Polymorphism In Breast Cancer Research Articles

Synergistic effect of collagenase-1 (MMP1), stromelysin-1 (MMP3) and gelatinase-B (MMP9) gene polymorphisms in breast cancer.

BackgroundExtracellular matrix degradation by matrix metalloproteinases (MMPs) is an important mechanism involved in tumor invasion and metastasis. Genetic variations of MMPs have shown association with multiple cancers. The present study is focused to elucidate the association of MMP-1, 3 and 9 genetic variants with respect to epidemiological and clinicopathological variables by haplotype, LD, MDR, survival in silico analyses among South Indian women.Material and methodsMMP3–1171 5A/6A and MMP9–1562 C/T SNPs were genotyped by Allele specific polymerase chain reaction and MMP1-1607 1G/2G polymorphism by restriction fragment length polymorphism assays respectively, in 300 BC patients and age-matched 300 healthy controls. Statistical analysis was performed using the SNPStats and SPSS software. Linkage disequilibrium and gene-gene interactions were performed using Haploview and MDR software respectively. Further, transcription factor binding sites in the promoter regions of SNPs under study were carried out using AliBaba2.1 software.ResultsWe have observed an increased frequency of 2G-allele of MMP1, 6A-allele of MMP3 and T-allele of MMP9 (p<0.05) respectively in BC subjects. The 2G-6A haplotype (minor alleles of MMP-1 and MMP-3 respectively) has shown an increased susceptibility to BC. Further, MMP polymorphisms were associated with the clinical characteristics of BC patients such as steroid hormone receptor status, lymph node involvement and metastasis. SNP combinations were in perfect LD in controls. MDR analysis revealed a positive interaction between the SNPs. 5-years survival rate and cox-regression analysis showed a significant association with clinicopathological variables.ConclusionOur results suggest that MMP1–1607 1G/2G, MMP3–1171 5A/6A and MMP9–1562 C/T gene polymorphisms have synergistic effect on breast cancer. The interactions of MMPs clinical risk factors such as lymph node involvement has shown a strong correlation and might influence the 5-years survival rate, suggesting their potential role in the breast carcinogenesis.

Role of CYP2E1 polymorphisms in breast cancer: a systematic review and meta-analysis

BackgroundCYP2E1 polymorphisms have been reported to influence individual’s breast cancer susceptibility as a phase I enzyme, but the results of these previous studies remain controversial. We performed a comprehensive meta-analysis to assess their association.MethodsA comprehensive search of literature included in various databases (PubMed, Web of Science and Google scholar), published before August 2016, was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) calculated in fixed or random-effects models were used to estimate the strength of the associations between three polymorphisms of CYP2E1 and breast cancer susceptibility. Subgroup analysis, sensitivity analysis and test for publication bias were also performed. A total of 11 separate comparisons involving 4311 cases and 4407 controls were included in the meta-analysis.ResultsOur result showed that there was no significant association between the two common polymorphisms CYP2E1 rs2031920 C>T, CYP2E1*5 Rsa I/Rst I (c1/c2) and BC risk. For CYP2E1*6 Dra I (D/C) polymorphism, a significantly increased BC risk in the overall population was found in genetic model D/C vs. D/D (OR = 1.29, 95% CI = 1.04–1.61, P = 0.023) and C/C + D/C vs. D/D (OR = 1.25, 95% CI = 1.04–1.51, P = 0.019), together with subjects who have at least one C allele (C vs. D: OR = 1.46, 95% CI = 1.20–1.79, P < 0.001). Similar results were also found in subgroup analyses in Caucasians of these three comparison models.ConclusionsThe present meta-analysis suggests that CYP2E1*6 Dra I (D/C) variation significantly associated with the risk of BC. Individuals with D/C and C/C + D/C genotypes or carried at least one C allele of CYP2E1*6 Dra I (D/C) polymorphism had a significant higher susceptibility to develop BC.

Analysis of DNA Repair Genes Polymorphisms in Breast Cancer.

Genetic polymorphisms in the DNA repair genes may be associated with increased cancer risk. The purpose of this study was to evaluate the association of the DNA repair genes polymorphisms with the risk of breast cancer development. The study included 200 breast cancer patients and 200 healthy controls. The following polymorphisms were studied: C/G (Ser326Cys, rs1052133) of the hOGG1, A/C (IVS5+33, rs3212961) of the ERCC1, A/C (Lys939Gln, rs2228001) of the XPC, C/T (Thr241Met, rs861539) of the XRCC3, G/T (Leu787Leu, rs1800392) of the WRN and G/T (Ser307Ser, rs1056503) of the XRCC4 gene. Presented study showed statistically significant increase in the breast cancer development risk of the G/G hOGG1 genotype (OR 8.13; 95% CI, 4.37-15.14; p<0.001) and for the G hOGG1 allele (OR 5.11; 95% CI, 3.69-7.06; p<0.001), as well as for the C/C ERCC1 genotype (OR 10.61; 95% CI, 5.72-19.69; p<0.001) and the C ERCC1 allele (OR 4.66; 95% CI, 3.43-6.34; p<0.001) in patients with breast cancer in comparison with healthy control group. We also observed positive association of the C/C XPC genotype (OR 3.80; 95% CI, 2.27-6.38; p<0.001) as well as the C XPC allele occurrence with an increased breast cancer development risk (OR 2.65; 95% CI, 1.98-3.55; p<0.001). Furthermore, we found an association of the G/T WRN gene polymorphism with increased risk of carcinoma. The hOGG1, ERCC1, XPC and WRN genes polymorphisms may be related to development of breast cancer.

The role of E-cadherin - 160C/A polymorphism in breast cancer

AbstractBreast cancer is the most prevalent cancer in women worldwide. Numerous studies have suggested that the E-cadherin adhesion system is dysregulated in cancer cells. These impaired functions of E-cadherin contribute to releasing cancer cells from the primary lesion to cell dedifferentiation. Some studies have shown that polymorphism may affect E-cadherin expression, and then play a role in susceptibility to breast cancer. However, the results remained controversial. In this short review, we summarize the functions of E-cadherin and the signaling pathways it regulates, and assess the association between CDH1 polymorphisms and breast cancer susceptibility. This study suggests that genetic variation in CDH1 and -160C/A polymorphism may have an association with breast cancer risk. The assessment of CDH1 polymorphisms may be used for the identification of patients suitable for anti- CDH1 therapy.

Detection of HER2 Gene Polymorphism in Breast Cancer: PCR Optimization Study.

Cancers are the most deadly diseases in the world and their incidences continue to increase over time. Particularly, breast cancer in females places 1st rank among other types of cancers in term of cancer cases (23%) and death incidence (14%). Recent findings support the correlation between Ile655Val SNP in the HER2 gene with breast cancer risk. Moreover, the Ile655Val HER2 gene polymorphism could be a predictive factor in a neoadjuvant therapy setting. Precise detection of the Ile655Val HER2 gene SNP in early breast cancer patients will be beneficial in designing the most suitable treatment and in increasing the efficacy of anticancer drugs. Here we develop a rapid and inexpensive method for Ile655Val SNP detection in the HER2 gene based on allele-specific PCR technology. Two forward primers and one common reverse primer were designed to anneal specifically either on the HER2 gene fragment containing the GG genotype or to the HER2 gene fragment containing the AA genotype where one of these primers had been added with poly-GC at 5’ upstream. Moreover, to increase discrimination level, mismatch bases at the SNP site and the 3rd base of each forward primers from 3’end were added. To test the performance of the designed primers in discriminating a polymorphism and its annealing temperature, breast cancer specimen-derived genomic DNA (with GG genotype) and pGEM_HER2/AA (with AA genotype) were used as templates in the PCR reaction. The optimal annealing temperature for SNP detection was at 51.5°C as showed by the appearance of a 150 base pair (bp) band as AA genotype (pGEM_HER2/AA template), 116bp band as GG genotype (genomic DNA template), and both types of bands as AG genotype (mix of pGEM_HER2/AA and genomic DNA template). Allelic types of breast cancer patients were also determined using this optimized method compared to sanger sequencing. The 100% accordance was shown for all types of genotypes in both methods. The allele-specific PCR in this study may have application in determining polymorphisms of the breast cancers-originated Ile655Val HER2 gene.

Associations of CYP1A1 gene polymorphisms and risk of breast cancer in Indian women: a meta-analysis

AbstractReported associations of CYP1A1 polymorphisms with breast cancer have been inconsistent. In this meta-analysis examining breast cancer associations of three CYP1A1 polymorphisms (M1, M2 and M4) among Indian women may yield information that may be of clinical and epidemiological use for this particular demography. We searched MEDLINE using PubMed and Embase for association studies. From seven published case-control studies, we estimated overall associations and applied subgroup analysis to explore differential effects. All three polymorphisms exhibited overall increased risk, significant in M1 (OR 1.61–1.65, p = 0.04) and M4 (OR 2.02–3.92, p = 0.02–0.04). Differential effects were observed only in the M1 polymorphism where M1 effects were significant in South Indians (OR 2.20–4.34, p &lt; 0.0001) but not the North population, who were at reduced risk (OR 0.64–0.77, p = 0.03–0.55). These populations were not materially different in regard to M2 and M4 as did the women stratified by menopausal status. In this meta-analysis, M1 and M4 effects may render Indian women susceptible, but may be limited by heterogeneity of the studies. Differential effects of the M1 polymorphism in breast cancer render South Indians susceptible compared to those in the North.

NRF2 AND P73 POLYMORPHISMS IN EGYPTIAN WOMEN WITH BREAST CANCER

The aim of the study was to assess the role of Nrf2 promoter and P73 G4C14 to A4T14 polymorphisms in breast cancer and the potential relation to the onset of the disease. Eighty six female patients with breast tumor were included in this study. Nrf2 (rs6721961) and p73 (G4A) genetic polymorphisms in promoter and exon2 region respectively were investigated using PCR-CTPP assay. The genotype frequencies of the three genotypes of Nrf2 promoter SNP (CC, CA, AA) showed no significant difference between benign and malignant groups. Genotype frequencies for P73 G4A SNP (GG, GA) showed no significant difference between benign and malignant groups, no patient have the AA genotype. Regarding the onset of disease, the three Nrf2 genotypes in pre - and post-menopausal patients, showed that the distribution differ significantly in the 2 patients groups and that the AA genotype is significantly higher in the pre-menopausal patients compared to post-menopausal patients. Nrf2 (rs6721961) AA genotype might be related to early breast cancer onset. P73 G4A polymorphism shows no relation to both disease risk and disease onset. Therefore Nrf2 (rs6721961) promoter genotyping might be related to the risk of pre-menopausal breast cancer. Key words : Breast cancer, Polymorphisms, Nrf2, P73

P113: The possible association of novel functional SNP of D-glucuronyl C5-epimerase (GLCE) gene with breast cancer in Siberia region

Background Heparansulfate (HS) is a glycosaminoglycan present on the cell surface and in the extracellular matrix, which interacts with diverse signal molecules and is essential for many physiological processes including embryonic development, cell growth, inflammation, and blood coagulation. d -glucuronyl C5-epimerase (GLCE) is a crucial enzyme in HS synthesis, converting d -glucuronic acid (GlcA) to l -iduronic acid (IdoA) to increase HS flexibility. Aberrant modification may result in wrong structure of polysaccharide chains of HS and defects of microenvironment associated with malignant transformation.We previously experimentally identified the GLCE polymorphism Ile597Val. Its localization close to the activity center of the enzyme and different physical parameters of the involved amino acids suggest that the polymorphism is functional. So, three different variants of GLCE dimers with different enzymatic activity may exist in heterozygous carriers. Bioinformatics’ search (PubMed resource) revealed interracial variations in allele frequency distribution. Unusual high frequency of allele G was shown for black race (45%) compared with white race (17%). Taking into account the increased resistance of negroid race to breast cancer, we assume a potential involvement of the GLCE polymorphism in breast cancer. Aim The estimation of effects of GLCE functional polymorphism A2017G (Ile597Val) on the gene expression levels in normal and breast cancer cells and LOH in breast tumors. Materials and methods Breast cancer patients (n = 144.) had histologically verified diagnoses. Blood and breast cancer tissue samples as well as matched control tissues were collected from each patient during surgery. Genomic DNA was isolated by phenol extraction. Total RNA was isolated by TRIZol, RNA quantity was accessed by Qubit instrument with appropriate reagents and cDNA was obtained using First Strand cDNA Synthesis kit. SNP A2017G (rs3865014) was analyzed by Custom Real-Time SNP Array and GLCE expression levels were determined using Taq-Man-based Real-Time PCR (Applied Biosystems). Statistical analysis was carried out using a Statistika 9.0 software. Results AA genotype carriers had a 2-fold increase in GLCE mRNA levels in tumors compared with control surrounding tissues (0.37 ± 0.77 versus 0.17 ± 0.16, respectively, p Conclusion The obtained data show a possible association between GLCE Ile597Val polymorphism and breast cancer, although the nature of the association remains ambiguous.

Evaluation of CYP17A1 and LEP Gene Polymorphisms in Breast Cancer

Background: Polymorphisms of estrogen synthesis- and adiposity-related genes can contribute to the development of breast cancer. The purpose of the current study was to analyze the association between CYP17A1 T27C (rs743572) and LEP -2548G>A (rs7799039) gene polymorphisms and breast cancer. Material and Methods: 199 breast cancer patients and 197 healthy controls were included in the study. The CYP17A1 and LEP gene polymorphisms were determined using polymerase chain reaction-based restriction fragment length polymorphism analysis. Results: No statistically significant association was found between these polymorphisms and breast cancer risk among a Turkish population. However, stratified analysis of these polymorphisms in relation to different clinicopathological characteristics of breast cancer revealed an association between breast cancer diagnosis and the CYP17A1 T27C polymorphism (p = 0.024). Conclusion: Our study suggests no strong association between the CYP17A1 T27C and LEP -2548G>A polymorphisms and the incidence of breast cancer in Turkish women. The potential association between CYP17A1 T27C and the type of breast cancer deserves further consideration.

Relationship between Genetic Polymorphisms in MTHFR (C677T, A1298C and their Haplotypes) and the Incidence Of Breast Cancer among Jordanian Females--Case-Control Study.

Breast cancer is a major cause of morbidity and mortality in Jordan and worldwide. Abnormality of DNA methylation is a possible mechanism for the development of cancer. Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA methylation. Our aim was to study the association between genetic polymorphisms of MTHFR at two sites (C677T and A1298C) and their haplotypes and the risk of breast cancer among Jordanian females. A case-control study involving 150 breast cancer cases and 150 controls was conducted. Controls were age-matched to cases. Polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) technique and sequencing were conducted to determine the genotypes. There was a significant difference in genotype frequency of C677T in the 41-60 year age category [cases: CC (37.4%), CT (49.5%) and TT (13.2%); controls: CC (56.3%), CT (35.6%) and TT (8%), p=0.04; ORTT vs. CC: 2.5, 95% CI: (0.9-6.9); ORat least on T: 2.1, 95%CI: (1.2-3.9)]. There was no significant difference in genotype frequency of A1298C between cases and controls [cases: AA (46.6%), AC (41.8%) and CC (11.6%); controls: AA (43%), AC (47.4%) and CC (9.6%); p=0.6]. There was a significant difference of MTHFR genetic polymorphism haplotypes among breast cancer cases and controls [cases/control: CA: 38.3/45.4%; CC: 28.9/25.2%; TA: 29.2/21; TC: 3.6/8.3; p value=0.01; ORTA vs. CA=1.6; 95% CI (1.1-2.5); p=0.02]. Genetic polymorphism of MTHFR C677T may modulate the risk of breast cancer especially in the 41-60 year age group. Additionally, TA haplotype amends the risk of breast cancer. Future studies with a larger sample size are needed to validate the role of MTHFR genetic polymorphisms in breast cancer.

Abstract P2-03-14: Long range expression patterns detected by RNASeq in breast cancer reveal cluster enriched with triple negative breast cancer

Abstract Background: Breast cancer subtyping using gene expression is well established in breast cancer research. While it is known that there are large chromosomal regions affected by copy number polymorphisms in breast cancer, it is not clear whether expression patterns reflect large genomic events affecting longer portion of the chromosome. We present a method to quantify long range gene expression patterns of larger genomic regions at 23kb, 100kb and 1mb. Methods: We used TCGA-level 2 breast cancer gene expression data (RNA-Seq) generated at the Carolina Center for Genome Sciences, UNC at Chapel Hill. We evaluated the long range expression patterns of 649 patients for which we had ER, PR and Her2 status data by IHC. For 221 samples we had ER, PR, Her2, age, menopausal status, p53 and PIK3CA mutation status. Our method defines long range expression within a window of a particular length (e.g. 23kb, 100kb). We take the mean expression scores for all genes that fall within each window and concatenate these windows to obtain larger chromosome-wide patterns. The final chromosome-wide vectors are concatenated to represent long range expression patterns across the entire genome. We then evaluate the variation of these window scores across all samples and keep top 2% varying windows. Then, we apply hierarchical clustering, and evaluate enrichment of clinically meaningful subtypes using hypergeometric test. Results: Simple hierarchical clustering revealed clear separation of triple negative breast cancer samples at any level of resolution: 23kb, 100kb in the available data set. While the 100kb resolution showed two distinct clusters, the 23kb resolution showed three distinct clusters. Interestingly, the hierarchical clustering of samples (n=649) using the top 214 (2%) highly varying long 100kb regions revealed a cluster which contained 99 samples and was enriched with 75 TNBC samples (out of 102 TNBC in the entire set) (p=1.7E-53). The long range expression of 23Kb regions on 221 samples revealed 319 (2%) such regions which further segregate the samples into three different clusters: Cluster1: Luminal enriched cluster with 147 samples out of which 104 are ER+PR+Her2- samples (p-value &amp;lt;&amp;lt;0.01), Cluster2: Her2+ enriched cluster with 31 samples out of which 23 are Her2+ (p-value&amp;lt;&amp;lt;0. 01), and Cluster3: TNBC enriched cluster containing 33 samples out of which 26 are TNBC (p=1.5E-18). There are a total number of 38 TNBC samples. Furthermore, in the TNBC cluster with 33 samples, 28 had p53 mutations and 24 of those were both TNBC and had p53 mutations (p-value &amp;lt;&amp;lt; 0.05). In this TNBC cluster, there is enrichment of samples lacking PIK3CA mutations (n=31)(p-value &amp;lt;&amp;lt;0.01). We found no clear association with age and menopausal status. Conclusions: Hierarchical clustering relying on long range expression regions produces clusters that are enriched with well known clinically relevant subtypes. The associations with known tumor biology are strong for different region sizes (23kb and 100kb). This is the first study to report long range gene expression patterns that reveal data-driven close association with tumor biology. Citation Format: Alex Mankovich, Vartika Agrawal, Nilanjana Banerjee, Nevenka Dimitrova. Long range expression patterns detected by RNASeq in breast cancer reveal cluster enriched with triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-03-14.

Prognostic impact of polymorphism of matrix metalloproteinase-2 and metalloproteinase tissue inhibitor-2 promoters in breast cancer in Tunisia: case-control study.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that play important roles in tumor invasion and metastasis by degrading extracellular matrix components. Genetic variations in promoter regions of MMP genes, affecting their expression, have been associated with susceptibility to cancers. The aim of this study was to investigate the susceptibility and prognostic implications of the matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) polymorphism in Tunisian breast cancer patients. MMP-2 genotypes were determined by real-time polymerase chain reaction (RT-PCR), and TIMP-2 genotypes were identified using a PCR-restriction fragment length polymorphism (RFLP) method in 210 breast cancer patients and 250 frequency-matched control women. Association of the clinicopathological parameters and the genetic markers with risk of breast cancer was assessed using univariate analyses. We found that the variant MMP-2 genotype (-1306CT or TT) was associated with substantially reduced risk of breast cancer [odds ratio (OR), 0.49; 95 % confidence interval (95 % CI), 0.033-0.73], compared with the CC genotype. For TIMP-2, a moderately reduced risk of the cancer (OR, 0.57; 95 % CI, 0.37-0.87) was also associated with the variant allele (-418GC or CC), compared with the GG common allele. Furthermore, polymorphisms in both genes seem to have additive effects and the highest risk for breast cancer has been observed in those with MMP-2 CC genotype and TIMP-2 GC or CC genotype (p = 0.006). A significant association was also found between the CC genotype and the aggressive forms of breast cancer as defined by advanced stages at the time of diagnosis and metastasis. This is the first report on the association of MMP-2 and TIMP-2 gene polymorphisms in breast cancer in Tunisian population. Our results suggest that the presence of the variant allele in the promoter of MMP-2 or TIMP-2 may be a protective factor for the development of breast cancer.

Prognostic and predictive role of vascular endothelial growth factor polymorphisms in breast cancer.

Current evidence indicates that angiogenesis plays an important role in the pathogenesis of several malignancies, including breast cancer. The vascular endothelial growth factor (VEGF) pathway has been investigated extensively, due to its important role in angiogenesis. The major mediator of tumor angiogenesis is VEGF-A, frequently referred to as VEGF, which activates the VEGF receptor-2. The VEGF gene is located on chromosome 6 and constitutes a highly polymorphic gene. Numerous SNPs in the promoter, 5'- and 3'-untranslated regions (UTR) of VEGF gene have been recognized. This genetic variability possibly influences the production and function of VEGF. Subsequently, the VEGF SNPs may have an impact on breast cancer risk and disease outcome. Moreover, these SNPs may be of predictive value in patients receiving agents targeting the VEGF pathway. This review presents an update on the potential role of VEGF SNPs as prognostic and/or predictive markers in patients with breast cancer.

Functional consequence of theMET-T1010I polymorphism in breast cancer

Major breast cancer predisposition genes, only account for approximately 30% of high-risk breast cancer families and only explain 15% of breast cancer familial relative risk. The HGF growth factor receptor MET is potentially functionally altered due to an uncommon germline single nucleotide polymorphism (SNP), MET-T1010I, in many cancer lineages including breast cancer where the MET-T1010I SNP is present in 2% of patients with metastatic breast cancer. Expression of MET-T1010I in the context of mammary epithelium increases colony formation, cell migration and invasion in-vitro and tumor growth and invasion in-vivo. A selective effect of MET-T1010I as compared to wild type MET on cell invasion both in-vitro and in-vivo suggests that the MET-T1010I SNP may alter tumor pathophysiology and should be considered as a potential biomarker when implementing MET targeted clinical trials.

278P - Association of Erp29 Genetic Polymorphism with Breast Cancer Risk and Prognosis

ABSTRACT Aim: ERP29, a tumor suppressor gene, was related with the onset of tumors. The influence of ERP29 c.*293A > G (rs7114) polymorphism in breast cancer (BC) risk and prognosis has never been performed before and was the aim of this study. Methods: We analyzed 737 BC patients and 742 healthy women. The BC patients were treated by conventional procedures. ERP29 c.*293A > G genotypes were obtained from genomic DNA by TaqMan® genotyping assays. The expression of ERP29 mRNA was determined by quantitative PCR using total RNA from blood leukocytes of healthy individuals with distinct genotypes (15 individuals with AA, 17 with AG, and six with GG). Overall survival (OS) was obtained from date of first diagnosis until the date of death or last follow-up. The differences in frequencies of distinct genotypes in patients and controls were analyzed by logistic regression model, serving to obtain age, ethnic origin and adjusted crude odds ratios (ORs), considering a confidence interval (CI) of 95%. OS time was calculated using the Kaplan-Meier estimate probabilities and differences between survival curves were analyzed by the log-rank test. Statistical significance was established at a P Results: The frequency of ERP29 AG + GG combined genotypes was higher in BC patients than in controls (36.5% vs. 30.7%, P= 0.03). Carriers of G allele were under a 1.32 (95% CI: 1.02-1.70)-fold increased risk for the tumor. The mRNA expression was lower in carriers of G allele than those with ERP29 AA genotype (0.75 arbitrary units (AUs) vs. 1.30 AUs; P= 0.008). The median of observation of BC patients enrolled in the study was 54 months (1-325). OS of BC patients with the ERP29 AG + GG combined genotypes was higher than that observed in those with the ERP29 AA wild genotype (67.5% vs. 59.0% at 120 months of follow up; P= 0.04). Conclusions: Our data suggest, for the first time, that ERP29 c.*293A > G polymorphism alters the risk and prognosis of BC possibly due to variation in the protein production. Disclosure: All authors have declared no conflicts of interest.

A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in breast cancer.

The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk has been extensively explored, but their results are conflicting rather than conclusive. To derive a more precise estimation, we carried out not only an updated meta-analysis but also a combined analysis based on all the available studies estimating the association between MTHFR C677T and/or A1298C and breast cancer risk. With respect to C677T polymorphism, the results suggested that 677T allele was associated with significantly elevated breast cancer risk in overall analysis (T vs. C: OR 1.073, 95 % CI 1.028-1.120; TT vs. CC: OR 1.177, 95 % CI 1.072-1.293; TT vs. CC + CT: OR 1.175, 95 % CI 1.073-1.288); Stratifying by ethnicity, significantly increased risk was only found in East Asians (T vs. C: OR 1.150, 95 % CI 1.039-1.273; TT vs. CC: OR 1.441, 95 % CI 1.145-1.814; TT vs. CC + CT: OR 1.413, 95 % CI 1.148-1.739); When stratified by menopausal status, statistically significant association was found for postmenopausal women (CT + TT vs. CC: OR 1.092, 95 % CI 1.011-1.179). In regard to A1298C polymorphism, no significant associations were found between the polymorphism and breast cancer risk. With respect to MTHFR haplotypes, significantly elevated breast cancer risk was associated with 677T-1298C for overall result (OR 1.498, 95 % CI 1.143-1.962) and for Caucasians (OR 2.088, 95 % CI 1.277-3.416) when compared with 677C-1298A; Haplotype 677C-1298C might provide higher protection than 677C-1298A in East Asians (OR 0.840, 95 % CI 0.742-0.949). The combined genotypes for C677T and A1298C produced a significant OR for the 677TT/1298AC relative to 677CC/1298AA in overall population (OR 2.047, 95 % CI 1.275-3.288); When stratified by ethnicity, significant ORs were only found for East Asians (677CC/1298CC vs. 677CC/1298AA: OR 0.686, 95 % CI 0.478-0.985; 677TT/1298AC vs. 677CC/1298AA: OR 2.181, 95 % CI 1.179-4.035). The findings suggest that the MTHFR C677T polymorphism but not A1298C, and some variants on their combined genotypes or haplotypes may be involved with the development of breast cancer.

ERP29 genetic polymorphism and breast cancer susceptibility and prognosis.

584 Background: ERP29, a tumor suppressor gene, was related with the onset of tumors. The influence of ERP29 c.*293A>G (rs7114) polymorphism in breast cancer (BC) risk and prognosis has never been ...

CRP 1059 G/C and 1846G/A polymorphisms and cancer risk: A meta-analysis of 26,634 subjects

Previous studies have shown that C-reactive protein (CRP) 1059G/C and 1846G/A polymorphisms may play a role in cancer risk. However, the results from the published studies are conflicting. To derive a more precise estimation of the relationship between CRP 1059G/C and 1846G/A polymorphisms and cancer risk, we conducted a meta-analysis of 21 studies involving a total of 26,634 subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. No significant association was found between CRP 1846G/A polymorphism and cancer risk. However, a significant association was found between CRP 1059G/C polymorphism and cancer risk (CC vs CG+GG: OR=3.60, 95% CI=1.63-7.92, PH=0.67; CC vs GG: OR=3.53, 95% CI=1.60-7.77, PH=0.69). In the subgroup analysis by ethnicity, a significant association was found for the CRP 1846G/A polymorphism among mixed population. Interestingly, when stratifying by cancer type, marginally increased risks were observed for CRP 1846G/A polymorphism in colorectal cancer (AA vs AG+GG: OR=1.17, 95% CI=1.00-1.36, PH=0.27) and significantly decreased risks were found for CRP 1846G/A polymorphism in breast cancer (AA vs GG: OR=0.73, 95% CI=0.56-0.95, PH=0.93; A vs G: OR=0.88, 95% CI=0.79-0.99, PH=0.54). For 1059G/C polymorphism, a significant association was found in colorectal cancer. This meta-analysis showed the evidence that CRP 1059G/C and 1846G/A polymorphisms were risk factors for the development of colorectal cancer, and CRP 1846G/A polymorphism is also a protective factor for decreasing breast cancer.

Cost-Effectiveness of a Genetic Test for Breast Cancer Risk—Letter

We read with great interest the article by Folse and colleagues (1). Their conclusion that “risk modeling may provide information that allows stratification of patients by disease risk, with alternate strategies of … screening and/or preventative treatment” has major potential implications. However, care needs to be taken with respect to the specific methods used, potential for acceptance of stratification by all actors (including subjects), and generalizability beyond the United States (as mentioned in the Discussion).Folse and colleagues assume an interest of alternative screening methods when lifetime risk exceeds 20%, regardless of the reasons for such risk. The only current demonstration of the value of adding MRI to mammography is applicable to genetic high-risk populations, who develop very early, aggressive cancers in dense breasts. This value is related to cancer detection, and as of yet shows no influence on survival. Such benefits may be very different if the expected cancers occur later and are less aggressive. Indeed, MRI currently shows little added value after the age of 60 to 70 years, even in BRCA carriers (2), and the value of MRI was previously documented in addition to current strategies, including mammography. The assumption made in this article that MRI may lead to the elimination of mammography, remains a hypothesis and is the object of currently ongoing trials (3). Furthermore, breast density, which is currently considered a major risk factor, is included in all recently developed or updated models (including Gail), and may be linked to the potential benefit of MRI screening (3). Adding density as a basic marker may refine the prediction and modify need for MRI.Finally, Folse and colleagues evaluate the added value of the first seven breast cancer polymorphisms described by GWAS, whereas more than 70 have been published, all with roughly equivalent predictive value (4). It is likely that the inclusion of 70 (or more) polymorphisms will largely increase the discrimination capability of current models. The per-SNP costs proposed are excessive, and a conservative estimate for cost-per-genotype in our laboratory is more than 10 times lower. Considerably more single-nucleotide polymorphisms (SNP) could be evaluated with higher discrimination and much lower costs using currently available techniques (e.g., PCR-based assays in custom microarrays).Exploring further the potential of stratifying women based on risk estimated from epidemiologic and genetic models, as well as how this stratification is viewed by the women themselves, is of importance to predictive medicine, and is the objective of our ongoing study, Primrose.See the Response, p. 476S. Ragusa is employed as a President Statlife and Epidemio3D and has commercial research grant and ownership interest (including patents) from Statlife and Epidemio3D. No potential conflicts of interest were disclosed by the other authors.

A genetic variant in p63 (rs17506395) is associated with breast cancer susceptibility and prognosis

Backgroundp63, homologous to p53, has been investigated to be involved in various aspects of tumorigenesis and cancer progression. Recently, we have identified a functional single nucleotide polymorphism (SNP) rs17506395 (T>G) in p63 which was associated with female reproduction and ovarian cancer development. The present study aimed to evaluate the association of rs17506395 genotypes with breast cancer susceptibility, clinicopathological characteristics and prognosis. Patients and methodsTaqMan assay was used to genotype the rs17506395 polymorphism. The expression of p63 mRNA was determined by quantitative reverse-transcription PCR (qRT-PCR). Unconditional logistic regression and univariate Cox hazard regression analyses were performed to evaluate the association of rs17506395 with breast cancer susceptibility and prognosis respectively. ResultsFirst, we found that breast tumors with TT genotype exhibited higher level of p63 mRNA compared with other genotypes in breast cancer tissues, indicating that rs17506395 may be a functional single nucleotide polymorphism in breast cancer. Further investigation revealed that the presence of TT genotype was statistically correlated with increased risk for breast cancer, compared with genotypes containing the G allele (GG and GT). Moreover, a significant association between rs17506395 polymorphism and age at diagnosis and status of hormone receptor was observed. Consistently, prognostic analysis showed that patients carrying TT genotype represent unfavorable survival, suggesting that TT genotype may be a biomarker for poor prognosis in breast cancer. ConclusionOur data suggest that rs17506395 polymorphism can function as a risk factor and prognostic indicator for breast cancer, whereas precise mechanism underlying the function of this polymorphism needs further investigation.