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 05E010-5; 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 05E010-5, 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.

FAM53A Affects Breast Cancer Cell Proliferation, Migration, and Invasion in a p53-Dependent Manner

“…FAM53A was shown to affect the sensitivity of breast cancer cell lines to doxorubicin, with opposing effects on breast cancer cell lines with different p53 status (27). However, the effects of FAM53A on breast cancer cells and their related mechanisms were unknown.…”

“…Several of these families have been linked to the development of tumors, including breast cancer, non-small cell lung cancer, lung adenocarcinoma, renal cell carcinoma, prostate cancer, colorectal cancer, and esophageal squamous cell carcinoma, where they are thought to play important roles in proliferation, apoptosis, migration, and invasion (16–23). FAM53 is a vertebrate-specific family of proteins that bind to transcriptional regulators of proliferation and neural tube development, encoded by three homologous genes: FAM53A, FAM53B , and FAM53C (24–27). FAM53A, also known as dorsal neural tube nuclear protein, is thought to play an important role in neurodevelopment by specifying the fate of dorsal cells within the neural tube (28, 29).…”

“…FAM53A, also known as dorsal neural tube nuclear protein, is thought to play an important role in neurodevelopment by specifying the fate of dorsal cells within the neural tube (28, 29). Expression quantitative trait loci variants of FAM53A identified in TP53 -based interaction analysis are associated with the use of therapeutic doxorubicin in breast cancer (27). In the triple-negative TP53 -missense mutant breast cancer cell line MDA-MB-231, downregulation of FAM53A increased doxorubicin resistance.…”

“…In the triple-negative TP53 -missense mutant breast cancer cell line MDA-MB-231, downregulation of FAM53A increased doxorubicin resistance. However, in the luminal B p53-truncated mutant line MDA-MB-361 and the luminal A p53-wild-type line MCF7, downregulation of FAM53A resulted in increased sensitivity to doxorubicin (27). The role of FAM53A in breast cancer is unclear, and its relevance to the clinical pathology of breast cancer has not been reported.…”

Risk, Prediction and Prevention of Hereditary Breast Cancer – Large-Scale Genomic Studies in Times of Big and Smart Data

“…The influence of common genetic variants on therapy efficacy and prognosis has previously been shown in several breast cancer studies 43 – 49 . Data from large international consortia additionally contribute to these questions 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 . The relation of common variants to well-known environmental risk factors as well as their interaction is of special interest as individuals who are at a higher risk could be identified.…”