Role In Breast Cancer Susceptibility Research Articles

LncRNA-SNPs in a Brazilian Breast Cancer Cohort: A Case-Control Study.

Long noncoding RNAs (lncRNAs) are a class of non-coding RNAs that contain more than 200 nucleotides and exhibit a versatile regulatory capacity. Genomic alterations in lncRNAs have already been investigated in several complex diseases, including breast cancer (BC). BC is a highly heterogeneous disease and is the most prevalent cancer type among women worldwide. Single nucleotide polymorphisms (SNPs) in lncRNA regions appear to have an important role in BC susceptibility; however, little is known about lncRNA-SNPs in the Brazilian population. This study used Brazilian tumor samples to identify lncRNA-SNPs with a biological role in BC development. We applied a bioinformatic approach intersecting lncRNAs that are differentially expressed in BC tumor samples using The Cancer Genome Atlas (TCGA) cohort data and looked for lncRNAs with SNPs associated with BC in the Genome Wide Association Studies (GWAS) catalog. We highlight four lncRNA-SNPs-rs3803662, rs4415084, rs4784227, and rs7716600-which were genotyped in Brazilian BC samples in a case-control study. The SNPs rs4415084 and rs7716600 were associated with BC development at higher risk. These SNPs were also associated with progesterone status and lymph node status, respectively. The rs3803662/rs4784227 haplotype GT was associated with BC risk. These genomic alterations were also evaluated in light of the lncRNA's secondary structure and gain/loss of miRNA binding sites to better understand its biological functions. We emphasize that our bioinformatics approach could find lncRNA-SNPs with a potential biological role in BC development and that lncRNA-SNPs should be more deeply investigated in a highly heterogeneous disease population.

Investigating the Role of Glutathione S- Transferase Genes, Histopathological and Molecular Subtypes, Gene-Gene Interaction and Its Susceptibility to Breast Carcinoma in Ethnic North- Indian Population.

Breast Cancer (BC) is a genetically and clinically heterogeneous disease including complex interactions between gene-gene and gene-environment components. This study aimed, to explore whether the Glutathione S- transferase (GSTs) gene polymorphism has role in BC susceptibility. We further evaluated the frequency of four subtypes of BC based on molecular classification followed by microscopic histological analysis to study the grades of invasive ductal carcinoma (IDC). Polymorphism in GST genes in North-Indian BC patients was assessed by multiplex-PCR and PCR-RFLP methods. 105 BC patients and 145 healthy controls were enrolled for this study. Data was analyzed by calculating the odds ratio (OR) and 95% CI from logistic regression analyses. Our findings revealed that GSTM1 null genotype (OR = 2.231; 95% CI = 1.332-3.737; p-value= 0.002) is significantly associated to BC risk in ethnic North- Indian population. However, the risk for BC susceptibility in North-Indians does not appear to be associated with GSTT1 null genotype. The GSTP1 (Val/Val) genotype (OR=1.545; CI=0.663-3.605; p-value= 0.314) was also found to be susceptible for BC risk. Combination of three high risk GST genotypes association exhibiting gene-gene interaction further confirmed the increased risk to BC in this region. The results of present study indicated that polymorphism in GSTM1 and rs1695 of GSTP1 genes may influence BC development among North-Indian women. Thus, the screening of GSTM1 and GSTP1 gene should be recommended for the earlier investigation for BC as a precautionary measure.

A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility.

Simple SummaryAround 50% of the familial breast cancer (BC) cases are estimated to be caused by variants in low-, moderate-, and high-risk susceptibility genes; however, the other half is of unknown origin. The finding of new susceptibility genes is key to improve diagnosis, take preventive measures, and identify new therapies. In this context, previous studies have discussed whether the genes encoding for the RECQ helicase family could play a role in BC susceptibility, without very conclusive results. To clarify this, in this study, we sequenced the whole coding sequence of the RECQL1, BLM, WRN, RECQL4, and RECQL5 genes in 1993 Spanish BC familial cases and compared it with controls from gnomAD. No association was found for RECQL1, BLM, WRN, and RECQL4; however, we did find an association between RECQL5 and breast cancer as a moderate-risk gene, making it a perfect candidate for further studies.Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18–4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene.

The rs4415084 and rs10941679 Might be Risk Conferring Factors for Breast Cancer among Iranian Women

Breast cancer is a major cause of cancer-associated death among Iranian women with an increasing trend in breast cancer incidence in recent years. However, few data about genetic determinants associated with breast cancer among Iranian females are available. According to the literature, the genetic variants at the non-coding region of 5q12 play a critical role in breast cancer susceptibility. Therefore, this study aims to determine the association of rs4415084 (T>C) and rs10941679 (A>G) with breast cancer risk in an Iranian sample population. Peripheral blood samples, taken from 72 patients and 65 controls, were subjected to DNA extraction and genotyping of the mentioned polymorphism by Tetra-primer amplification refractory mutation system PCR (Tetra-ARMS-PCR) assay. Also, the demographic characteristics of the participants were obtained. The results show that the majority of patients had estrogen-receptor (ER) and progesterone-receptor (PR) positive tumors (75% for either receptor) and 36 % were human epidermal growth factor receptor-2 (HER2) positive. Also, the majority of the tumors were at T2 (59.7 %), N0 (41.6 %), and M0 (86.1 %) grade. Moreover, a considerable association between the rs10941679 polymorphism and breast cancer was noticed (p=0.01) with significantly increased susceptibility of AG genotype. Genotyping of rs4415084 also revealed that TC and CC genotypes significantly increased breast cancer risk. This work revealed that the rs4415084 and rs10941679 at 5q12 might be risk-conferring factors for breast cancer among Iranian women, which could be employed in breast cancer screening and prognosis approaches.

Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility

Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility.

Thai patients who fulfilled NCCN criteria for breast/ovarian cancer genetic assessment demonstrated high prevalence of germline mutations in cancer susceptibility genes: implication to Asian population testing

BackgroundGermline genetic mutation plays a significant role in breast cancer susceptibility. The strength of such predisposition varies among ethnic groups across the globe, and clinical data from Asian population to develop a strategic approach to who should undergo a genetic test are lacking.MethodsWe performed a multigene test with next generation sequencing in Thai patients whose clinical history fulfilled NCCN criteria for breast/ovarian cancer genetic assessment, consists of 306 breast cancer patients, 62 ovarian cancer patients, 14 pancreatic cancer patients and 7 prostate cancer patients. Genetic test result and clinical history were then checked with each NCCN criteria to determined detection rate for each indication.ResultsThere were 83 pathogenic/likely pathogenic (P/LP) variants identified in 104 patients, 44 of these P/LP variants were novel. We reported a high rate of germline P/LP variants in breast cancer (24%), ovarian cancer (37%), pancreatic cancer (14%), and prostate cancer (29%). Germline P/LP variants in BRCA1 and BRCA2 accounted for 80% of P/LP variants found in breast cancer and 57% of P/LP variants found in ovarian cancer. The detection rate of patients who fulfilled NCCN 2019 guideline for genetic/familial high-risk assessment of breast and ovarian cancers was 22–40%.ConclusionOverall, the data from this study strongly support the consideration of multigene panel test as a diagnostic tool for patients with inherited cancer susceptibility in Thailand and Asian population. Implementation of the NCCN guideline is applicable, some modification may be needed to be more suitable for Asian population.

Association of RAD51C germline mutations with breast cancer among Bahamians.

RAD51C is known as an ovarian cancer gene; however, its role in breast cancer susceptibility is less clear. As part of a larger study, we assessed the role of germline RAD51C mutations in breast cancer development. We studied 387 unselected, BRCA1- and BRCA2-negative, Bahamian breast cancer cases and 653 controls to search for novel genetic associations with breast cancer development. During the first phase of the study, whole exome sequencing was utilized in 96 cases to identify an association between novel genes and breast cancer susceptibility. In the second phase of the study, targeted gene sequencing was utilized in the entirety of the cases and controls to identify an association between novel genetic mutations and breast cancer development. A RAD51C mutation was found in five breast cancer cases and in no control (5/387 versus 0/653; p = 0.007). None of the mutation-positive cases reported a family history of ovarian cancer. These data support increasing evidence that RAD51C mutations contribute to breast cancer susceptibility, although the impact may vary substantially from country to country.

An investigation of the relationship between TMPRSS6 gene expression, genetic variants and clinical findings in breast cancer.

Breast cancer is one of the most common types of cancer among women worldwide. The TMPRSS6 (Transmembrane Serine Protease 6) gene encodes matriptase-2, which plays an important role in iron hemostasis as the hepcidin regulator and may play a role in breast cancer susceptibility. In this study, we examined the expression levels of the TMPRSS6 gene in healthy tissues and tumor tissues of breast cancer patients; and the relationship between these levels and pathological findings. The relationship between TMPRSS6 polymorphisms (rs733655, rs5756506, rs2413450, rs855791, rs2235324, rs4820268) and patients' hematological parameters. The gene expression study encompassed 47 breast cancer patients and the gene polymorphism study consisted of 181 breast cancer patients and 100 healthy controls. Gene expression analysis was performed by qRT-PCR. The genotyping of TMPRSS6 polymorphisms was performed by RT-PCR. TMPRSS6 gene expression levels in tumor tissues were found to be 1.88 times higher than the expression levels in the control tissues. We examined the relationship between TMPRSS6 gene expression levels and pathological data, statistically significant relationship was found between patient's estrogen receptor (ER) and HER2 findings and TMPRSS6 gene expression (respectively p = 0.02, p = 0.002). When the relationship between TMPRSS6 gene polymorphisms related genotypes distributions and hematological findings was investigated, a significant relationship was identified between mean corpuscular hemoglobin concentration (MCHC) parameter and the polymorphism of only the rs733655. According to our findings, the increase in TMPRSS6 gene expression in cancerous tissues shows that matriptase-2 may be effective in the cancer process. Thus TMPRSS6 gene polymorphisms may affect the disease process by affecting the blood parameters of patients.

Identification of germline pathogenic variants in DNA damage repair genes by a next-generation sequencing multigene panel in BRCAX patients

BackgroundApproximately 5–10% of breast carcinomas have been related to hereditary conditions and are attributable to pathogenic variants in the BRCA1 and BRCA2 genes, which is referred to as hereditary breast and ovarian cancer (HBOC) syndrome. The inclusion of additional genes that can be related to HBOC syndrome is under intense evaluation due to the high proportion of patients with HBOC criteria who do not present pathogenic mutations in BRCA genes, named BRCAX, despite having high clinical suspicion of hereditary cancer. The main aim is to identify new potentially pathogenic gene variants that may contribute to HBOC to improve the efficiency of routine diagnostic tests in this hereditary condition. MethodsA retrospective cohort of 77 HBOC BRCAX patients was analyzed by next-generation sequencing using a targeted multigene panel composed of 25 genes related to hereditary cancer and deficiencies in DNA repair pathways. ResultsWe found 9 variants in 7 different genes, which were confirmed by automated sequencing. Six variants were classified as pathogenic or likely pathogenic. Three of them were located in the PALB2 gene, one in the BRIP1 gene, one in the BARD1 gene and 1 in the RAD50 gene. In addition, three variants of uncertain significance (VUS) were detected in the TP53, CHEK2, and CDH1 genes. ConclusionsWe identified that 8% of BRCAX patients were carriers of pathogenic variants in genes other than BRCA1 and BRCA2. Therefore, wide gene panels, including clinically actionable genes, should be routinely used in the screening of HBOC in our population. We observed differences from other studies in the prevalence of mutated genes, most likely due to differences in the selection criteria of the probands and in the population analyzed. The high incidence of deleterious variant detection in PALB2 supports its significant role in breast cancer susceptibility and reinforces its inclusion in the HBOC genetic diagnostic process.

Inherited thrombophilic risk factors in Serbian breast cancer patients

Breast cancer is the leading cause of cancer-related death among women. An increased burden of thrombotic events among breast cancer patients, leading to higher mortality and morbidity rates, is well established. There are a number of genetic risk factors associated with thrombosis, but their contribution to thrombotic tendencies in patients with cancer is not completely elucidated. We aimed to investigate possible role of FV Leiden, FII G20210A, MTHFR C677T and PAI-1 4G/5G gene variants in etiopathology of breast cancer and accompanying thrombosis in cohort of Serbian patients. Our study included 316 subject divided in three groups: breast cancer patients with (97) or without (99) accompanying thrombosis and healthy control group (120). According to our results, the prevalence for all four prothrombotic gene variants were similar in cancer patients with and without thrombosis and no statistically significant difference was observed between these groups. We detected lower frequency of MTHFR 677TT genotype in breast cancer patients when compared to control group (P=0.014; OR=0.145 (95%CI 0.031-0.679)), indicated that MTHFR C677T homozygosity could play a protective role in breast cancer susceptibility. Our study noted the lack of association between common prothrombotic gene variants and increased prothrombotic risk in Serbian breast cancer patients. Also, our results point out possible role of MTHFR 677TT genotype in etiology of breast cancer, but further studies on larger cohort of patients are needed.

Association of E-selectin S128R Polymorphism with Hereditary Breast Carcinoma Susceptibility in Turkish Patients Without BRCA1/2 Germline Mutations.

Inherited genetic factors play an important role in breast cancer susceptibility. The BRCA1 and BRCA2 mutations are the most well-known genetic factors associated with increased risk of breast cancer. E-selectin is a cell surface glycoprotein and its serum levels are known to increase in various cancers. The present retrospective study aimed to evaluate whether E-selectin S128R polymorphism (NG_012124.1: g.7161A>C, NM_000450.2: c.445A>C, NP_000441.2: p.Ser149Arg), which is known to have a role in cancer risk, is associated with breast cancer susceptibility in BRCA 1/2 mutation non carriers with breast cancer. The study included 90 patients with breast cancer and 270 healthy controls. All breast cancer patients were screened for BRCA 1/2 mutations and confirmed to be BRCA 1/2 mutation non carriers before inclusion in the study. Genotyping for the E-selectin S128R polymorphism was performed using real-time polymerase chain reaction (PCR) analysis. The frequencies of the AA, AC and CC genotypes were 70.0, 25.5 and 4.5%, respectively, in the patient group and 79.25, 19.25 and 1.5%, respectively, in the controls. The frequencies of A and C alleles were 84.8 and 15.2% in the patient group, respectively, and 88.9 and 11.1%, respectively, in the controls. No significant differences were determined in the genotype and allele frequencies of the E-selectin S128R polymorphism between the patient and control groups (p = 0.095). The S128R (A/C) polymorphism was not found to be associated with an increased risk of breast cancer [odds ratio (OR) = 0.69; 95% confidence interval (95% CI): 0.43-1.10; p = 0.1248). There was no association between the S128R polymorphism and breast cancer susceptibility in BRCA 1/2 mutation non carriers with breast cancer in the studied Turkish population. Further studies with larger sample sizes are needed to validate our findings.

Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1

BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.

Abstract PD1-11: Moderate risk genes matter: Multigene testing for hereditary breast cancer

Abstract Background: Many genes have been associated with hereditary breast cancer (BC). For some genes, the associated cancer risks have been debated; however, recent studies have helped resolve some uncertainties. For example, ATM, BARD1, CHEK2, and RAD51D were associated with a moderate risk of BC (odds ratio (OR) 2- to 5-fold) in a recent study by Couch et al. Though many BC susceptibility genes have NCCN® management guidelines for at least one cancer type, some lack recommendations for BC risk management and others are missing altogether due to limited data. We aim to examine the mutation frequencies of genes on a BC focused multigene panel test (MGPT) and the possible clinical impact of these findings. Methods: Sequential BC cases submitted to our laboratory for a BC focused MGPT between March 2012 and December 2016 were retrospectively reviewed. De-identified medical and family history data from test request forms and accompanying medical records as well as MGPT results were analyzed. Panel yield was assessed based on history of single or multiple primary diagnoses (MPD), level of BC risk, and clinical impact of test results. Results: Of 30,161 BC cases tested, 3,174 (10.5%) were positive for a mutation, and 143 (0.5%) had more than one mutation identified. Mutations in high (>5-fold risk) and moderate risk (<5-fold risk) BC genes were detected in 3.9% and 6.6% of BC patients, respectively. Furthermore, 80.0% of the gene mutations identified (8.4% of all BC patients) occurred in genes with NCCN® management guidelines for at least one cancer type. Detection rate also varied based on personal history, with mutations detected in 10.2% of single BC cases only, 12.7% of BC cases with MPD only, and 14.0% of cases with breast and other cancers (see Table for gene specific frequencies). Breast Cancer Only N (%)MPD Only N (%)Breast + Other Cancers N (%)ATM246 (1.0%)62 (1.5%)33 (1.9%)BARD158 (0.2%)19 (0.5%)3 (0.2%)BRCA1273 (1.2%)65 (1.7%)13 (0.8%)BRCA2336 (1.4%)68 (1.8%)36 (2.2%)BRIP169 (0.3%)6 (0.1%)7 (0.4%)CDH112 (0.1%)5 (0.1%)1 (0.1%)CHEK2412 (1.7%)105 (2.6%)58 (3.3%)CHEK2 (p.I157T)122 (0.5%)28 (0.7%)13 (0.7%)MRE11A31 (0.1%)6 (0.1%)2 (0.1%)MUTYH carrier312 (1.3%)44 (0.1%)31 (1.8%)NBN44 (0.2%)5 (0.1%)5 (0.3%)NF139 (0.2%)9 (0.3%)6 (0.4%)PALB2221 (0.9%)43 (1.1%)14 (0.8%)PTEN14 (0.1%)4 (0.1%)1 (0.1%)RAD5057 (0.2%)8 (0.2%)9 (0.5%)RAD51C32 (0.1%)13 (0.3%)2 (0.1%)RAD51D17 (0.1%)5 (0.1%)2 (0.1%)TP5347 (0.2%)16 (0.4%)12 (0.7%) Discussion: Findings from this large clinical testing cohort indicate that clinicians can expect approximately 3.9% and 6.6% of BC patients to have mutations in high and moderate risk genes, respectively. Though these values may shift as gene-specific BC risks continue to be refined, it is clear that moderate risk genes play a significant role in BC susceptibility. Five genes recently added to NCCN® management guidelines (BRIP1, NBN, NF1, RAD51C, and RAD51D) accounted for 9.9% of mutations identified (1.0% of all BC cases). Including these genes in MGPT provides patients and their families clinically relevant information about cancer risks and management options. Further studies are needed on genes such as BARD1 and RAD51D that have recently been shown to predispose to BC but lack guidelines for BC risk management. Citation Format: Jackson M, LaDuca H, Profato-Partlow J, Espenschied C. Moderate risk genes matter: Multigene testing for hereditary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-11.

Pathway-based discovery of genetic interactions in breast cancer.

Breast cancer is the second largest cause of cancer death among U.S. women and the leading cause of cancer death among women worldwide. Genome-wide association studies (GWAS) have identified several genetic variants associated with susceptibility to breast cancer, but these still explain less than half of the estimated genetic contribution to the disease. Combinations of variants (i.e. genetic interactions) may play an important role in breast cancer susceptibility. However, due to a lack of statistical power, the current tests for genetic interactions from GWAS data mainly leverage prior knowledge to focus on small sets of genes or SNPs that are known to have an association with breast cancer. Thus, many genetic interactions, particularly among novel variants, remain understudied. Reverse-genetic interaction screens in model organisms have shown that genetic interactions frequently cluster into highly structured motifs, where members of the same pathway share similar patterns of genetic interactions. Based on this key observation, we recently developed a method called BridGE to search for such structured motifs in genetic networks derived from GWAS studies and identify pathway-level genetic interactions in human populations. We applied BridGE to six independent breast cancer cohorts and identified significant pathway-level interactions in five cohorts. Joint analysis across all five cohorts revealed a high confidence consensus set of genetic interactions with support in multiple cohorts. The discovered interactions implicated the glutathione conjugation, vitamin D receptor, purine metabolism, mitotic prometaphase, and steroid hormone biosynthesis pathways as major modifiers of breast cancer risk. Notably, while many of the pathways identified by BridGE show clear relevance to breast cancer, variants in these pathways had not been previously discovered by traditional single variant association tests, or single pathway enrichment analysis that does not consider SNP-SNP interactions.

Increased genomic burden of germline copy number variants is associated with early onset breast cancer: Australian breast cancer family registry

BackgroundWomen with breast cancer who have multiple affected relatives are more likely to have inherited genetic risk factors for the disease. All the currently known genetic risk factors for breast cancer account for less than half of the average familial risk. Furthermore, the genetic factor(s) underlying an increased cancer risk for many women from multiple-case families remain unknown. Rare genomic duplications and deletions, known as copy number variants (CNVs), cover more than 10% of a human genome, are often not assessed in studies of genetic predisposition, and could account for some of the so-called “missing heritability”.MethodsWe carried out a hypothesis-generating case-control study of breast cancer diagnosed before age 40 years (200 cases, 293 controls) using population-based cases from the Australian Breast Cancer Family Study. Genome-wide scanning for CNVs was performed using the Human610-Quad BeadChip and fine-mapping was conducted using PennCNV.ResultsWe identified deletions overlapping two known cancer susceptibility genes, (BRCA1 and BLM), and a duplication overlapping SMARCB1, associated with risk. The number of deletions across the genome was 1.5-fold higher for cases than controls (P = 10-16), and 2-fold higher when only rare deletions overlapping genes (frequency <1%) were assessed (P = 5 × 10-4). Association tests of CNVs, followed by experimental validation of CNV calls, found deletions overlapping the OR4C11 and OR4P4 genes were associated with breast cancer (P = 0.02 and P = 0.03, respectively).ConclusionThese results suggest rare CNVs might have a role in breast cancer susceptibility, at least for disease at a young age.

The hOGG1 Ser326Cys Gene Polymorphism and Breast Cancer Risk in Saudi Population.

The purpose of this study was to test the association between human 8-oxoguanine glycosylase 1 (hOGG1) gene polymorphisms and susceptibility to breast cancer in Saudi population. We have also aimed to screen the hOGG1 Ser326Cys polymorphism effect on structural and functional properties of the hOGG1 protein using in silico tools. We have analyzed four SNPs of hOGG1 gene among Saudi breast cancer patients along with healthy controls. Genotypes were screened using TaqMan SNP genotype analysis method. Experimental data was analyzed using Chi-square, t test and logistic regression analysis using SPSS software (v.16). In silco analysis was conducted using discovery studio and HOPE program. Genotypic analysis showed that hOGG1 rs1052133 (Ser326Cys) is significantly associated with breast cancer samples in Saudi population, however rs293795 (T >C), rs2072668 (C>G) and rs2075747 (G >A) did not show any association with breast cancer. The hOGG1 SNP rs1052133 (Ser326Cys) minor allele T showed a significant association with breast cancer samples (OR = 1.78, χ2 = 7.86, p = 0.02024). In silico structural analysis was carried out to compare the wild type (Ser326) and mutant (Cys326) protein structures. The structural prediction studies revealed that Ser326Cys variant may destabilize the protein structure and it may disturb the hOGG1 function. Taken together this is the first In silico study report to confirm Ser326Cys variant effect on structural and functional properties of hOGG1 gene and Ser326Cys role in breast cancer susceptibility in Saudi population.

Association Between Leptin (-2548G/A) Genes Polymorphism and Breast Cancer Susceptibility: A Meta-Analysis.

Leptin is a confirmed breast cancer susceptibility gene. However, published studies reported mixed results. This meta-analysis was conducted to systematically get a more accurate estimation of the association between the Leptin (-2548G/A) gene polymorphism and breast cancer risk.To assess the effect of Leptin (-2548G/A) gene polymorphism on breast cancer susceptibility, we searched PUBMED, ISI Web of Knowledge, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases until September 2015 to identify eligible studies, without restriction. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to breast cancer. Separate analyses were conducted on features of the population such as ethnicity, source of controls, and country.A total of 9 case-control studies on Leptin (-2548G/A) gene polymorphism and breast cancer risk, including 3725 cases and 3093 case-free controls were identified. The results revealed that compared with the G allele, the A allele was associated with modestly increased risk of overall breast cancer (A vs G: OR = 1.12, 95%CI = 1.04 − 1.20, P = 0.002, PhetP < 0.00001). Following further stratified analyses, in the subgroup analyses by ethnicity, a significantly increased risk was observed among Caucasian (A vs G: OR = 1.11, 95%CI = 1.03–1.20, P = 0.006, Phet = 0.00001). No publication bias was found in the present study.In conclusion, our meta-analysis suggests that the Leptin (-2548G/A) gene polymorphism plays an important role in breast cancer susceptibility, especially in Caucasian.

No association of the TGF-β1 29T/C polymorphism with breast cancer risk in Caucasian and Asian populations: evidence from a meta-analysis involving 55,841 subjects.

The transforming growth factor-β1 (TGF-β1) gene 29 T/C polymorphism is thought to be associated with breast cancer risk. However, reports are largely conflicting and underpowered. We therefore conducted a meta- analysis of all available case-control studies relating the TGF-β1 29T/C polymorphism to the risk of developing breast cancer by including a total of 31 articles involving 24,021 cases and 31,820 controls. Pooled ORs were generated for the allele contrasts, with additive genetic, dominant genetic and recessive genetic models. Subgroup analysis was also performed by ethnicity for the TGF-β1 29T/C polymorphism. No association was found in the overall analysis (C vs T: OR=1.028, 95% CI=0.949-1.114, p-value 0.500; CC vs TC: OR=1.022, 95% CI=0.963- 1.085, p-value 0.478; CC vs TT: OR=1.054, 95% CI=0.898-1.236, p-value 0.522; CC vs TT+TC: OR=1.031, 95% CI=0.946-1.124, p-value 0.482; TT vs CC+TC: OR=0.945, 95% CI=0.827-1.080, p-value 0.403). Similarly, in the subgroup analysis by ethnicity, no association was found in Caucasian (C vs T: OR=1.041, 95% CI=0.932-1.162, p-value 0.475; CC vs TC: OR=1.031, 95% CI=0.951-1.118, p-value 0.464; CC vs TT: OR=1.081, 95% CI=0.865- 1.351, p-value 0.493; CC vs TT+TC: OR=1.047, 95% CI=0.929-1.180, p-value 0.453; TT vs CC+TC: OR= 0.929, 95% CI=0.775-1.114, p-value 0.429;) and Asian populations (C vs T: OR=1.004, 95% CI=0.908-1.111, p-value 0.931; CC vs TC: OR= 0.991, 95% CI=0.896-1.097, p-value 0.865; CC vs TT: OR=1.015, 95% CI=0.848-1.214, p-value 0.871; CC vs TT+TC: OR=1.000, 95% CI=0.909-1.101, p-value 0.994; TT vs CC+TC: OR= 0.967, 95% CI=0.808-1.159, p-value 0.720;). No evidence of publication bias was detected during the analysis. No significant association with breast cancer risk was demonstrated overall or on subgroup (Caucasian and Asian) analysis. It can be concluded that TGF-β1 29T/C polymorphism does not play a role in breast cancer susceptibility in overall or ethnicity-specific manner.

Abstract A018: Genomic evaluation of inherited predisposition to breast cancer in women from the University of Arizona Cancer Center High Risk Breast Cancer Genetics Clinic

Abstract A018: Genomic evaluation of inherited predisposition to breast cancer in women from the University of Arizona Cancer Center High Risk Breast Cancer Genetics Clinic

Vascular endothelial growth factor −634G/C polymorphism is associated with increased breast cancer risk and aggressiveness

Polymorphisms in the promoter and 5' untranslated region of vascular endothelial growth factor (VEGF) have been associated with VEGF levels. To investigate the role of VEGF polymorphisms in breast cancer, the VEGF ‑2578C/A, ‑1498C/T, ‑1154G/A and ‑634G/C polymorphisms were genotyped in 483 breast cancer patients and 524 healthy controls. VEGF mRNA levels in breast cancer tissue were determined using semi‑quantitative RT‑PCR. The genotypes, ‑634G/C and ‑634C/C, were associated with an increased risk for breast cancer when compared with the ‑634G/G genotype. The VEGF ‑634G/C genotype was associated with tumor size >20 mm, perineural invasion and stage II‑IV. Individuals with ‑634C/C had lower disease‑free survival. Patients with the VEGF ‑634C/C genotype exhibited the highest VEGF mRNA levels. High VEGF mRNA expression correlated with tumor size >20 mm, presence of lymphovascular invasion and axillary nodal metastasis. These observations suggested that VEGF ‑634G/C polymorphisms have a significant role in breast cancer susceptibility and aggressiveness.