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Functional Screenings Identify Regulatory Variants Associated with Breast Cancer Susceptibility.

ABSTRACT: Genome-wide association studies (GWAS) have identified more than 2000 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, most of which are located in the non-coding region. However, the causal SNPs functioning as gene regulatory elements still remain largely undisclosed. Here, we applied a Dinucleotide Parallel Reporter sequencing (DiR-seq) assay to evaluate 288 breast cancer risk SNPs in nine different breast cancer cell lines. Further multi-omics analysis with the ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), DNase-seq (DNase I hypersensitive sites sequencing) and histone modification ChIP-seq (Chromatin Immunoprecipitation sequencing) nominated seven functional SNPs in breast cancer cells. Functional investigations show that rs4808611 affects breast cancer progression by altering the gene expression of NR2F6. For the other site, rs2236007, the alteration promotes the binding of the suppressive transcription factor EGR1 and results in the downregulation of PAX9 expression. The downregulated expression of PAX9 causes cancer malignancies and is associated with the poor prognosis of breast cancer patients. Our findings contribute to defining the functional risk SNPs and the related genes for breast cancer risk prediction.

SUBMITTER: Ren N

PROVIDER: S-EPMC8928974 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Functional Screenings Identify Regulatory Variants Associated with Breast Cancer Susceptibility.

Ren Naixia N Li Yingying Y Xiong Yulong Y Li Panfeng P Ren Yutian Y Huang Qilai Q

Current issues in molecular biology 20211026 3

Genome-wide association studies (GWAS) have identified more than 2000 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, most of which are located in the non-coding region. However, the causal SNPs functioning as gene regulatory elements still remain largely undisclosed. Here, we applied a Dinucleotide Parallel Reporter sequencing (DiR-seq) assay to evaluate 288 breast cancer risk SNPs in nine different breast cancer cell lines. Further multi-omics analysis with ...[more]

PMID: 34889888

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Project description:ImportanceRare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.ObjectiveTo characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.Design, setting, and participantsThe multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.ExposuresProtein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.Main outcomes and measuresThe intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.ResultsThe mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.Conclusions and relevanceThe results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

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Functional Screenings Identify Regulatory Variants Associated with Breast Cancer Susceptibility.

Publications

Functional Screenings Identify Regulatory Variants Associated with Breast Cancer Susceptibility.

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