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 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 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 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.

A case of familial breast cancer with double heterozygosity for BRCA1 and BRCA2 genes

Breast Cancer ◽  
2012 ◽  
Vol 22 (5) ◽  
pp. 557-561 ◽  
Author(s):  
Tadashi Nomizu ◽  
Masami Matsuzaki ◽  
Naoto Katagata ◽  
Yusuke Kobayashi ◽  
Takeshi Sakuma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Familial Breast Cancer ◽  
Brca1 And Brca2 ◽  
Brca1 And Brca2 Genes ◽  
Double Heterozygosity

CHEK2*1100delC Genotyping for Clinical Assessment of Breast Cancer Risk: Meta-Analyses of 26,000 Patient Cases and 27,000 Controls

2008 ◽  
Vol 26 (4) ◽  
pp. 542-548 ◽  
Author(s):  
Maren Weischer ◽  
Stig Egil Bojesen ◽  
Christina Ellervik ◽  
Anne Tybjærg-Hansen ◽  
Børge Grønne Nordestgaard
Keyword(s):  
Breast Cancer ◽  
Early Onset ◽  
Familial Breast Cancer ◽  
Brca2 Mutation ◽  
Mutation Screening ◽  
Cumulative Risk ◽  
Brca1 And Brca2 ◽  
Chek2 1100Delc ◽  
Increased Risk ◽  
Meta Analyses

Purpose CHEK2*1100delC heterozygosity may be associated with an increased risk of breast cancer; however, it is unclear whether the evidence is sufficient to recommend genotyping in clinical practice. Patients and Methods We identified studies on CHEK2*1100delC heterozygosity and the risk of unselected, early-onset, and familial breast cancer through comprehensive, computer-based searches of PubMed, EMBASE, and Web of Science. Aggregated risk estimates were compared with previous estimates for BRCA1 and BRCA2 mutation heterozygotes. Results By using fixed-effect models for CHEK2*1100delC heterozygotes versus noncarriers, we found aggregated odds ratios of 2.7 (95% CI, 2.1 to 3.4) for unselected breast cancer, 2.6 (95% CI, 1.3 to 5.5) for early-onset breast cancer, and 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer. For familial breast cancer, this corresponds to a cumulative risk of breast cancer at age 70 years in CHEK2*1100delC heterozygotes of 37% (95% CI, 26% to 56%), which compares with similar previous estimates of 57% (95% CI, 47% to 66%) for BRCA1 mutation heterozygotes and 49% (95% CI, 40% to 57%) for BRCA2 mutation heterozygotes. Conclusion These meta-analyses emphasize that CHEK2*1100delC is an important breast cancer–predisposing gene, which increases the risk three- to five-fold. Because the cumulative risk of breast cancer at age 70 years among familial patient cases for CHEK2*1100delC heterozygotes is almost as high as that for BRCA1 and BRCA2 mutation heterozygotes, genotyping for CHEK2*1100delC should be considered together with BRCA1 and BRCA2 mutation screening in women with a family history of breast cancer.

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.

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