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Breast cancer (BC) is the most common cancer diagnosis in women worldwide. Among causative BC genes, MRE11, ERCC1, TNRC9 (TOX3), and CASC16 play an important role in DNA damage repair; FGFR2, CCNE1, ZMIZ1, and LSP1 involve in cell cycle checkpoint. A functional polymorphism of these genes may alter DNA repair capacity and genomic stability. Single Nucleotide Polymorphisms (SNPs) can modify the risk of cancer, and thus, SNPs may be considered as potential markers of carcinogenesis. Among them, eight SNPs (rs2981582, rs569550, rs3218035, rs704010, rs2155209, rs3212986, rs12443621 and rs4784227) are significantly associated with BC risk in various populations. This study was conducted to investigate the genetic susceptibility of these SNPs in the development of BC in Vietnamese women. MRE11 rs2155209 and CASC162 rs4784227 were found to be associated with BC risk (CC vs. CT + TT: OR = 0.57, 95% CI 0.34 to 0.97, P = 0.03 and CT vs. CC + TT: OR = 1.43, 95% CI 1.03 to 1.97, P = 0.03; respectively). These findings suggest that SNPs involved in DNA repair genes may affect the susceptibility of BC in Vietnamese women.

(1) Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. (2) Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. (3) Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 × 10-8), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 × 10-8 on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. (4) Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.

Polycystic ovary syndrome (PCOS) appears to have a genetic predisposition and a fetal origin. We compared the expression levels of 25 PCOS candidate genes from adult control and PCOS human ovaries (n = 16) using microarrays. Only one gene was potentially statistically different. Using qRT-PCR, expression of PCOS candidate genes was examined in bovine fetal ovaries from early stages when they first developed stroma through to completion of development (n = 27; 60–270 days of gestation). The levels of ERBB3 mRNA negatively correlated with gestational age but positively with HMGA2, FBN3, TOX3, GATA4, and DENND1A.X1,2,3,4, previously identified as correlated with each other and expressed early. PLGRKT and ZBTB16, and less so IRF1, were also correlated with AMH, FSHR, AR, INSR, and TGFB1I1, previously identified as correlated with each other and expressed late. ARL14EP, FDFT1, NEIL2, and MAPRE1 were expressed across gestation and not correlated with gestational age as shown previously for THADA, ERBB4, RAD50, C8H9orf3, YAP1, RAB5B, SUOX, and KRR1. LHCGR, because of its unusual bimodal expression pattern, had some unusual correlations with other genes. In human ovaries (n = 15

Polycystic ovary syndrome (PCOS) is the most common endocrine disease among premenopausal women. The genetic risk of PCOS in the Saudi population is still unclear. Therefore, it is of interest to study the genotype and allele frequency for six gene variants (THADA rs13429458, TOX3 rs4784165, FSHR rs2268361, YAP1 rs1894116, RAB5B rs705702, and HMGA2 rs2272046) in patients with PCOS in western Saudi population. The study included 95 PCOS patients and 94 normal ovulatory females as controls. Genotyping was performed using TaqMan™ real-time polymerase chain reaction assays. There was significant link between the THADA rs13429458 variant and PCOS. Homozygosity in allele A of the rs13429458 variant was correlated with hyperandrogenism (HA) risk. Homozygosity in the T allele of the FSHR rs2268361 variant was associated with normal levels of AMH among non-PCOS women. The THADA rs13429458 and TOX3 rs4784165 variants were significantly associated with the combined oligo/amenorrhea (OA) and polycystic ovarian morphology subgroups while the HMGA2 rs2272046 variant was significantly associated with the combined HA and OA subgroup. Thus, results show the genetic risk of the THADA rs13429458, TOX3 rs4784165, and HMGA2 rs2272046 variants on PCOS patients in the western Saudi population.

Thymocyte selection-associated HMG box (TOX) is a transcription factor that belongs to the high mobility group box (HMG-box) superfamily, which includes four subfamily members: TOX, TOX2, TOX3, and TOX4. TOX is related to the formation of multiple malignancies and contributes to CD8+ T cell exhaustion in solid tumors. However, little is known about the role of TOX genes in hematological malignancies. In this study, we explored the prognostic value of TOX genes from 40 patients with de novo acute myeloid leukemia (AML) by quantitative real-time PCR (qRT-PCR) in a training cohort and validated the results using transcriptome data from 167 de novo AML patients from the Cancer Genome Atlas (TCGA) database. In the training cohort, higher expression of TOX and TOX4 was detected in the AML samples, whereas lower TOX3 expression was found. Moreover, both the training and validation results indicated that higher TOX2, TOX3, and TOX4 expression of AML patients (3-year OS: 0% vs. 37%, P = 0.036; 3-year OS: 4% vs. 61%, P < 0.001; 3-year OS: 0% vs. 32%, P = 0.010) and the AML patients with highly co-expressed TOX, TOX2, TOX4 genes (3-year OS: 0% vs. 25% vs. 75%, P = 0.001) were associated with poor overall survival (OS). Interestingly, TOX2 was positively correlated with CTLA-4, PD-1, TIGIT, and PDL-2 (rs = 0.43, P = 0.006; rs = 0.43, P = 0.006; rs = 0.56, P < 0.001; rs = 0.54, P < 0.001). In conclusion, higher expression of TOX genes was associated with poor OS for AML patients, which was related to the up-regulation of immune checkpoint genes. These data might provide novel predictors for AML outcome and direction for further investigation of the possibility of using TOX genes in novel targeted therapies for AML.

About 80% of colorectal cancers (CRCs) have chromosomal instability, which is an integral part of aggressive malignancy development, but the importance of specific copy number aberrations (CNAs) in modulating gene expression, particularly within the framework of clinically relevant molecular subtypes, remains mostly elusive. We performed DNA copy number profiling of 257 stage I-IV primary CRCs and integrative gene expression analysis in 151 microsatellite stable (MSS) tumors, focusing on high-level amplifications and the effect of CNAs on the characteristics of the gene expression-based consensus molecular subtypes (CMS). The results were validated in 323 MSS tumors from TCGA. Novel recurrent high-level amplifications (≥15 additional copies) with a major impact on gene expression were found for TOX3 (16q) at 1.5% frequency, as well as for CCND2 (12p) and ANXA11 (10q) at 1% frequency, in addition to the well-known targets ERBB2 (17q) and MYC (8q). Focal amplifications with ≥15 or ≥5 additional copies of at least one of these regions were associated with a poor overall survival among patients with stage I-III MSS CRCs (multivariable hazard ratio ≥3.2, p ≤ 0.01). All high-level amplifications were focal and had a more consistent relationship with gene expression than lower amplitude and/or broad-range amplifications, suggesting specific targeting during carcinogenesis. Genome-wide, copy number driven gene expression was enriched for pathways characteristic of the CMS2-epithelial/canonical subtype, including DNA repair and cell cycle progression. Furthermore, 50% of upregulated genes in CMS2-epithelial/canonical MSS CRCs were driven by CNAs, an enrichment compared with the other CMS groups, and associated with the stronger correspondence between CNAs and gene expression in malignant epithelial cells than in the cells of the tumor microenvironment (fibroblasts, endothelial cells, leukocytes). In conclusion, we identify novel recurrent amplifications with impact on gene expression in CRC and provide the first evidence that CMS2 may have a stronger copy-number related genetic basis than subtypes more heavily influenced by gene expression signals from the tumor microenvironment. publishedVersion

In recent years there have been important advances in molecular genetics and linkage analysis of the breast cancer. Beside germline BRCA1 or BRAC2 mutations, and somatic genetic alterations, epigenetic alterations in numerous genes play an essential role in the tumorigenesis of breast cancer. TP53, STK11, PTEN, CDH1, NF1 or NBN mutations are associated with high breast cancer associated syndromes. Mutations in DNA repair associated genes (ATM, CHEK2, BRIP1, PALB2 and RAD50) are associated with increased breast cancer risk. Moreover, several single nucleotide polymorphisms (SNPs) were considered as breast cancer susceptibility polymorphisms within genes (FGFR2, TOX3, LSP1, MAP3K1, and TGFB1). This review discusses breast cancer genetic susceptibility, highlights recent advances in breast cancer genetics, with a particular focus in Saudi women. Keywords: Breast cancer susceptibility, Single nucleotide polymorphisms (SNPs), Breast cancer genetics, Hereditary breast cancer

Background Based on estrogen active substances, many women consume soy foods in the belief that it could prevent breast cancer (BC). Women with different molecular subtypes would be likely to have diverse reactions to soy foods, especially those with the estrogen-receptor-positive (ER+) subtype. The aim of the current study is to identify the differentially expressed genes (DEGs) on soy foods in premenopausal patients with Lumina A subtype of BC (LABC) after soy food treatment, and to further investigate the critical molecule change. Materials and Methods GSE58792 retrieved from Gene Expression Omnibus was analyzed to obtain DEGs using GEO2R. Gene Ontology and pathway enrichment analysis were performed using FunRich and GeneMINIA. Overall survival of critical genes was performed by the Kaplan-Meier plotter online tool. Results A total of 108 DEGs were obtained from the dataset, among which 35 were up-regulated and 73 down-regulated. Soy foods significantly reduced the expression of TFF3, TFF1, GATA3, and ESR1, which were related to the activity of the ER-related pathway and the sensitivity of tamoxifen. Furthermore, the lower expressions of TOX3, FSIP1, ESR1, and CLGN were related to prolonged survival time of patients with BC. The most significant signaling pathways were epithelial-to-mesenchymal transition in up-regulated DEGs, mesenchymal-to-epithelial transition, and mammary gland alveolus development in down-regulated DEGs, which were all related to the development and prognosis of BC. Conclusions Soy foods could dramatically alter the ER-related gene profile in LABC. Particularly, down-regulated DEGs of TFF3, TFF1, GATA3, and ESR1 might weaken the sensitivity of tamoxifen and increase the efficacy of neoadjuvant chemotherapy in premenopausal patients with LABC.

This study aim to investigate the association of breast cancer risk and prognostic factors with single nucleotide variants of the BRCA1, BRCA2, DAPK1, MMP9, TOX3, and TP53 genes in Jordanian women. Blood samples were collected from 230 Jordanian breast cancer patients for use in DNA extraction followed by genotyping and subsequent statistical analysis. We found that two single nucleotide variants (SNVs) of the BRCA2 gene, namely rs1799944 and rs766173, were significantly associated with breastfeeding status. Likewise, the rs11141901 and rs1041326 SNVs of the DAPK1 gene were linked with co-morbidity (p-value = 0.002) and family history of BC (p-value = 0.015), while the rs1045042 SNV of the same gene was associated with both allergy (p-value = 0.001) and family history of BC (p-value = 0.02). Tumor differentiation was correlated with the DAPK1 SNVs rs11141901 (p-value = 0.041) and rs1041326 (p-value = 0.005). Additionally, the rs2250889 SNV of the MMP9 gene was significantly associated with HER2 status, whereas the TP53 SNVs rs12951053 and rs1042522 were associated with age at menarche (p-value = 0.043) and breastfeeding status (p-value = 0.013), respectively. In contrast, the TP53 SNV rs2287497 was significantly linked to age at first pregnancy (p-value = 0.001), smoking (p-value = 0.041), and axillary lymph node status (p-value = 6e-4). No such association was found for the BRCA1 and TOX3 SNVs. The current findings suggest significant associations between certain SNVs and breast cancer risk and prognosis in Jordanian women.

The most prevalent form of cancer in females is breast cancer. Roughly 5%-10% of breast cancers are hereditary, and they are associated with Germline gene mutations, inherited from parents. Germline gene mutations increase the risk of developing cancer earlier in life compared to noninherited cases (sporadic cancer). BRCA1 and BRCA2 are well-studied tumour suppressor genes associated with hereditary breast cancer. Even though mutations in BRCA1 and BRCA2 are assumed to responsible the majority of hereditary breast cancers cases, many other breast cancer susceptibility genes have been identified in the last few decades. Identification of many germline mutations was possible due to advance sequencing technologies. Most of these genes are belongs to tumour suppressors and DNA damage repair gene families (DNA double-strand break repair and DNA mismatch repair). These genes play a vital role in genomic stability and cell cycle control suggesting that any alteration in these genes trigger uncontrolled growth and tumour formation. These genes are categorized according to the penetrance level, the proportion of carriers express the associated trait of the mutated gene. Mutations in high penetrance genes such as BRCA1, BRCA2, TP53, PTEN, and SKT11 greatly increase the risk of developing breast cancer. Moderate penetrance gene such as PALB2, ATM, CHEK2, BARD1, BRIP1 and low penetrance gene such as PARP4, CASP8, TOX3 confer moderate to low increase risk of developing breast cancer. Aim of this review is to summarize genes associated with hereditary breast cancer according to their penetrance level (high, moderate and low penetrance).

Polycystic ovary syndrome is characterized by reproductive and metabolic disturbances throughout the female lifespan. Therefore, this study aimed to determine whether genome-wide association studies (GWAS)-identified risk variants for PCOS could confer risk of metabolic syndrome (MS) or insulin resistance (IR). Fifteen independent SNPs mapping to 11 GWAS loci genotyped in a total of 2,082 Han Chinese women independent of previous GWAS and phenotype-genotype correlations were assessed. The CC group for rs12478601 in THADA was associated with decreased rate of MS after adjustment for age (23.2 vs. 27%, P = 0.042, OR = 0.81). Using a dominant model, the GG+AG group for rs2059807 in INSR was associated with increased risk of MS after adjustment for age (26.8 vs. 22.5%, P = 0.023, OR = 1.27). The GG + GT group for rs4784165 in TOX3 was found to be associated with an increased rate of IR after adjustment for age and BMI(53.3 vs. 48.5%, P = 0.027, OR = 1.27). The GG+AG group for rs2479106 in DENND1A was associated with a decreased rate of IR (48.3 vs. 53.6%, adjusted P = 0.039, OR = 0.80). After exclusion of PCOS cases with a family history of diabetes, hypertension, or dyslipidemia, the phenotype-genotype correlations between the genes INSR and TOX3 and MS or IR were still significant (P < 0.05). Three SNPs (rs13429458 in THADA, rs10818854 in DENND1A, and rs2059807 in INSR) were significantly associated with IR; however, their association was not significant after adjustment for age and BMI. This genotype-phenotype study thus provides clues that THADA, INSR, TOX3, and DENND1A play a role in PCOS possibly through a metabolic disorder-related pathway.

The number of teats is a morphological trait that influences the mothering ability of the sows and thus their reproduction performances. In this study, we carried out GWASs for the total number of teats and other 12 related parameters in 821 Italian Large White heavy pigs. All pigs were genotyped with the Illumina PorcineSNP60 BeadChip array. For four investigated parameters (total number of teats, the number of teats of the left line, the number of teats of the right line and the maximum number of teats comparing the two sides), significant markers were identified on SSC7, in the region of the vertnin (VRTN) gene. Significant markers for the numbers of posterior teats and the absolute difference between anterior and posterior teat numbers were consistently identified on SSC6. The most significant SNP for these parameters was an intron variant in the TOX high mobility group box family member 3 (TOX3) gene. For the other four parameters (absolute difference between the two sides; anterior teats; the ratio between the posterior and the anterior number of teats; and the absence or the presence of extra teats) only suggestively significant markers were identified on several other chromosomes. This study further supported the role of the VRTN gene region in affecting the recorded variability of the number of teats in the Italian Large White pig population and identified a genomic region potentially affecting the biological mechanisms controlling the developmental programme of morphological features in pigs.

Cancer is one of the deadliest complex diseases having multigene nature where the role of single-nucleotide polymorphism (SNP) has been well explored in multiple genes. TOX high mobility group box family member 3 (TOX3) is one such gene, in which SNPs have been found to be associated with breast cancer. In this study, we have examined the potentially damaging nonsynonymous SNPs(nsSNPs) in TOX3 gene using in silico tools, namely PolyPhen2, SNP&GO, PhD-SNP and PROVEAN, which were further confirmed by I-Mutant, MutPred1.2 and ConSurf for their stability, functional and structural effects. nsSNPs rs368713418 (A266D), rs751141352 (P273S, P273T), rs200878352 (A275T) have been found to be the most deleterious that may have a vital role in breast cancer. Premature stop codon producing SNPs (Q527STOP), rs1259790811 (G495STOP), rs1294465822 (S395STOP) and rs1335372738 (G8STOP) were also found having prime importance in truncated and malfunctional protein formation. We also characterized regulatory SNPs for its potential effect on TOX3 gene regulation and found nine SNPs that may affect the gene regulation. Further, we have also designed 3D models using I-TASSER for the wild type and four mutant TOX3 proteins. Our study concludes that these SNPs can be of prime importance while studying breast cancer and other associated diseases as well. They are required to be studied in model organisms and cell cultures, and may have potential importance in personalized medicines and gene therapy.

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., ESR1, FGFR2, and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10−8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10−9) and one new noncoding variant at 7q21.11 (P < 5 × 10−8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 × 10−8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 × 10−8) and CNFN (P = 3.77 × 10−4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development. Significance: Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. Cancer Res; 78(11); 3087–97. ©2018 AACR.

Objective: Breast cancer is the most widespread cancer in women, with a high mortality rate. This study aims to assess the association between single nucleotide polymorphisms (SNPs) of LOC643714 (rs12922061) and TOX3 (rs3803662) and breast cancer, as well as the clinical characteristics of tumors. Materials and methods: In total, 104 breast cancer patients and 118 healthy controls were recruited to our study. The genotyping was performed by the SNP scan method. General characteristics, the clinical characteristics of tumors and reproductive factors were included in the analysis. Statistical tests included the Student t-test, the Chi-square test (X2) or Fisher’s exact test, and unconditional logistic regression analysis. The receiver operating characteristic curves were used to evaluate the predictive role of rs12922061 in breast cancer. Results: The LOC643714 polymorphism was a risk factor for breast cancer under a dominant model (TT+TC vs. CC: OR 1.801; 95% CI 1.048, 3.095; statistical power=60%), recessive model (TT vs. TC + CC: OR 4.297; 95% CI 1.164, 15.867; statistical power=64%) and log-additive (TT vs. CC: OR 5.163; 95% CI 1.368, 19.485; statistical power= 73%). Furthermore, the rs12922061 polymorphism was associated with menopause status in patients ( P=0.005). No statistically significant association was found between the rs3803662 polymorphism and breast cancer in patients or healthy controls. Conclusions: Our study found that rs12922061 of LOC643714 was related to breast cancer risk. With a limited sample size and statistical power, further multi-center studies are needed to confirm the influence of the LOC643714 polymorphisms on breast cancer based on larger populations.

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 + subjects and ER − subjects all had increased breast cancer risk, if they carried this polymorphism (OR = 1.27; 95% CI: 1.19–1.35; P < 0.00001; OR = 1.12; 95%CI: 1.08–1.17; P < 0.00001). Similarly, both progesterone receptor–positive (PR +) subjects and PR − subjects all showed increased breast cancer risk, if they carried this polymorphism (OR = 1.32; 95% CI: 1.17–1.49; P < 0.00001; OR = 1.15; 95% CI: 1.09–1.23; P < 0.00001). Conclusions: This meta-analysis suggested that TOX3 rs3803662 polymorphism was associated with increased breast cancer risk.

Cancer develops by accumulation of somatic driver mutations, which impact cellular function. Mutations in non-coding regulatory regions can now be studied genome-wide and further characterized by correlation with gene expression and clinical outcome to identify driver candidates. Using a new two-stage procedure, called ncDriver, we first screened 507 ICGC whole-genomes from 10 cancer types for non-coding elements, in which mutations are both recurrent and have elevated conservation or cancer specificity. This identified 160 significant non-coding elements, including the TERT promoter, a well-known non-coding driver element, as well as elements associated with known cancer genes and regulatory genes (e.g., PAX5, TOX3, PCF11, MAPRE3). However, in some significant elements, mutations appear to stem from localized mutational processes rather than recurrent positive selection in some cases. To further characterize the driver potential of the identified elements and shortlist candidates, we identified elements where presence of mutations correlated significantly with expression levels (e.g., TERT and CDH10) and survival (e.g., CDH9 and CDH10) in an independent set of 505 TCGA whole-genome samples. In a larger pan-cancer set of 4128 TCGA exomes with expression profiling, we identified mutational correlation with expression for additional elements (e.g., near GATA3, CDC6, ZNF217, and CTCF transcription factor binding sites). Survival analysis further pointed to MIR122, a known marker of poor prognosis in liver cancer. In conclusion, the screen for significant mutation patterns coupled with correlative mutational analysis identified new individual driver candidates and suggest that some non-coding mutations recurrently affect expression and play a role in cancer development., Decoding the driver mutations of cancer Mutations in the “non-coding” part of the genome have been identified that could be involved in driving cancer development. Jakob Pedersen, Henrik Hornshøj and colleagues from Aarhus University Hospital in Denmark and MIT in the United States developed a two-stage procedure to identify elements that could be driving cancer development in the part of DNA that does not code for proteins. They conducted statisical analyses on catalogs of tumor genomes to identify recurrent mutations. They then evaluated how specific these mutations were to different cancer types, their predicted functional impact, and their association with gene expression and patient survival. The analyses identified mutations in the non-coding part of cancer genomes that could be driving tumor development, but further analyses on larger sample sets need to be conducted to validate the results, which could provide a basis for biomarker discovery and precision medical treatment.

Breast cancer (BC) is the leading cause of morbidity and mortality among women around the world. Single nucleotide polymorphisms (SNPs) of TOX3 have been reported to be associated with susceptibility of BC in a number of studies. However, the results are inconsistent basing on limited number of studies and samples. To evaluate the overall effect between SNPs of TOX3 and risk of BC, we conducted a meta-analysis by combining all available studies. Studies were searched from the database of PubMed, PsycINFO and ISI web of Knowledge up to June 2016. The meta-analysis was conducted based on statement of preferred reporting items for systematic reviews and meta-analyses (PRISMA). Ten studies including 24,829 participants (10,778 cases and 14,051 controls) were available for the meta-analysis. Among three investigated SNPs, significant associations with risk of BC were observed in rs12443621 (allele A vs. allele G, OR = 0.94, P-value = 0.03; A/A + G/A vs. G/G, OR = 0.89, P-value = 0.01) and rs8051542 (allele C vs. allele T, OR = 0.89, P-value = 0.0002; C/C + T/C vs. T/T, OR = 0.77, P-value = 0.01; C/C vs. T/C + T/T, OR = 0.89, P-value = 0.01). Meanwhile, significant associations were observed in rs3803662 for males (allele C vs. allele T, OR = 0.65, P-value vs. T/T, OR = 0.54, P-value vs. T/C + T/T, OR = 0.59, P-value vs. allele T, OR = 0.70, P-value vs. T/T, OR = 0.61, P-value vs. T/C + T/T, OR = 0.69, P-value

This study investigated the possible association between single nucleotide polymorphism (SNP) sites on a genome wide level and the presence of polycystic ovary syndrome (PCOS) in a local population. Patients treated for PCOS in the outpatient clinic of the reproductive medicine center of Changzhou Maternal and Child Health Care Hospital (affiliated to Nanjing Medical University) from January of 2010 to December 2012 were selected. Female patients affected by infertility due to simple oviduct reasons or male factors, during the same period, were enrolled for the control group. A genome-wide association study was performed. Specific experimental steps included extraction of the total human DNA and optimization of PCR amplification of target genes; flight mass spectrometry for genotyping; and statistical analyses of sequencing results. By primary selection and secondary verification at two stages in the experiment, three SNP sites were found to contain significantly different allele frequencies between the patient and control groups (P

Large-scale genotyping studies have identified over 70 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. However, knowledge regarding genetic risk factors associated with the prognosis is limited. The aim of this study was therefore to investigate the prognostic effect of nine known breast cancer risk SNPs. BC patients (n = 1687) randomly sampled in an adjuvant, randomized phase III trial (SUCCESS A study) were genotyped for nine BC risk SNPs: rs17468277(CASP8), rs2981582(FGFR2), rs13281615(8q24), rs3817198(LSP1), rs889312(MAP3K1), rs3803662(TOX3), rs13387042(2q35), rs4973768(SLC4A7), rs6504950(COX11). Cox proportional hazards models were used to test the SNPsʼ association with overall survival (OS) and progression-free survival (PFS). Additional analyses were carried out for molecular subgroups. rs3817198 in LSP1 (lymphocyte-specific protein 1) was the only SNP that significantly influenced OS (p = 0.01) and PFS (p

Multiple common variants identified by genome-wide association studies showed limited evidence of the risk of breast cancer in Taiwan. In this study, we analyzed the breast cancer risk in relation to 13 individual single-nucleotide polymorphisms (SNPs) identified by a GWAS in an Asian population. In total, 446 breast cancer patients and 514 healthy controls were recruited for this case–control study. In addition, we developed a polygenic risk score (PRS) including those variants significantly associated with breast cancer risk, and also evaluated the contribution of PRS and clinical risk factors to breast cancer using receiver operating characteristic curve (AUC). Logistic regression results showed that nine individual SNPs were significantly associated with breast cancer risk after multiple testing. Among all SNPs, six variants, namely FGFR2 (rs2981582), HCN1 (rs981782), MAP3K1 (rs889312), TOX3 (rs3803662), ZNF365 (rs10822013), and RAD51B (rs3784099), were selected to create PRS model. A dose–response association was observed between breast cancer risk and the PRS. Women in the highest quartile of PRS had a significantly increased risk compared to women in the lowest quartile (odds ratio 2.26; 95% confidence interval 1.51–3.38). The AUC for a model which contained the PRS in addition to clinical risk factors was 66.52%, whereas that for a model which with established risk factors only was 63.38%. Our data identified a genetic risk predictor of breast cancer in Taiwanese population and suggest that risk models including PRS and clinical risk factors are useful in discriminating women at high risk of breast cancer from those at low risk.

Background: We previously revealed that single nucleotide polymorphisms (SNPs) of CYP19A1, MAP3K1 rs889312, and ABCB1 rs2032582 were associated with overall survival (OS) in early-stage hormone receptor (HR)-positive breast cancer patients. Previous studies also showed that FGFR2 rs1219468 and TOX3 rs8051542 influenced OS in early-stage breast cancer patients. In this study, we assessed whether undiscovered SNPs of CYP19A1, MAP3K1, ABCB1, FGFR2, and TOX3 are associated with clinical outcome of patients with early-stage HR-positive breast cancer. Patients and Methods: We used next-generation sequencing (NGS) methods to explore unidentified SNPs of CYP19A1, MAP3K1, ABCB1, FGFR2, and TOX3 in 80 patients who had HR+, T1 to T2, and N0 to N1 breast cancer and had matched clinicopathological features and clinical outcomes (experimental cohort). The mapping selected SNPs identified from NGS were located in different chromosomes, such as chromosome 5 (MAP3K), 7 (ABCB1), 10 (FGFR2), 15 (CYP19A1), and 16 (TOX3), were analyzed. The multivariate-adjusted hazard ratio (aHR) of OS associated with the individual genotypes of the experimental cohort was assessed after adjusting for age, tumor size, tumor grade, HER2 status, menopausal status, and chemotherapy using Cox regression analyses. We further correlated identified significant novel SNPs with disease-free survival (DFS) and OS in 195 patients with HR-positive, T1-T2, and N0-1 breast cancer (validation cohort) using stepwise selection multiple Cox model analyses. Results: Through target region re-sequencing, we identified 69 novel SNPs, including 18 CYP19A1 SNPs, 16 MAP3K SNPs, 18 ABCB1 SNPs, 12 FGFR2 SNPs, and 5 TOX3 SNPs in the experimental cohort (n = 80). After multivariate-adjusted analyzing, FGFR2 rs2981460(C/C) (p = 0.0115), and MAP3K1 rs3822625 (A/A) (p = 0.0475), rs702689 (G/G) (p = 0.0312), rs832567 (C/C) (p = 0.0312), and rs9687226 (C/C) (p = 0.0475), and ABCB1 rs2032582 (T/T+T/C) (p = 0.0061) were significantly associated with the poorer OS of the experimental cohort. In a validated cohort (n =195) (Table 1), we found that MAP3K1 rs702689 (G/G) was significantly associated with poorer DFS (aHR = 2.3; 95% confidence interval [CI] = 1.1 to 5.1; p = 0.03) and OS (aHR = 4.9; 95% CI = 1.3 to 18.7; p = 0.02). In addition, MAP3K1 rs832567 (C/C) was significantly associated with poorer DFS (aHR = 2.5; 95% CI = 1.1 to 5.5; p = 0.02) and OS (aHR = 5.4; 95% CI = 1.4 to 21.6; p = 0.02). In premenopausal women of validation cohort (n = 108), ABCB1 rs2032582 (T/T+T/C) was significantly associated with a poor OS (aHR = 62.3; 95% CI = 2.0 to 1911.7; p = 0.02). Conclusions: Our results indicate that 3 novel SNPs, MAP3K1 rs702689, MAP3K1 rs832567, and ABCB1 rs2032582, may affect the prognosis of early-stage HR-positive breast cancer. Further validation of these SNPs in a large series of patients with early-stage HR-positive breast cancer who received adjuvant endocrine therapy alone is warranted. Table 1. The Associations of Hormone Receptor-Positive Breast Cancer Patients with Various Genotypes in multiple Cox model (validation cohort)Disease-free survivalOverall survivalGenotypeaHR (95%CI)PaHR (95%CI)PTotal (n = 195)FGFR2_ rs2981460 (C/C vs.C/T+T/T)0.4 (0.1-1.8)0.220.6 (0.1-5.4)0.68MAP3K1_ rs3822625 (A/A vs. G/A+GG)2.0 (0.7-5.3)0.192.7 (0.6-12.9)0.20MAP3K1_ rs702689 (G/G vs. A/A+A/G)2.3 (1.1-5.1)0.034.9 (1.3-18.7)0.02MAP3K1_rs832567 (C/C vs. A/A+A/C)2.5 (1.1-5.5)0.025.4 (1.4-21.6)0.02MAP3K1_rs9687226 (C/C vs. T/T+T/C)2.0 (0.7-5.3)0.192.7 (0.6-12.9)0.20Premenopausal (n=108)ABCB1_rs2032582 (T/T+T/C vs. C/C)2.0 (0.8-5.0)0.1562.3 (2.0-1911.7)0.02aHR: adjusted by age, estrogen receptor and progesterone receptor status, number of lymph nodes, menopausal status, adjuvant chemotherapy, lymphovascular invasion, and tumor size. Citation Format: Sung-Hsin Kuo, Shi-Yi Yang, Po-Han Lin, Chen-Hsin Chen, Hsin-Chou Yang, Chih-Yuan Hsu, Chiun-Sheng Huang. Identification of novel single nucleotide polymorphisms located in MAP3K1 and ABCB1 genes as markers for poor overall survival in early-stage hormone receptor-positive breast cancer using next-generation sequencing [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-30.

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. 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. Seventeen of the candidate SNPs were nominally associated with young-onset breast cancer in our 1296 non-Hispanic white affected families (uncorrected p value

Background Association between several single‐nucleotide polymorphisms (SNPs) and breast cancer risk has been identified through genome‐wide association studies (GWAS), but little is known about their significance in patients’ prognosis. We screened SNPs which were related to the prognosis of breast cancer in Henan Han population, analyzed relevant genes by bioinformatics in database, and further constructed the genetic regulatory network involved in the pathogenesis of breast cancer. Methods We evaluated five SNPs in 232 cases of breast cancer at the Affiliated Tumor Hospital of Zhengzhou University. Relationships between five SNPs, clinical prognostic indicators, and disease‐free survival (DFS) were evaluated by Kaplan–Meier analysis and Cox proportional hazards model. Gene ontology (GO) functional annotation and Kyoto Encyclopedia of genes and Genome (KEGG) analysis were carried out to preliminarily establish genetic regulation network model of breast cancer. Bayesian algorithm was used to optimize the model. Results The multivariate Cox proportional hazards model confirmed that SNP rs3803662 (TOX3/TNRC9) had correlation with DFS independently. In the multivariate Cox proportional hazards model, compared with GA/AA, GG increased the recurrent risk of breast cancer (p = .021, hazard ratio [HR] = 2.914). GO analysis showed that the function of TOX3/TNRC9 included biological_process, molecular_function, and cellular_component. According to KEGG signaling pathway database, the map of breast cancer‐related gene regulatory network was obtained. IGF‐IGF1R‐PI3K‐Akt‐mTOR‐S6K was the best possible pathway for the differentiation of breast cancer cells in this network and ER‐TOX3/TNRC9 was the best possible pathway for the survival of tumor cells in this network by Bayesian theorem optimization. Conclusions SNP rs3803662 (TOX3/TNRC9) is an independent prognostic factor for breast cancer in Henan Han Population. ER‐TOX3/TNRC9 is the best possible pathway involved in the pathogenesis of breast cancer.