Gene Summary

Gene:TOX3; TOX high mobility group box family member 3
Aliases: CAGF9, TNRC9
Summary:The protein encoded by this gene contains an HMG-box, indicating that it may be involved in bending and unwinding of DNA and alteration of chromatin structure. The C-terminus of the encoded protein is glutamine-rich due to CAG repeats in the coding sequence. A minor allele of this gene has been implicated in an elevated risk of breast cancer. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:TOX high mobility group box family member 3
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Genetic Association Studies
  • Chromosome 16
  • Alleles
  • FGFR2
  • Receptors, Progesterone
  • Sensitivity and Specificity
  • Case-Control Studies
  • Genetic Predisposition
  • Genome-Wide Association Study
  • African Americans
  • Cohort Studies
  • BRCA2
  • Age of Onset
  • Gene Expression
  • Biomarkers, Tumor
  • Cancer Gene Expression Regulation
  • Estrogen Receptor alpha
  • Risk Assessment
  • European Continental Ancestry Group
  • Logistic Models
  • Risk Factors
  • China
  • Staging
  • BRCA1
  • Estrogen Receptors
  • Survival Rate
  • Mammary Glands, Human
  • Odds Ratio
  • Genetic Loci
  • Breast Cancer
  • Genotype
  • Single Nucleotide Polymorphism
  • Polycystic Ovary Syndrome
  • BRCA1 Protein
  • Mutation
  • BRCA2 Protein
  • Neoplasm Proteins
  • Asian Continental Ancestry Group
  • Genetic Markers
  • Triple Negative Breast Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TOX3 (cancer-related)

Thanh NTN, Lan NTT, Phat PT, et al.
Two polymorphisms, rs2046210 and rs3803662, are associated with breast cancer risk in a Vietnamese case-control cohort.
Genes Genet Syst. 2018; 93(3):101-109 [PubMed] Related Publications
Breast cancer is the most common cancer in women worldwide. Breast tumorigenesis encompasses both extrinsic and intrinsic factors. Among intrinsic aspects, the appearance of DNA variation can cause genetic instability, which may lead to carcinogenesis. Genome-wide association studies have found several potential breast cancer-associated single nucleotide polymorphisms (SNPs) in many different populations. Among these, seven (rs2046210, rs1219648, rs3817198, rs3803662, rs889312, rs10941679 and rs13281615) have been shown to be significantly associated with breast cancer risk in various populations including those very similar to the Vietnamese. Here, therefore, we have investigated the relationship between these SNPs and breast cancer risk in a Vietnamese population case-control cohort. Real-time PCR high-resolution melt analysis was performed to genotype 300 breast cancer cases and 325 healthy controls, and the association between the seven SNPs and breast cancer risk was determined by analyzing the differences in allelic and genotypic frequencies between case and control groups using R software. While five of the seven showed no association with breast cancer, there was a relationship between the other two SNPs, rs2046210 and rs3803662, and the risk of developing this disease in Vietnamese women. The A allele is the risk allele for both rs2046210 (OR [95% CI] = 1.43 [1.14 - 1.78], P = 0.0015) and rs3803662 (OR [95% CI] = 1.45 [1.16 - 1.83], P = 0.001). We conclude that two polymorphisms, rs2046210 in ESR1 and rs3803662 in TNRC9, are associated with breast cancer risk in the Vietnamese population.

Li L, Guo G, Wang F, et al.
TOX high mobility group box family member 3 rs3803662 and breast cancer risk: A meta-analysis.
J Cancer Res Ther. 2018; 14(Supplement):S208-S212 [PubMed] Related Publications
Aims: Some studies suggested that TOX high mobility group box family member 3 (TOX3) rs3803662 polymorphism was associated with the risk of breast cancer. However, the results were controversy. Therefore, in order to derive a more comprehensive estimation of the association between TOX3 rs3803662 polymorphism and breast cancer risk, we conducted a meta-analysis to investigate this relationship.
Materials and Methods: An electronic literature search was conducted using the following database: PubMed, EMBASE, and China National Knowledge Infrastructure till to March 31, 2015. The strength of the associations between the TOX3 rs3803662 polymorphism and breast cancer risk in per alle model was measured by odds ratios (ORs) and 95% confidence intervals (CIs).
Results: A statistically significant association between TOX3 rs3803662 polymorphism and breast cancer risk was fond. The data showed that TOX3 rs3803662 polymorphism could increase the risk of breast cancer (OR = 1.20; 95% CI: 1.16-1.25; P < 0.00001). In the subgroup analysis of race, Caucasians, Asians, and Hispanics also showed increased breast cancer risk (OR = 1.21; 95% CI: 1.17-1.25; P < 0.00001; OR = 1.20; 95% CI: 1.08-1.33; P = 0.0004; OR = 1.32; 95% CI: 1.12-1.57; P = 0.001). However, African-Americans with TOX3 rs3803662 polymorphism showed decreased breast cancer risk (OR = 0.95; 95% CI: 0.86-1.04; P = 0.28), although the result was not significant. When considered estrogen receptor (ER) status, we found that ER
Conclusions: This meta-analysis suggested that TOX3 rs3803662 polymorphism was associated with increased breast cancer risk.

Zhang B, Chen MY, Shen YJ, et al.
A Large-Scale, Exome-Wide Association Study of Han Chinese Women Identifies Three Novel Loci Predisposing to Breast Cancer.
Cancer Res. 2018; 78(11):3087-3097 [PubMed] Related Publications
Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g.,

Polinyk SI, Rybchenko LA, Klimyk BT
Reserch of the gene polymorphism TOX3 / LOC643714 and the risk of breast cancer development in persons exposed to ionizing radiation after Chornobyl disaster.
Probl Radiac Med Radiobiol. 2017; 22:450-462 [PubMed] Related Publications
OBJECTIVE: The objective of this work was to identify and compare the polymorphism of the rs3803662 polymorphism of the TOX3/LOC643714 gene in breast cancer patients who have undergone ionizing radiation due to the Chornobyl accident and in patients without ionizing radiation (IR) in the history.
MATERIALS AND METHODS: The determination of the rs3803662 polymorphism of the TOX3/LOC643714 gene was per formed by polymerase chain reaction (PCR) in 83 patients with breast cancer: 42 subjects who were exposed to ion izing radiation due to the Chornobyl accident, 41 people without ionizing radiation in history and 17 controls in Ukraine without cancer pathology. In order to compare the obtained data on spontaneous and radiation associated breast cancer and to calculate the differences in the frequencies of alleles and the risk of oncopathology, data from literature on control groups of the populations of the Russian Federation, Sweden, and the United Kingdom were used.
RESULTS: Comparing with the literature data and the group of exposed subjects, the homozygous carriers of the minor alleles of the TOX3/LOC643714 ТТ gene revealed an increased risk of developing breast cancer: OR = 2.89, p = 0.02 (CI 95% 1.17 7,16). In subjects without the influence of IR in history, the carrier of homozygous minor axis of the gene TOX3/LOC643714 ТТ is also associated with the risk of breast cancer: OR = 3.83, p = 0.0002 (CI 95% 0.82-14.14). In the homozygous carriers of the minor alleles of the TOX3 / LOC643714 gene exposed to IR, there was no increase in the risk of developing breast cancer (OR = 0.65, p = 0.46, CI 95% 0.21-2.04) compared with the con trol group of Ukrainian population.
CONCLUSIONS: The carrier of homozygous minor alleles of the TOX3/LOC643714 gene is not a risk factor for the devel opment of breast cancer under conditions of exposure to ionizing radiation in the study group of the Ukrainian population.

Jara L, Morales S, de Mayo T, et al.
Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations.
Biol Res. 2017; 50(1):35 [PubMed] Free Access to Full Article Related Publications
Breast cancer (BC) is the most common malignancy among women worldwide. A major advance in the understanding of the genetic etiology of BC was the discovery of BRCA1 and BRCA2 (BRCA1/2) genes, which are considered high-penetrance BC genes. In non-carriers of BRCA1/2 mutations, disease susceptibility may be explained of a small number of mutations in BRCA1/2 and a much higher proportion of mutations in ethnicity-specific moderate- and/or low-penetrance genes. In Central and South American populations, studied have focused on analyzing the distribution and prevalence of BRCA1/2 mutations and other susceptibility genes that are scarce in Latin America as compared to North America, Europe, Australia, and Israel. Thus, the aim of this review is to present the current state of knowledge regarding pathogenic BRCA variants and other BC susceptibility genes. We conducted a comprehensive review of 47 studies from 12 countries in Central and South America published between 2002 and 2017 reporting the prevalence and/or spectrum of mutations and pathogenic variants in BRCA1/2 and other BC susceptibility genes. The studies on BRCA1/2 mutations screened a total of 5956 individuals, and studies on susceptibility genes analyzed a combined sample size of 11,578 individuals. To date, a total of 190 different BRCA1/2 pathogenic mutations in Central and South American populations have been reported in the literature. Pathogenic mutations or variants that increase BC risk have been reported in the following genes or genomic regions: ATM, BARD1, CHECK2, FGFR2, GSTM1, MAP3K1, MTHFR, PALB2, RAD51, TOX3, TP53, XRCC1, and 2q35.

Moazzeni H, Najafi A, Khani M
Identification of direct target genes of miR-7, miR-9, miR-96, and miR-182 in the human breast cancer cell lines MCF-7 and MDA-MB-231.
Mol Cell Probes. 2017; 34:45-52 [PubMed] Related Publications
Some microRNAs have carcinogenic or tumor suppressive effects in breast cancer, which is the most common cancer in women worldwide. MiR-7 and miR-9 are tumor suppressor microRNAs, which induce apoptosis and inhibit proliferation in breast cancer cells. Moreover, miR-96 and miR-182 are onco-microRNAs that increase proliferation, migration, and tumorigenesis in breast cancer cells. This study aimed to identify the direct target genes of these four microRNAs in the human breast cancer cell lines MCF-7 and MDA-MB-231. Initially, bioinformatics tools were used to identify the target genes that have binding sites for miR-7, MiR-9, MiR-96, and miR-182 and are also associated with breast cancer. Subsequently, the findings of the bioinformatics analysis relating to the effects of these four microRNAs on the 3'-UTR activity of the potential target genes were confirmed using the dual luciferase assay in MCF-7 and MDA-MB-231 cells co-transfected with the vectors containing 3'-UTR segments of the target genes downstream of a luciferase coding gene and each of the microRNAs. Finally, the effects of microRNAs on the endogenous expression of potential target genes were assessed by the overexpression of each of the four microRNAs in MCF-7 and MDA-MB-231 cells. Respectively, three, three, three, and seven genes were found to have binding sites for miR-7, miR-9, miR-96, and miR-182 and were associated with breast cancer. The results of empirical studies including dual luciferase assays and real-time PCR confirmed that miR-7 regulates the expression of BRCA1 and LASP1; MiR-9 regulates the expression of AR; miR-96 regulates the expression of ABCA1; and miR-182 regulates the expression of NBN, TOX3, and LASP1. Taken together, our results suggest that the tumor suppressive effects of miR-7 may be mediated partly by regulating the expression of BRCA1 as a tumor suppressor gene in breast cancer. In addition, this microRNA and miR-182 may have effects on the nodal-positivity and tumor size of breast carcinoma through the regulation of LASP1. The tumor suppressive functions of miR-9 may be mediated partly by suppressing the expression of AR-an oncogene in breast cancer. Moreover, miR-96 may play an oncogenic role in breast cancer by suppressing the apoptosis through the regulation of ABCA1.

Ning Z, Jiayi L, Jian R, Wanli X
Relationship between abnormal TOX3 gene methylation and polycystic ovarian syndrome.
Eur Rev Med Pharmacol Sci. 2017; 21(9):2034-2038 [PubMed] Related Publications
OBJECTIVE: The purpose of this work was to examine the relationship between abnormal TOX3 gene methylation and the occurrence of polycystic ovarian syndrome (PCOS).
PATIENTS AND METHODS: We selected 30 patients with PCOS and 30 control volunteers. Serum luteinizing hormone, estradiol, testosterone, and thyroid stimulating hormone were detected, methylation, mRNA and protein level of TOX3 were measured.
RESULTS: Serum luteinizing hormone, estradiol, testosterone, and thyroid stimulating hormone were significantly higher and follicle stimulating hormone and prolactin were significantly lower in PCOS patients than in the control group. Methylation of the promoter of TOX3 in serum and granular cells was significantly lower in PCOS than in the control group. The mRNA levels of TOX3 in serum were lower in the PCOS group. The levels of TOX3 protein in serum and granular cells was significantly lower in PCOS group than in the control group.
CONCLUSIONS: Overall, abnormal TOX3 methylation possibly resulting in changes in TOX3 protein expression is closely related to the occurrence of PCOS and may play a role the development of the pathology.

Feng Y, Rhie SK, Huo D, et al.
Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry.
Cancer Epidemiol Biomarkers Prev. 2017; 26(7):1016-1026 [PubMed] Free Access to Full Article Related Publications

Al-Eitan LN, Jamous RI, Khasawneh RH
Candidate Gene Analysis of Breast Cancer in the Jordanian Population of Arab Descent: A Case-Control Study.
Cancer Invest. 2017; 35(4):256-270 [PubMed] Related Publications
This study aimed to investigate whether there are specific polymorphisms within six genes (BRCA1, BRCA2, TP53, DAPK1, MMP9 promoter, and TOX3) that are associated with breast cancer among the Jordanian population. Sequenom MassARRAY system was used to genotype 17 single nucleotide polymorphisms (SNPs) within these genes in 230 Jordanian breast cancer patients and 225 healthy individuals. Three SNPs (MMP9 (rs6065912), TOX3 (rs1420546), and DAPK1 (rs11141901) were found to be significantly associated with an increased risk of breast cancer (p < .05). This study is the first to provide evidence that genetic variation in MMP9, TOX3, and DAPK1 genes contribute to the development of breast cancer in the Jordanian population.

Kuo SH, Yang SY, You SL, et al.
Polymorphisms of ESR1, UGT1A1, HCN1, MAP3K1 and CYP2B6 are associated with the prognosis of hormone receptor-positive early breast cancer.
Oncotarget. 2017; 8(13):20925-20938 [PubMed] Free Access to Full Article Related Publications
In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10.6 years, 363 patients were alive, and 51 (12.3%) had died. Multiple-adjusted hazard ratios (aHRs) and the corresponding 95% confidence intervals for distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS) in association with the genotypes of 34 SNPs from the above-mentioned 16 genes were evaluated, using the stepwise selection Cox model. We found that the SNP, ESR1-codon325 rs1801132 (G/G+G/C), was associated with a longer DDFS, whereas UGT1A1 rs4148323 (A/A+A/G), and HCN1 rs981782 (A/A+A/C) were significantly associated with poorer DDFS. MAP3K1 rs889312 (C/C) and CYP2B6 rs3211371 (T/C) were significantly associated with poor DFS, DDFS and OS. Among premenopausal women, MAP3K1 rs889312 (C/C), CYP2B6 rs3211371 (T/C), CYP2B6 rs4802101 (T/T), ABCB1 rs2032582 (C/C), and ALDH3A1 rs2231142 (G/G) were significantly associated with poor DDFS, DFS, or OS. Our results provide additional evidence that genetic polymorphisms observed in SNPs are associated with the prognoses of patients with HR-positive breast cancers; this may indicate different treatment strategies for these patients.

Pau CT, Mosbruger T, Saxena R, Welt CK
Phenotype and Tissue Expression as a Function of Genetic Risk in Polycystic Ovary Syndrome.
PLoS One. 2017; 12(1):e0168870 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies and replication analyses have identified (n = 5) or replicated (n = 10) DNA variants associated with risk for polycystic ovary syndrome (PCOS) in European women. However, the causal gene and underlying mechanism for PCOS risk at these loci have not been determined. We hypothesized that analysis of phenotype, gene expression and metformin response as a function of genotype would identify candidate genes and pathways that could provide insight into the underlying mechanism for risk at these loci. To test the hypothesis, subjects with PCOS (n = 427) diagnosed according to the NIH criteria (< 9 menses per year and clinical or biochemical hyperandrogenism) and controls (n = 407) with extensive phenotyping were studied. A subset of subjects (n = 38) underwent a subcutaneous adipose tissue biopsy for RNA sequencing and were subsequently treated with metformin for 12 weeks with standardized outcomes measured. Data were analyzed according to genotype at PCOS risk loci and adjusted for the false discovery rate. A gene variant in the THADA locus was associated with response to metformin and metformin was a predicted upstream regulator at the same locus. Genotype at the FSHB locus was associated with LH levels. Genes near the PCOS risk loci demonstrated differences in expression as a function of genotype in adipose including BLK and NEIL2 (GATA4 locus), GLIPR1 and PHLDA1 (KRR1 locus). Based on the phenotypes, expression quantitative trait loci (eQTL), and upstream regulatory and pathway analyses we hypothesize that there are PCOS subtypes. FSHB, FHSR and LHR loci may influence PCOS risk based on their relationship to gonadotropin levels. The THADA, GATA4, ERBB4, SUMO1P1, KRR1 and RAB5B loci appear to confer risk through metabolic mechanisms. The IRF1, SUMO1P1 and KRR1 loci may confer PCOS risk in development. The TOX3 and GATA4 loci appear to be involved in inflammation and its consequences. The data suggest potential PCOS subtypes and point to the need for additional studies to replicate these findings and identify personalized diagnosis and treatment options for PCOS.

Hu DG, McKinnon RA, Hulin JA, et al.
Novel Nine-Exon AR Transcripts (Exon 1/Exon 1b/Exons 2-8) in Normal and Cancerous Breast and Prostate Cells.
Int J Mol Sci. 2016; 18(1) [PubMed] Free Access to Full Article Related Publications
Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named isoforms 3a and 3b. The proteins encoded by these new AR variants could regulate androgen-responsive reporters in breast and prostate cancer cells under androgen-depleted conditions. Analysis of type 3 AR-GFP fusion proteins showed partial nuclear localization in PC3 cells under androgen-depleted conditions, supporting androgen-independent activation of the AR. Type 3 AR proteins inhibited androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of prostate cancer (

Shi M, O'Brien KM, Sandler DP, et al.
Previous GWAS hits in relation to young-onset breast cancer.
Breast Cancer Res Treat. 2017; 161(2):333-344 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Genome-wide association studies (GWAS) have identified dozens of single-nucleotide polymorphisms (SNPs) associated with breast cancer. Few studies focused on young-onset breast cancer, which exhibits etiologic and tumor-type differences from older-onset disease. Possible confounding by prenatal effects of the maternal genome has also not been considered.
METHODS: Using a family-based design for breast cancer before age 50, we assessed the relationship between breast cancer and 77 GWAS-identified breast cancer risk SNPs. We estimated relative risks (RR) for inherited and maternally mediated genetic effects. We also used published RR estimates to calculate genetic risk scores and model joint effects.
RESULTS: Seventeen of the candidate SNPs were nominally associated with young-onset breast cancer in our 1296 non-Hispanic white affected families (uncorrected p value <0.05). Top-ranked SNPs included rs3803662-A (TOX3, RR = 1.39; p = 7.0 × 10
CONCLUSIONS: The results of this family-based study indicate that no effects of previously identified risk SNPs were explained by prenatal effects of maternal variants. Many of the known breast cancer risk variants were associated with young-onset breast cancer, with evidence that TOX3, ESR1, FGFR2, and RAD51B are important for young-onset disease.

Han YJ, Zhang J, Zheng Y, et al.
Genetic and Epigenetic Regulation of TOX3 Expression in Breast Cancer.
PLoS One. 2016; 11(11):e0165559 [PubMed] Free Access to Full Article Related Publications
Genome wide association studies (GWAS) have identified low penetrance and high frequency single nucleotide polymorphisms (SNPs) that contribute to genetic susceptibility of breast cancer. The SNPs at 16q12, close to the TOX3 and CASC16 genes, represent one of the susceptibility loci identified by GWAS, showing strong evidence for breast cancer association across various populations. To examine molecular mechanisms of TOX3 regulation in breast cancer, we investigated both genetic and epigenetic factors using cell lines and datasets derived from primary breast tumors available through The Cancer Genome Atlas (TCGA). TOX3 expression is highly up-regulated in luminal subtype tumors compared to normal breast tissues or basal-like tumors. Expression quantitative trait loci (eQTL) analyses revealed significant associations of rs3803662 and rs4784227 genotypes with TOX3 expression in breast tumors. Bisulfite sequencing of four CpG islands in the TOX3 promoter showed a clear difference between luminal and basal-like cancer cell lines. 5-Aza-2'-deoxycytidine treatment of a basal-like cancer cell line increased expression of TOX3. TCGA dataset verified significantly lower levels of methylation of the promoter in luminal breast tumors with an inverse correlation between methylation and expression of TOX3. Methylation QTL (mQTL) analyses showed a weak or no correlation of rs3803662 or rs4784227 with TOX3 promoter methylation in breast tumors, indicating an independent relationship between the genetic and epigenetic events. These data suggest a complex system of TOX3 regulation in breast tumors, driven by germline variants and somatic epigenetic modifications in a subtype specific manner.

Mazhar A, Jamil F, Bashir Q, et al.
Genetic variants in FGFR2 and TNRC9 genes are associated with breast cancer risk in Pakistani women.
Mol Med Rep. 2016; 14(4):3443-51 [PubMed] Related Publications
Single nucleotide polymorphisms (SNPs) lead to genetic differences in breast cancer (BC) susceptibility among women from different ethnicities. The present study aimed at investigating the involvement of SNPs of three genes, including fibroblast growth factor receptor 2 (FGFR2), trinucleotide-repeat-containing 9 (TNRC9) and mitogen-activated protein kinase kinase kinase 1 (MAP3K1), as risk factors for the development of BC. A case‑control study (90‑100 cases; 90‑100 controls) was performed to evaluate five genetic variants of three genes, including FGFR2 (SNPs: rs1219648, rs2981582), TNRC9 (SNPs: rs8051542, rs3803662) and MAP3K1 (SNP: rs889312) as BC risk factors in Pakistani women. Significant associations were observed between BC risk and two SNPs of FGFR2 [rs2981582 (P=0.005), rs1219648 (P=9.08e‑006)] and one SNP of TNRC9 [rs3803662) (P=0.012)] in Pakistani women. On examining the different interactions of these SNPs with various clinicopathological characteristics, all three associated genetic variants, rs2981582 rs1219648 and rs3803662, exhibited a greater predisposition to sporadic, in comparison to familial, BC. Furthermore, there was an increased effect of BC risk between haplotype combinations of the two SNPs of FGFR2 (rs2981582 and rs1219648) in Pakistani women. The results of the present study suggest that variants of FGFR2 and TNRC9 may contribute to the genetic susceptibility of BC in Pakistani women.

Jiang C, Yu S, Qian P, et al.
The breast cancer susceptibility-related polymorphisms at the TOX3/LOC643714 locus associated with lung cancer risk in a Han Chinese population.
Oncotarget. 2016; 7(37):59742-59753 [PubMed] Free Access to Full Article Related Publications
It has been well established that besides environmental factors, genetic factors are also associated with lung cancer risk. However, to date, the prior identified genetic variants and loci only explain a small fraction of the familial risk of lung cancer. Hence it is vital to investigate the remaining missing heritability to understand the development and process of lung cancer. In the study, to test our hypothesis that the previously identified breast cancer risk-associated genetic polymorphisms at the TOX3/LOC643714 locus might contribute to lung cancer risk, 16 SNPs at the TOX3/LOC643714 locus were evaluated in a Han Chinese population based on a case-control study. Pearson's chi-square test or Fisher's exact test revealed that rs9933638, rs12443621, and rs3104746 were significantly associated with lung cancer risk (P < 0.001, P < 0.001, and P = 0.005, respectively). Logistic regression analyses displayed that lung cancer risk of individuals with rs9933638(GG+GA) were 1.89 times higher than that of rs9933638AA carriers (OR = 1.893, 95% CI = 1.308-2.741, P = 0.001). Similar findings were manifested for rs12443621 (OR = 1.824, 95% CI = 1.272-2.616, P = 0.001, rs12443621(GG+GA) carriers vs. rs12443621AA carriers) and rs3104746 (OR = 1.665, 95% CI = 1.243-2.230, P = 0.001, rs3104746TT carriers vs. rs3104746(TA+AA) carriers). The study discovered for the first time that three SNPs (rs9933638, rs12443621, and rs3104746) at the TOX3/LOC643714 locus contributed to lung cancer risk, providing new evidences that lung cancer and breast cancer are linked at the molecular and genetic level to a certain extent.

Lavrov AV, Chelysheva EY, Smirnikhina SA, et al.
Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia.
BMC Genet. 2016; 17 Suppl 1:14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genome variability of host genome and cancer cells play critical role in diversity of response to existing therapies and overall success in treating oncological diseases. In chronic myeloid leukemia targeted therapy with tyrosine kinase inhibitors demonstrates high efficacy in most of the patients. However about 15 % of patients demonstrate primary resistance to standard therapy. Whole exome sequencing is a good tool for unbiased search of genetic variations important for prognosis of survival and therapy efficacy in many cancers. We apply this approach to CML patients with optimal response and failure of tyrosine kinase therapy.
RESULTS: We analyzed exome variations between optimal responders and failures and found 7 variants in cancer-related genes with different genotypes in two groups of patients. Five of them were found in optimal responders: rs11579366, rs1990236, rs176037, rs10653661, rs3803264 and two in failures: rs3099950, rs9471966. These variants were found in genes associated with cancers (ANKRD35, DNAH9, MAGEC1, TOX3) or participating in cancer-related signaling pathways (THSD1, MORN2, PTCRA).
CONCLUSION: We found gene variants which may become early predictors of the therapy outcome and allow development of new early prognostic tests for estimation of therapy efficacy in CML patients. Normal genetic variation may influence therapy efficacy during targeted treatment of cancers.

Zhang L, Long X
Association of three SNPs in TOX3 and breast cancer risk: Evidence from 97275 cases and 128686 controls.
Sci Rep. 2015; 5:12773 [PubMed] Free Access to Full Article Related Publications
The associations of SNPs in TOX3 gene with breast cancer risk were investigated by some Genome-wide association studies and epidemiological studies, but the study results were contradictory. To derive a more precise estimate of the associations, we conducted a meta-analysis. ORs with 95% CI were used to assess the strength of association between TOX3 polymorphisms and breast cancer risk in fixed or random effect model. A total of 37 publications with 97275 cases and 128686 controls were identified. We observed that the rs3803662 C > T, rs12443621 A > G and rs8051542 C > T were all correlated with increased risk of breast cancer. In the stratified analyses by ethnicity, significantly elevated risk was detected for all genetic models of the three SNPs in Caucasians. In Asian populations, there were significant associations of rs3803662 and rs8051542 with breast cancer risk. Whereas there was no evidence for statistical significant association between the three SNPs and breast cancer risk in Africans. Additionally, we observed different associations of rs3803662 with breast cancer risk based on different ER subtype and BRCA1/BRCA2 mutation carriers. In conclusion, the meta-analysis suggested that three SNPs in TOX3 were significantly associated with breast cancer risk in different populations.

Campa D, Barrdahl M, Gaudet MM, et al.
Genetic risk variants associated with in situ breast cancer.
Breast Cancer Res. 2015; 17:82 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS.
METHODS: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile.
RESULTS: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies.
CONCLUSIONS: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.

Palomba G, Loi A, Porcu E, et al.
Genome-wide association study of susceptibility loci for breast cancer in Sardinian population.
BMC Cancer. 2015; 15:383 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles.
METHODS: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs.
RESULTS: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p <  0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts.
CONCLUSIONS: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.

Keller BM, McCarthy AM, Chen J, et al.
Associations between breast density and a panel of single nucleotide polymorphisms linked to breast cancer risk: a cohort study with digital mammography.
BMC Cancer. 2015; 15:143 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast density and single-nucleotide polymorphisms (SNPs) have both been associated with breast cancer risk. To determine the extent to which these two breast cancer risk factors are associated, we investigate the association between a panel of validated SNPs related to breast cancer and quantitative measures of mammographic density in a cohort of Caucasian and African-American women.
METHODS: In this IRB-approved, HIPAA-compliant study, we analyzed a screening population of 639 women (250 African American and 389 Caucasian) who were tested with a validated panel assay of 12 SNPs previously associated to breast cancer risk. Each woman underwent digital mammography as part of routine screening and all were interpreted as negative. Both absolute and percent estimates of area and volumetric density were quantified on a per-woman basis using validated software. Associations between the number of risk alleles in each SNP and the density measures were assessed through a race-stratified linear regression analysis, adjusted for age, BMI, and Gail lifetime risk.
RESULTS: The majority of SNPs were not found to be associated with any measure of breast density. SNP rs3817198 (in LSP1) was significantly associated with both absolute area (p = 0.004) and volumetric (p = 0.019) breast density in Caucasian women. In African-American women, SNPs rs3803662 (in TNRC9/TOX3) and rs4973768 (in NEK10) were significantly associated with absolute (p = 0.042) and percent (p = 0.028) volume density respectively.
CONCLUSIONS: The majority of SNPs investigated in our study were not found to be significantly associated with breast density, even when accounting for age, BMI, and Gail risk, suggesting that these two different risk factors contain potentially independent information regarding a woman's risk to develop breast cancer. Additionally, the few statistically significant associations between breast density and SNPs were different for Caucasian versus African American women. Larger prospective studies are warranted to validate our findings and determine potential implications for breast cancer risk assessment.

Seksenyan A, Kadavallore A, Walts AE, et al.
TOX3 is expressed in mammary ER(+) epithelial cells and regulates ER target genes in luminal breast cancer.
BMC Cancer. 2015; 15:22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A breast cancer susceptibility locus has been mapped to the gene encoding TOX3. Little is known regarding the expression pattern or biological role of TOX3 in breast cancer or in the mammary gland. Here we analyzed TOX3 expression in murine and human mammary glands and in molecular subtypes of breast cancer, and assessed its ability to alter the biology of breast cancer cells.
METHODS: We used a cell sorting strategy, followed by quantitative real-time PCR, to study TOX3 gene expression in the mouse mammary gland. To study the expression of this nuclear protein in human mammary glands and breast tumors, we generated a rabbit monoclonal antibody specific for human TOX3. In vitro studies were performed on MCF7, BT474 and MDA-MB-231 cell lines to study the effects of TOX3 modulation on gene expression in the context of breast cancer cells.
RESULTS: We found TOX3 expression in estrogen receptor-positive mammary epithelial cells, including progenitor cells. A subset of breast tumors also highly expresses TOX3, with poor outcome associated with high expression of TOX3 in luminal B breast cancers. We also demonstrate the ability of TOX3 to alter gene expression in MCF7 luminal breast cancer cells, including cancer relevant genes TFF1 and CXCR4. Knockdown of TOX3 in a luminal B breast cancer cell line that highly expresses TOX3 is associated with slower growth. Surprisingly, TOX3 is also shown to regulate TFF1 in an estrogen-independent and tamoxifen-insensitive manner.
CONCLUSIONS: These results demonstrate that high expression of this protein likely plays a crucial role in breast cancer progression. This is in sharp contrast to previous studies that indicated breast cancer susceptibility is associated with lower expression of TOX3. Together, these results suggest two different roles for TOX3, one in the initiation of breast cancer, potentially related to expression of TOX3 in mammary epithelial cell progenitors, and another role for this nuclear protein in the progression of cancer. In addition, these results can begin to shed light on the reported association of TOX3 expression and breast cancer metastasis to the bone, and point to TOX3 as a novel regulator of estrogen receptor-mediated gene expression.

Lin Y, Fu F, Chen M, et al.
Associations of two common genetic variants with breast cancer risk in a chinese population: a stratified interaction analysis.
PLoS One. 2014; 9(12):e115707 [PubMed] Free Access to Full Article Related Publications
Recent genome-wide association studies (GWAS) have identified a series of new genetic susceptibility loci for breast cancer (BC). However, the correlations between these variants and breast cancer are still not clear. In order to explore the role of breast cancer susceptibility variants in a Southeast Chinese population, we genotyped two common SNPs at chromosome 6q25 (rs2046210) and in TOX3 (rs4784227) in a case-control study with a total of 702 breast cancer cases and 794 healthy-controls. In addition, we also evaluated the multiple interactions among genetic variants, risk factors, and tumor subtypes. Associations of genotypes with breast cancer risk was evaluated using multivariate logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (95% CI). The results indicated that both polymorphisms were significantly associated with the risk of breast cancer, with per allele OR = 1.35, (95%CI = 1.17-1.57) for rs2046210 and per allele OR = 1.24 (95%CI = 1.06-1.45) for rs4784227. Furthermore, in subgroup stratified analyses, we observed that the T allele of rs4784227 was significantly associated with elevated OR among postmenopausal populations (OR = 1.44, 95%CI 1.11-1.87) but not in premenopausal populations, with the heterogeneity P value of P = 0.064. These findings suggest that the genetic variants at chromosome 6q25 and in the TOX3 gene may play important roles in breast cancer development in a Chinese population and the underlying biological mechanisms need to be further elucidated.

Garrisi VM, Strippoli S, De Summa S, et al.
Proteomic profile and in silico analysis in metastatic melanoma with and without BRAF mutation.
PLoS One. 2014; 9(12):e112025 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Selective inhibitors of BRAF, vemurafenib and dabrafenib are the standard of care for metastatic melanoma patients with BRAF V600, while chemotherapy continued to be widely used in BRAF wild type patients.
MATERIALS AND METHODS: In order to discover novel candidate biomarkers predictive to treatment, serum of 39 metastatic melanoma vemurafenib (n = 19) or chemotherapy (n = 20) treated patients at baseline, at disease control and at progression, were analyzed using SELDI-TOF technology. In silico analysis was used to identify more significant peaks.
RESULTS: In patients with different BRAF status, we found 5 peptides significantly deregulated, with the down-regulation of the m/z 9176 peak strongly associated with BRAF mutation. At baseline as predictive biomarkers we identified 2 peptides - m/z 6411, 4075 - as significantly up-regulated in responders to chemotherapy and 4 peaks - m/z 5900, 12544, 49124 and 11724 - significantly up-regulated in longer vs shorter responders to vemurafenib. After response, 3 peptides (m/z 4658, 18639, and 9307) resulted significantly down regulated while 3 peptides m/z 9292, 7765 and 9176 appeared up-regulated respectively in chemotherapy and vemurafenib responder patients. In vemurafenib treated patients, 16 peaks appeared deregulated at progression compared to baseline time. In silico analysis identified proteins involved in invasiveness (SLAIN1) and resistance (ABCC12) as well as in the pathway of detoxification (NQO1) and apoptosis (RBM10, TOX3, MTEFD1, TSPO2). Proteins associated with the modulation of neuronal plasticity (RIN1) and regulatory activity factors of gene transcription (KLF17, ZBTB44) were also highlighted.
CONCLUSION: Our exploratory study highlighted some factors that deserve to be further investigated in order to provide a framework for improving melanoma treatment management through the development of biomarkers which could act as the strongest surrogates of the key biological events in stage IV melanoma.

Cui Y, Zhao S, Zhao H, et al.
Mutational analysis of TOX3 in Chinese Han women with polycystic ovary syndrome.
Reprod Biomed Online. 2014; 29(6):752-5 [PubMed] Related Publications
A previous genome-wide association study of polycystic ovary syndrome (PCOS) identified several susceptibility loci. TOX3 is the nearest gene to signal rs4784165. In the present study, all exons and exon-intron boundaries of TOX3 were amplified and sequenced in 200 Chinese women with PCOS. A 3-bp nucleotide deletion of CAG repeat and two known single nucleotide polymorphisms were identified. No plausible pathogenic mutations were detected. The results suggest that mutations in TOX3 are not common in Chinese Han women with PCOS.

Elematore I, Gonzalez-Hormazabal P, Reyes JM, et al.
Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population.
Mol Biol Rep. 2014; 41(6):3715-22 [PubMed] Related Publications
Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95%CI 1.02-13.84, P = 0.046) and 8.0 (95%CI 2.20-29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28-1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.

He X, Yao G, Li F, et al.
Risk-association of five SNPs in TOX3/LOC643714 with breast cancer in southern China.
Int J Mol Sci. 2014; 15(2):2130-41 [PubMed] Free Access to Full Article Related Publications
The specific mechanism by which low-risk genetic variants confer breast cancer risk is currently unclear, with contradictory evidence on the role of single nucleotide polymorphisms (SNPs) in TOX3/LOC643714 as a breast cancer susceptibility locus. Investigations of this locus using a Chinese population may indicate whether the findings initially identified in a European population are generalizable to other populations, and may provide new insight into the role of genetic variants in the etiology of breast cancer. In this case-control study, 623 Chinese female breast cancer patients and 620 cancer-free controls were recruited to investigate the role of five SNPs in TOX3/LOC643714 (rs8051542, rs12443621, rs3803662, rs4784227, and rs3112612); Linkage disequilibrium (LD) pattern analysis was performed. Additionally, we evaluated how these common SNPs influence the risk of specific types of breast cancer, as defined by estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status. Significant associations with breast cancer risk were observed for rs4784227 and rs8051542 with odds ratios (OR) of 1.31 ((95% confidence intervals (CI), 1.10-1.57)) and 1.26 (95% CI, 1.02-1.56), respectively, per T allele. The T-rs8051542 allele was significantly associated with ER-positive and HER2-negative carriers. No significant association existed between rs12443621, rs3803662, and rs3112612 polymorphisms and risk of breast cancer. Our results support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations, which may together explain an appreciable fraction of the genetic etiology of breast cancer.

Chen F, Zhou J, Xue Y, et al.
A single nucleotide polymorphism of the TNRC9 gene associated with breast cancer risk in Chinese Han women.
Genet Mol Res. 2014; 13(1):182-7 [PubMed] Related Publications
A single nucleotide polymorphism (SNP) in the TNRC9 gene was identified as a breast cancer susceptibility genetic variant in recent genome-wide association studies of women of European ancestry. We investigated whether TNRC9 polymorphisms are associated with risk of breast cancer in Chinese women of the Han nationality. We genotyped the SNPs rs3803662, rs1362548, rs1123428 in 870 women, including 388 breast cancer patients and 482 healthy controls, via the PCR-single strand conformation polymorphism procedure and by sequence detection. We found that the T allele and the TT genotype of the SNP rs38033662 is significantly associated with risk for breast cancer in Chinese Han women; however, no significant association was found for rs1362548 or rs1123428. We conclude that SNP rs3803662 is a putative risk factor for breast cancer in Chinese Han women.

O'Brien KM, Cole SR, Poole C, et al.
Replication of breast cancer susceptibility loci in whites and African Americans using a Bayesian approach.
Am J Epidemiol. 2014; 179(3):382-94 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) and candidate gene analyses have led to the discovery of several dozen genetic polymorphisms associated with breast cancer susceptibility, many of which are considered well-established risk factors for the disease. Despite attempts to replicate these same variant-disease associations in African Americans, the evaluable populations are often too small to produce precise or consistent results. We estimated the associations between 83 previously identified single nucleotide polymorphisms (SNPs) and breast cancer among Carolina Breast Cancer Study (1993-2001) participants using maximum likelihood, Bayesian, and hierarchical methods. The selected SNPs were previous GWAS hits (n = 22), near-hits (n = 19), otherwise well-established risk loci (n = 5), or located in the same genes as selected variants (n = 37). We successfully replicated 18 GWAS-identified SNPs in whites (n = 2,352) and 10 in African Americans (n = 1,447). SNPs in the fibroblast growth factor receptor 2 gene (FGFR2) and the TOC high mobility group box family member 3 gene (TOX3) were strongly associated with breast cancer in both races. SNPs in the mitochondrial ribosomal protein S30 gene (MRPS30), mitogen-activated protein kinase kinase kinase 1 gene (MAP3K1), zinc finger, MIZ-type containing 1 gene (ZMIZ1), and H19, imprinted maternally expressed transcript gene (H19) were associated with breast cancer in whites, and SNPs in the estrogen receptor 1 gene (ESR1) and H19 gene were associated with breast cancer in African Americans. We provide precise and well-informed race-stratified odds ratios for key breast cancer-related SNPs. Our results demonstrate the utility of Bayesian methods in genetic epidemiology and provide support for their application in small, etiologically driven investigations.

O'Brien KM, Cole SR, Engel LS, et al.
Breast cancer subtypes and previously established genetic risk factors: a bayesian approach.
Cancer Epidemiol Biomarkers Prev. 2014; 23(1):84-97 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene expression analyses indicate that breast cancer is a heterogeneous disease with at least five immunohistologic subtypes. Despite growing evidence that these subtypes are etiologically and prognostically distinct, few studies have investigated whether they have divergent genetic risk factors. To help fill in this gap in our understanding, we examined associations between breast cancer subtypes and previously established susceptibility loci among white and African-American women in the Carolina Breast Cancer Study.
METHODS: We used Bayesian polytomous logistic regression to estimate ORs and 95% posterior intervals for the association between each of 78 single nucleotide polymorphisms (SNP) and five breast cancer subtypes. Subtypes were defined using five immunohistochemical markers: estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptors 1 and 2 (HER1/2), and cytokeratin (CK) 5/6.
RESULTS: Several SNPs in TNRC9/TOX3 were associated with luminal A (ER/PR+, HER2-) or basal-like breast cancer (ER-, PR-, HER2-, HER1, or CK 5/6+), and one SNP (rs3104746) was associated with both. SNPs in FGFR2 were associated with luminal A, luminal B (ER/PR+, HER2+), or HER2+/ER- disease, but none were associated with basal-like disease. We also observed subtype differences in the effects of SNPs in 2q35, 4p, TLR1, MAP3K1, ESR1, CDKN2A/B, ANKRD16, and ZM1Z1.
CONCLUSION AND IMPACT: We found evidence that genetic risk factors for breast cancer vary by subtype and further clarified the role of several key susceptibility genes. .

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