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TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.

ABSTRACT: TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

SUBMITTER: Fagerholm R

PROVIDER: S-EPMC5392336 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.

Fagerholm Rainer R Khan Sofia S Schmidt Marjanka K MK García-Closas Montserrat M Heikkilä Päivi P Saarela Jani J Beesley Jonathan J Jamshidi Maral M Aittomäki Kristiina K Liu Jianjun J Ali H Raza HR Andrulis Irene L IL Beckmann Matthias W MW Behrens Sabine S Blows Fiona M FM Brenner Hermann H Chang-Claude Jenny J Couch Fergus J FJ Czene Kamila K Fasching Peter A PA Figueroa Jonine J Floris Giuseppe G Glendon Gord G Guo Qi Q Hall Per P Hallberg Emily E Hamann Ute U Holleczek Bernd B Hooning Maartje J MJ Hopper John L JL Jager Agnes A Kabisch Maria M Keeman Renske R Kosma Veli-Matti VM Lambrechts Diether D Lindblom Annika A Mannermaa Arto A Margolin Sara S Provenzano Elena E Shah Mitul M Southey Melissa C MC Dennis Joe J Lush Michael M Michailidou Kyriaki K Wang Qin Q Bolla Manjeet K MK Dunning Alison M AM Easton Douglas F DF Pharoah Paul D P PD Chenevix-Trench Georgia G Blomqvist Carl C Nevanlinna Heli H

Oncotarget 20170301 11

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 statu ...[more]

PMID: 28179588

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Project description:BackgroundGenome-wide association studies have identified 55 genetic variants associated with colorectal cancer risk to date. However, potential causal genes and pathways regulated by these risk variants remain to be characterized. Therefore, we performed gene ontology enrichment and pathway analyses to determine if there was an enrichment of genes in proximity to the colorectal cancer risk variants that could further elucidate the probable causal genes and pathways involved in colorectal cancer biology.ResultsFor the 65 unique genes that either contained, or were immediately neighboring up- and downstream, of these variants there was a significant enrichment for the KEGG pathway, Pathways in Cancer (p-value = 2.67 × 10-5) and an enrichment for multiple biological processes (FDR < 0.05), such as cell junction organization, tissue morphogenesis, regulation of SMAD protein phosphorylation, and odontogenesis identified through Gene Ontology analysis. To identify potential causal genes, we conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using gene expression and genotype data from the Genotype-Tissue Expression (GTEx) Project portal in normal sigmoid (n = 124) and transverse (n = 169) colon tissue. In addition, we also did a cis-eQTL analysis on colorectal tumor tissue (n = 147) from The Cancer Genome Atlas (TCGA). We identified two risk alleles that were significant cis-eQTLs for FADS2 (rs1535) and COLCA1 and 2 (rs3802842) genes in the normal transverse colon tissue and two risk alleles that were significant cis-eQTLs for the CABLES2 (rs2427308) and LIPG (rs7229639) genes in the normal sigmoid colon tissue, but not tumor tissue.ConclusionsOur data reaffirm the potential to identify an enrichment for biological processes and candidate causal genes based on expression profiles correlated with genetic risk alleles of colorectal cancer, however, the identification of these significant cis-eQTLs is context and tissue specific.

Dataset Information

TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.

Publications

TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.

Similar Datasets

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