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Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility.

ABSTRACT: Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility.

SUBMITTER: Wen W

PROVIDER: S-EPMC8438084 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility.

Wen Wanqing W Chen Zhishan Z Bao Jiandong J Long Quan Q Shu Xiao-Ou XO Zheng Wei W Guo Xingyi X

Nature communications 20210913 1

Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs wi ...[more]

PMID: 34518541

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Project description:BackgroundCancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatic analyses, The Cancer Genome Atlas (TCGA) project has identified panels of somatic mutations that contributed to the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these significantly mutated genes (SMGs) and lung cancer susceptibility.Patients and methodsWe comprehensively evaluated 1655 tagged single nucleotide polymorphisms (SNPs) located in 127 SMGs identified by TCGA, and test their association with lung cancer risk in large-scale case-control study. Functional effect of the validated SNPs, gene mutation frequency and pathways were analyzed.ResultsWe found 11 SNPs in 8 genes showed consistent association (P < 0.1) and 8 SNPs significantly associated with lung cancer risk (P < 0.05) in both discovery and validation phases. The most significant association was rs10412613 in PPP2R1A, with the minor G allele associated with a decreased risk of lung cancer [odds ratio = 0.91, 95% confidence interval (CI): 0.87-0.96, P = 2.3 × 10-4]. Cumulative analysis of risk score built as a weight sum of the 11 SNPs showed consistently elevated risk with increasing risk score (P for trend = 9.5 × 10-9). In stratified analyses, the association of PPP2R1A:rs10412613 and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The expression quantitative trait loci analysis indicated that rs10412613, rs10804682, rs635469 and rs6742399 genotypes significantly correlated with the expression of PPP2R1A, ATR, SETBP1 and ERBB4, respectively. From TCGA data, expression of the identified genes was significantly different in lung tumors compared with normal tissues, and the genes' highest mutation frequency was found in lung cancers. Integrative pathway analysis indicated the identified genes were mainly involved in AKT/NF-κB regulatory pathway suggesting the underlying biological processes.ConclusionThis study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.

Project description:BackgroundPublished data on the association between genetic variants on the 8q24 chromosome and gastric cancer (GC) susceptibility are inconclusive. Here we present a meta-analysis designed to evaluate the relationship between 8q24 variants (single nucleotide polymorphisms (SNPs) labeled rs6983267 and rs1447295) and risk of developing GC.MethodsA literature search was performed using studies published on PubMed, Science Direct, OVID and Web of Science databases up to December 2016. Studies were selected based on our enrollment criteria, relevant data was extracted from each study and the odds ratios (OR), and 95% confidence intervals (CI) were calculated and used to assess the strength of associations found between 8q24 polymorphisms and GC risk. Conclusions about acceptable strong associations were made after taking into account sample heterogeneity and sensitivity analyses.ResultsA total of seven studies containing ten case-control studies were selected. Among these studies were six studies of 1,421 GC patients and 3,393 controls examining the role of the rs6983267 SNP and four studies including 779 cases and 1,266 controls examining rs1447295 SNP. The pooled results of these studies indicated that there was no significant association between both genetic variants and GC susceptibility using an allele, dominant, recessive and homozygote genetic models. When using a heterozygote genetic model, a significant increase was found in the association of GC risk for rs6983267 SNP (OR = 1.07, 95% CI = 1.01-1.12, P = 0.015), whereas for rs1447295 SNP a significant decreased risk was detected (OR = 0.82, 95% CI = 0.69-0.98, P = 0.030). In subgroup analyses based on ethnicity and genotyping methods, similar non-significant results were observed for the rs1447295 variant using the four genetic models (allele, dominant, recessive or homozygote models) and for the rs6983267 variant using only the allele, recessive and homozygote models. However, after a multiple testing correction to our calculations, these associations remained non-significant.ConclusionMeta-analysis of gastrointestinal cancer genetic analysis studies did not confirm an association between 8q24 chromosome polymorphisms (specifically rs6983267 and rs1447295) and susceptibility to GC in the general populations.

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Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility.

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Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility.

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