quality of life. Prophylactic surgery is cost-effective for years of life saved compared with other medical interventions that are deemed cost-effective.

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Prevalence Rates of Pathogenic Mutations in theBRCA1andBRCA2Genes in Families with Different Disease Histories: Results from the German Consortium for Hereditary Breast and Ovarian Cancer.

10.1158/0008-5472.sabcs-09-4073 ◽

2009 ◽

Cited By ~ 1

Author(s):

K. Kast ◽

R. Schmutzler ◽

W. Distler ◽

N. Arnold ◽

C. Bartram ◽

...

Keyword(s):

Ovarian Cancer ◽

Prevalence Rates ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations

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Indications for BRCA1 and BRCA2 mutation testing in hereditary breast and ovarian cancer families

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.9720 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 9720-9720

Author(s):

R. Schmutzler ◽

U. Schwarz-Boeger ◽

G. Bastert ◽

Bender ◽

Beckmann ◽

...

Keyword(s):

Ovarian Cancer ◽

Brca2 Mutation ◽

Mutation Testing ◽

Breast And Ovarian Cancer ◽

Brca1 And Brca2

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Screening of BRCA2 mutated men for detection of prostate cancer: Preliminary results from a national high volume cancer center.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16567 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16567-e16567

Author(s):

Monica Zuradelli ◽

Nicolo' Buffi ◽

Paolo Bianchi ◽

Carla Barbara Ripamonti ◽

Monica Barile ◽

...

Keyword(s):

Prostate Cancer ◽

Ovarian Cancer ◽

Screening Program ◽

Brca2 Mutation ◽

Specific Antigen ◽

Digital Rectal Examination ◽

Brca2 Gene ◽

Pathogenic Mutation ◽

Genealogical Trees ◽

Targeted Screening

e16567 Background: Up to 10% of cases of Prostate Cancer (PCa) are hereditary. Germline pathogenic mutations in BRCA2 gene confer the highest risk (2.5 to 8.6 fold in men ≤ 65 yr). Beyond periodic Prostate Specific Antigen (PSA) dosage and digital rectal examination (DRE), a targeted screening for carriers is still undefined. Prostate Health Index (PHI), a combination of the tPSA, fPSA and proPSA tests, may be a more accurate biomarker than PSA only to detect PCa. We evaluated how to better screen BRCA2 mutated men for PCa. Methods: We reviewed the genealogical trees of all women tested positive for germline BRCA2 pathogenic mutation at our clinic. We offered targeted BRCA2 mutational analysis to all first/second degree relative men between 40 and 69 yr. A targeted screening program (annual PSA and PHI dosages and DRE) was proposed to all men tested positive. In case of PSA and/or PHI values out of range ( > 4ng/ml and > 20, respectively) we proceeded with a multiparametric Magnetic Resonance Imaging (mpMRI) and fusion biopsy of suspected lesions. Results: From June 2008 to October 2018 610 breast/ovarian cancer patients had BRCA test: 35 (5.7%) tested positive for BRCA1 pathogenic mutation, 32 (5.2%) for BRCA2 pathogenic mutation. From October 2017 90 relatives were checked for the familial mutation and 24 (27%) (12 women, 12 men) tested positive for BRCA2 mutation. All the 12 men (median age 48 yr, IQR 44 to 60) accepted to join our screening program. During the first year all men had negative DRE. Median PSA was 0.70 (IQR 0.43 to 1.02), median PHI was 17.56 (IQR 11.85 to 24.06). One patient with out of range PHI value already had mpMRI resulted negative. During the second year 4 men underwent screening so far: they had negative DRE. Median PSA was 0.57 (IQR 0.38-0.77), median PHI was 16.88 (IQR 11.87-21.90). Two men had PHI out of range and will undergo mpMRI. Conclusions: An accurate review of the genealogical trees of breast/ovarian cancer BRCA2 mutated patients allows to identify male relatives potentially carriers of the same mutation. These men have a high lifetime risk of PCa and require an appropriate screening, currently absent. Our approach may be leveraged as proof of concept of selection and screening program in carriers of BRCA2 mutations.

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Results of NGS panel of hereditary breast and ovarian cancer in Lebanese women.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13045 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13045-e13045

Author(s):

Joseph Al Ajami ◽

Nadine Jalkh ◽

Ghadi Moubarak ◽

Roland Eid ◽

Fady Haddad ◽

...

Keyword(s):

Ovarian Cancer ◽

High Risk ◽

Mutation Rate ◽

Founder Effect ◽

Familial Cancer ◽

Brca1 Gene ◽

Pathogenic Mutation ◽

Genetic Alterations ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations

e13045 Background: Hereditary breast (BC) and ovarian cancer (OC) genetic alterations are considered the most prevalent among familial cancer. To date, four studies have exposed the mutations related to hereditary BC predisposition in the Lebanese population , with percentage of BRCA-related pathogenic mutations ranging between 5 % and 15 %. Methods: Between 2017 and 2019, 117 patients with high risk hereditary breast and ovarian cancer were referred to undergo the testing at the Unité de Génétique médicale (UGM) of Saint-Joseph University of Beirut, Lebanon. The sequencing was accomplished by using the 21-panel Next-Generation Sequencing (NGS) method for all of our patients, to which we also added the MLPA technique followed by the Sanger sequencing for validation whenever a genetic alteration was found. Results: From 117 Lebanese women with high-risk hereditary breast and ovarian cancer predisposition, 19 pathogenic mutations were identified in this study: 11 BRCA1, 1 BRCA2, 2 PALB2, 1 ATM, 1 CDH1, 1 MSH6, 1 RAD51C, and 1 BRIP1. Among those, 13 patients had BC, one had OC and five were healthy individuals. Five similar mutations were found within the BRCA1 gene, the p.C44F mutation, accounting for 45.4 %, thus suggesting a founder effect. Average age at diagnosis in the BC patients carrying a mutation was 41 years and 38.5% had a triple negative BC. Conclusions: The overall pathogenic mutation rate was equal to 16.2% while the BRCA deleterious mutation rate was 10.3% lower to those reported in the literature. The p.C44F mutation appeared five times suggesting a founder effect. [Table: see text]

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