scholarly journals Breast Cancer and BRCA1 and BRCA2 Pathogenic Variants

2020 ◽  
Author(s):  
Naren Basu ◽  
D. Gareth Evans
Keyword(s):  
Breast Cancer ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants

scholarly journals Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yun Liu ◽  
Honglian Wang ◽  
Xin Wang ◽  
Jiaqi Liu ◽  
Junjian Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Assessment ◽  
Chinese Population ◽  
Functional Assay ◽  
Healthy Controls ◽  
Brca1 And Brca2 ◽  
Chinese Han ◽  
Pathogenic Variants ◽  
Breast Cancer Cohort ◽  
Invasive Carcinomas

AbstractAccurate interpretation of BRCA1/2 variants is critical for risk assessment and precise treatment of breast cancer (BC). Hence, the establishment of an ethnicity-based BRCA1/2 variant database of the Chinese population is of paramount importance. In this study, panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 BC patients and 6434 healthy controls. Overall, the percentage of subjects carrying pathogenic variants was 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls. We identified 13 pathogenic variants as high-frequency variants that had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients), none of which has been reported in Caucasians. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC (TNBC), invasive carcinomas, high histological grades, and family history of BC and other cancers. Furthermore, the percentage of the subjects carrying VUS was 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls. Based on our cohort study, we unambiguously reclassified 7 out of the 858 VUS resulting in lower VUS ratio in patients (from 9.8 to 7.9%) as well as in healthy control (from 6.9 to 5.3%). We also re-analyzed the 100 variants in 13 exons (2–5 and 15–23) of the BRCA1 genes using a functional assay (saturation genome editing; SGE). 55 of the 59 VUS had distinct status in the SGE study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign. Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment.

scholarly journals Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Hikmat Abdel-Razeq
Keyword(s):  
Breast Cancer ◽  
Brca1 And Brca2 ◽  
Healthy Women ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of ◽  
Risk Reducing ◽  
Current Guidelines ◽  
Missed Opportunity

Since the identification of BRCA1 and BRCA2 genes 3 decades ago, genetic testing and genetic counseling have become an integral part of routine clinical practice. The risk of breast cancer among carriers of germline pathogenic variants, like BRCA1 and BRCA2, is well established. Risk-reducing interventions, including bilateral mastectomies and salpingo-oophorectomies are both effective and have become more acceptable. Many researchers and professional societies view current guidelines as restrictive and may miss many at-risk women, and are calling to expand testing to include all patients with breast cancer, regardless of their personal or family history of cancer, while others are calling for wider adoption to even include all healthy women at age 30 or older. This review will address expanding testing in two directions; horizontally to include more patients, and even healthy women, and vertically to include more genes using next-generation sequencing-based multi-gene panel testing.

scholarly journals Identification of Recurrent Variants in BRCA1 and BRCA2 across Multiple Cancers in the Chinese Population

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yue Jiang ◽  
Ting Tian ◽  
Chengxiao Yu ◽  
Wen Zhou ◽  
Junzhe Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hepatocellular Carcinoma ◽  
Cervical Cancer ◽  
Genetic Screening ◽  
Chinese Population ◽  
Familial Breast Cancer ◽  
Cervical Cancer Patient ◽  
Breast Cancer Cell Lines ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants

BRCA1 and BRCA2 as important DNA repair genes have been thoroughly investigated in abundant studies. The potential relationships of BRCA1/2 pathogenic variants between multicancers have been verified in Caucasians but few in Chinese. In this study, we performed a two-stage study to screen BRCA1/2 pathogenic variants or variants of uncertain significance (VUS) with 7580 cancer cases and 4874 cancer-free controls, consisting of a discovery stage with 70 familial breast cancer cases and a subsequent validation stage with 7510 cases (3217 breast cancer, 1133 cervical cancer, 2044 hepatocellular carcinoma, and 1116 colorectal cancer). 48 variants were obtained from 70 familial breast cancer cases after BRCA1/2 exon detection, and finally, 20 pathogenic variants or VUS were selected for subsequent validation. Four recurrent variants in sporadic cases (BRCA1 c.4801A>T, BRCA1 c.3257del, BRCA1 c.440del, and BRCA2 c.7409dup) were identified and three of them were labeled Class 5 by ENIGMA. Two variants (BRCA1 c.3257del and c.440del) were specific in breast cancer cases, while BRCA2 c.7409dup and c.4307T>C were detected in two hepatocellular carcinoma patients and the BRCA1 c.4801A>T variant in one cervical cancer patient, respectively. Moreover, BRCA1 c.3257del was the most frequent variant observed in Chinese sporadic breast cancer and showed increased proliferation of BRCA1c.3257del-overexpressing triple-negative breast cancer cell lines (MDA-MB-231) in vitro. In addition to the known founder deleterious mutations, our findings highlight that the recurrently pathogenic variants in breast cancer cases could be taken as candidate genetic screening loci for a more efficient genetic screening of the Chinese population.

scholarly journals Breast and ovarian cancer risk reduction options for women with pathogenic variables in the brca1 and brca2 genes

Mastology ◽  
2020 ◽  
Vol 30 (Suppl 1) ◽  
Author(s):  
Sandro Vinícius Machado Melo ◽  
Thamyse Fernanda de Sa Dassie ◽  
Felipe Eduardo Martins de Andrade ◽  
Erica Maria Monteiro Santos ◽  
Benedito Mauro Rossi
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Risk Reduction ◽  
Surgical Management ◽  
Tertiary Hospital ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Brca1 And Brca2 Genes ◽  
Risk Reduction Measures ◽  
Risk Reducing

Introduction: Most breast and ovarian cancers in women are sporadic. However, five to ten percent of these individuals may have an inherited predisposition to cancer (Famorca-Tram, 2015). Women with pathogenic variants in BRCA1 are at risk of breast cancer of up to 72% and of ovarian cancer of up to 44%. Pathogenic variants of the BRCA2 gene increase the risk of breast cancer by up to 69% and of ovarian cancer by up to 25%. Risk reduction measures include: risk-reducing mastectomy, salpingo-oophorectomy, and chemoprevention. For women who do not choose any of these measures, follow-up with periodic examinations is necessary. In this work, the risk reduction measures adopted by 52 women with pathogenic variants in BRCA1 or BRCA2 in a tertiary hospital in São Paulo, Brazil, are analyzed. In addition, it was analyzed what factors could influence the risk-reducing measure adopted. Materials and methods: cross-sectional study with a sample of 52 women with pathogenic variants identified in the BRCA1 and BRCA2 genes seen at a tertiary hospital. Results: 80.8% opted for surgical management as a risk-reducing measure, with 46.2% of women having had prophylactic mastectomy, 11.5% having had bilateral salpingo-oophorectomy, and 23.1% having undergone both surgical procedures. Non-surgical management occurred in 19.2% of the cases, with 8% (3 cases) undergoing chemoprophylaxis with tamoxifen and 15.4% undergoing surveillance. Conclusion: Most patients opted for surgical intervention, with risk-reducing mastectomy being the most frequent one, followed by salpingo-oophorectomy. When testing was not requested by the geneticist, there was a greater tendency toward the surgical option.

Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort

2018 ◽  
Vol 55 (12) ◽  
pp. 794-802 ◽  
Author(s):  
Jee-Soo Lee ◽  
Sohee Oh ◽  
Sue Kyung Park ◽  
Min-Hyuk Lee ◽  
Jong Won Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
External Validation ◽  
Brca1 And Brca2 ◽  
Clinical Genetic ◽  
Validation Data ◽  
Data Set ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Highly Correlated

BackgroundBRCA1 and BRCA2 (BRCA1/2) variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2, we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer.MethodsWe used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. In total, 83 BRCA1/2 VUSs (BRCA1, n=26; BRCA2, n=57) were analysed. The multifactorial probability was estimated by combining the prior probability with the overall likelihood ratio derived from co-occurrence of each VUS with pathogenic variants, personal and family history, and tumour characteristics. The classification was compared with the interpretation according to the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG/AMP) guidelines. An external validation was conducted using independent data set of 810 patients.ResultsWe were able to redefine 38 VUSs (BRCA1, n=10; BRCA2, n=28). The revised classification was highly correlated with the ACMG/AMP guideline-based interpretation (BRCA1, p for trend=0.015; BRCA2, p=0.001). Our approach reduced the proportion of VUS from 19% (154/810) to 8.9% (72/810) in the retrospective validation data set.ConclusionThe classification in this study would minimise the ‘uncertainty’ in clinical interpretation, and this validated multifactorial model can be used for the reliable annotation of BRCA1/2 VUSs.

scholarly journals Long-Term Evaluation of Women Referred to a Breast Cancer Family History Clinic (Manchester UK 1987–2020)

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3697
Author(s):  
Anthony Howell ◽  
Ashu Gandhi ◽  
Sacha Howell ◽  
Mary Wilson ◽  
Anthony Maxwell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Gene Families ◽  
Mammographic Screening ◽  
Good Prognosis ◽  
Lifetime Risk ◽  
Breast Cancers ◽  
Moderate Risk ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants

Clinics for women concerned about their family history of breast cancer are widely established. A Family History Clinic was set-up in Manchester, UK, in 1987 in a Breast Unit serving a population of 1.8 million. In this review, we report the outcome of risk assessment, screening and prevention strategies in the clinic and propose future approaches. Between 1987–2020, 14,311 women were referred, of whom 6.4% were from known gene families, 38.2% were at high risk (≥30% lifetime risk), 37.7% at moderate risk (17–29%), and 17.7% at an average/population risk who were discharged. A total of 4168 (29.1%) women were eligible for genetic testing and 736 carried pathogenic variants, predominantly in BRCA1 and BRCA2 but also other genes (5.1% of direct referrals). All women at high or moderate risk were offered annual mammographic screening between ages 30 and 40 years old: 646 cancers were detected in women at high and moderate risk (5.5%) with a detection rate of 5 per 1000 screens. Incident breast cancers were largely of good prognosis and resulted in a predicted survival advantage. All high/moderate-risk women were offered lifestyle prevention advice and 14–27% entered various lifestyle studies. From 1992–2003, women were offered entry into IBIS-I (tamoxifen) and IBIS-II (anastrozole) trials (12.5% of invitees joined). The NICE guidelines ratified the use of tamoxifen and raloxifene (2013) and subsequently anastrozole (2017) for prevention; 10.8% women took up the offer of such treatment between 2013–2020. Since 1994, 7164 eligible women at ≥25% lifetime risk of breast cancer were offered a discussion of risk-reducing breast surgery and 451 (6.2%) had surgery. New approaches in all aspects of the service are needed to build on these results.

scholarly journals Analysis of the pathogenic variants of BRCA1 and BRCA2 using next-generation sequencing in women with familial breast cancer: a case–control study

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Omar Alejandro Zayas-Villanueva ◽  
Luis Daniel Campos-Acevedo ◽  
José de Jesús Lugo-Trampe ◽  
David Hernández-Barajas ◽  
Juan Francisco González-Guerrero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Next Generation Sequencing ◽  
Familial Breast Cancer ◽  
Case Control Study ◽  
Case Control ◽  
Next Generation ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Generation Sequencing ◽  
Control Study

scholarly journals Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort

2018 ◽  
Vol 144 (5) ◽  
pp. 1195-1204 ◽  
Author(s):  
Jingmei Li ◽  
Wei Xiong Wen ◽  
Martin Eklund ◽  
Anders Kvist ◽  
Mikael Eriksson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Breast Cancer Cohort
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