Detection of novel germline mutations in six breast cancer predisposition genes by targeted next-generation sequencing

Dong, Li; Wu, Nan; Wang, Shaojing; Cheng, Yanan; Han, Lei; Zhao, Jing; Long, Xin-Xin; Mu, Kun; Li, Menghui; Wei, Lijuan; Wang, Wanheng; Zhang, Weijia; Cao, Yandong; Liu, Juntian; Yu, Jinpu; Hao, Xishan

doi:10.1002/humu.23597

Cited by 6 publications

(12 citation statements)

References 42 publications

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“…A total of 265 studies were further assessed by the full-text review, of which 145 studies not meeting the criteria (described in the Methods section and Figure S1 ) were excluded. Finally, for the analysis, we included 123 studies: 120 studies from the PubMed search and 3 hand-searched studies [ 15 , 16 , 18 , 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , …”

Section: Resultsmentioning

confidence: 99%

Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations

Suszyńska

Kozlowski

2020

Genes

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Over the last two decades, numerous BARD1 mutations/pathogenic variants (PVs) have been found in patients with breast cancer (BC) and ovarian cancer (OC). However, their role in BC and OC susceptibility remains controversial, and strong evidence-based guidelines for carriers are not yet available. Herein, we present a comprehensive catalog of BARD1 PVs identified in large cumulative cohorts of ~48,700 BC and ~20,800 OC cases (retrieved from 123 studies examining the whole coding sequence of BARD1). Using these resources, we compared the frequency of BARD1 PVs in the cases and ~134,100 controls from the gnomAD database and estimated the effect of the BARD1 PVs on BC and OC risks. The analysis revealed that BARD1 is a BC moderate-risk gene (odds ratio (OR) = 2.90, 95% CIs:2.25–3.75, p < 0.0001) but not an OC risk gene (OR = 1.36, 95% CIs:0.87–2.11, p = 0.1733). In addition, the BARD1 mutational spectrum outlined in this study allowed us to determine recurrent PVs and evaluate the variant-specific risk for the most frequent PVs. In conclusion, these precise estimates improve the understanding of the role of BARD1 PVs in BC and OC predisposition and support the need for BARD1 diagnostic testing in BC patients.

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Section: Resultsmentioning

confidence: 99%

Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations

Suszyńska

Kozlowski

2020

Genes

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“…BRCA1 and BRCA2 are 2 well-known high penetration predisposition genes in hereditary BC. Hereditary BC with BRCA mutations is more invasive than that without BRCA mutations 9,22,56 . In this study, comparative analyses of clinicopathological features also showed that patients with BRCA mutations had a younger age of onset, more advanced stage, and higher risk of axillary lymph node metastasis than those without mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Four VUS were considered high risk based on software predictions and literature reports. In this article, P/LP mutations and high risk VUS were defined as possible disease-causing mutations 22 . 3).…”

Section: Identification Of Germline Mutationsmentioning

confidence: 99%

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families

Dong¹,

Zhang²,

Zhang³

et al. 2021

Cancer Biol Med

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Objective: Approximately 5%-10% of breast cancer (BC) patients display familial traits that are genetically inherited among the members of a family. The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families. Methods: Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families.Results: Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8% (96/116) of the cases. Among these, 80.8% of the mutated genes were related to DNA damage repair. Fourteen possible disease-causing variants were identified in 13 of 27 BC families. Only 25.9% (7/27) of the BC families exhibited hereditary deficiency in BRCA1/2 genes, while 22.2% of the BC families exhibited defects in non-BRCA genes. In all, 41.7% (40/96) of the mutation carriers had BRCA mutations, 88.5% (85/96) had non-BRCA mutations, and 30.2% (29/96) had both BRCA and non-BRCA mutations. The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations (P < 0.05). However, the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations (P < 0.05). Conclusions: In addition to BRCA1/2, genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC. Therefore, profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

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“…1 The carcinogenesis in breast tissue involves the accumulation of germline and somatic abnormalities. 2 Early diagnosis and preventive interventions could improve the survival rate in patients with breast cancer. 3 Therefore, numerous studies have focused on the molecular biological mechanisms underlying the tumorigenesis and progression of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Breast cancer is recognized as one of the most diagnosed cancers and the leading cause of cancer deaths in females 1 . The carcinogenesis in breast tissue involves the accumulation of germline and somatic abnormalities 2 . Early diagnosis and preventive interventions could improve the survival rate in patients with breast cancer 3 .…”

Section: Introductionmentioning

confidence: 99%

MiR‐429 suppresses proliferation and invasion of breast cancer via inhibiting the Wnt/β‐catenin signaling pathway

Zhang

Liu

et al. 2020

Thoracic Cancer

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Background microRNAs ( miRNAs) have been verified as molecular targets for regulating tumor proliferation, invasion, and metastasis in tumor progression. However, the relationship between miRNAs and cellular energy metabolism in breast cancer still needs to be clarified. This study aimed to investigate the role of miR‐429 in breast cancer progression. Methods Bioinformatic analyses were employed to detect the relationship between miR‐429 and cancer‐related signaling pathways. We used a Kaplan‐Meier curve to analyze survival rate in patients with high or low expression of miR‐429. We used real‐time quantitative PCR (RT‐qPCR) to detect the expression of miR‐429 in different cell lines. Sh‐con, over‐miR‐429, miR‐429 inhibitor, and sh‐inhibitor control were transfected. Colony formation and EDU assay were used to detect the proliferation of transfected cells. Wound healing and transwell assays were performed to detect the mobility and invasion ability of transfected cells. Western blot assay was used to detect relative protein expression in transfected cells and different tissues. Bioinformatic analyses were conducted to detect the target proteins expression in different breast cancer databases. Dual luciferase reporter assay was used to confirm the binding site between miR‐429 and fibronectin 1 (FN1). Results The results of our study indicate that MiR‐429 and its target genes are associated with cancer‐related signaling pathways and that higher miR‐429 expression corresponds with a better prognosis. When miR‐429 was overexpressed, the proliferation, invasion of MDA‐MB‐231 were inhibited. MiR‐429 was able to suppress the Wnt/β‐catenin signaling pathway, and FN1 overexpression could rescue the influence of over‐miR‐429. Conclusions The results of our study suggest that miR‐429 suppresses the proliferation and invasion of breast cancer via inhibiting the Wnt/β‐catenin signaling pathway.

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Detection of novel germline mutations in six breast cancer predisposition genes by targeted next-generation sequencing

Cited by 6 publications

References 42 publications

Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations

Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families

MiR‐429 suppresses proliferation and invasion of breast cancer via inhibiting the Wnt/β‐catenin signaling pathway

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