Association between Toll-like receptor 2 rs4696483 and rs1898830 polymorphisms and the risk of triple-negative breast cancer.

PURPOSE: Breast cancer (BC) is heterogeneous in clinical manifestation, of which the triple-negative (TNBC) subtype is the most aggressive. This study examines the associations between Toll-Like Receptor (TLR)-2 polymorphisms and the susceptibility to BC and TNBC. METHODS: Genotyping of TLR-2 rs1898830 and rs4696483 polymorphisms was done by real-time PCR in 488 women with BC (130 TNBC, 358 non-TNBC) and 476 cancer-free control women. RESULTS: The minor allele frequency (MAF) of rs4696483 was significantly lower in BC cases compared to controls, and significantly lower frequencies of rs4696483 C/T and higher frequencies of rs1898830 G/G genotypes were seen in BC cases. Significantly higher MAF of rs4696483 and higher C/T and T/T rs4696483 genotypes frequencies were seen in TNBC than in non-TNBC cases. Considering the prevalent AC haplotype as a reference, 2-locus TLR-2 haplotype analysis did not identify any 2-locus TLR-2 haplotype associated with an altered risk of BC or TNBC. Positive associations of rs1898830 and rs4966483 were seen with the histological type in TNBC and negatively with distant metastasis and HR status in TNBC and non-TNBC rs1898830 carriers. In addition, rs4696483 was positively correlated with hormonotherapy and surgery in non-TNBC cases, while rs1898830 was negatively associated with hormonotherapy. Furthermore, rs1898830 was negatively and positively correlated with BMI in TNBC and TNBC cases, respectively, but positively with Ki-67 status. CONCLUSIONS: Our study highlights the association between TLR-2 genetic polymorphisms and BC and TNBC susceptibility, suggesting these variants' diagnostic/prognostic capacity in BC patients and patient subgroups.

Association of IL-1ß gene polymorphisms rs1143627, rs1799916, and rs16944 with altered risk of triple-negative breast cancer.

PURPOSE: Breast cancer (BC) is the most recognized malignancy in females globally and is heterogeneous in its clinical manifestation, among which the triple-negative (TNBC) subtype is the most aggressive. This study examines the associations between IL-1ß polymorphisms and BC and TNBC susceptibility. METHODS: Genotyping ofIL-1ßrs1143627, rs1799916, and rs16944 polymorphisms was done in 488 women with BC (130 TNBC, 358 non-TNBC) and 476 cancer-free control women using real-time PCR genotyping. RESULTS: The minor allele and genotype frequencies of rs1799916, rs1143627, and rs16944 significantly differed among BC cases and controls and remained after correcting key covariates. On the other hand, minor allele and genotype frequencies of only rs16944 significantly differed between TNBC and non-TNBC cases. Spearman correlation analyses demonstrated that all three variants correlated positively with menopausal status and Her2 status but negatively with menarche, breastfeeding, and cancer type. In addition, rs1143627 and rs16944 correlated positively with HR and ER, while rs1799916 correlated positively with Ki67 status. The three variants correlated negatively with menarche, breastfeeding, and cancer type in non-TNBC cases but positively with histological grading in non-TNBC and Her2 in TNBC cases. A positive correlation was noted between rs1143627 and rs1799916 and age (<40 years) and between rs1799916 and rs16944 with menopausal status. We confirmed that GCG haplotype imparted BC susceptibility, while TCA and TTG haplotypes were protective of BC. Among TNBC cases, only GCG and TCA haplotypes remained protective of TNBC after adjustment. CONCLUSIONS: Our study highlights the association between IL-1ßgenetic polymorphisms and BC and TNBC susceptibility, suggesting these variants' diagnostic/prognostic capacity in BC patients.

Novel Association of IGF2BP2 Gene Variants With Altered Risk of Breast Cancer and as Potential Molecular Biomarker of Triple Negative Breast Cancer.

BACKGROUND: Several studies documented that insulin-like growth factor-2 mRNA-binding protein 2 (IGF2BP2) contributes to carcinogenesis, and 1 report documented the association of IGF2BP2 rs4402960 with increased risk of breast cancer (BC). This study investigated the association of rs4402960 and rs1470579 IGF2BP2 variants with BC and triple negative BC (TNBC). MATERIALS AND METHODS: This case-control study included 488 BC patients comprising 130 TNBC and 358 non-TNBC patients, and 476 cancer-free controls. Genomic DNA was obtained from peripheral venous blood, and genotyping was done by allelic exclusion method on real-time PCR. RESULTS: The rs440960, but not rs1470579, minor allele was significantly associated with BC, and significantly higher rs4402960 T/T genotype frequency was noted in BC patients than controls; the distribution of rs1470579 genotypes were comparable between BC patients and controls. In contrast, significantly lower rs1470579 minor allele frequency, and reduced rs1470579 A/C and C/C, and rs4402960 T/T genotype frequencies were seen in TNBC cases. Among TNBC cases, rs4402960 and rs1470579 correlated with menses pattern, histological type, breastfeeding, oral contraceptive use and hormonotherapy. Among non-TNBC patients, and rs1470579 correlated significantly with breast feeding, oral contraceptive use, hormonotherapy, and nodal status; rs4402960 also correlated with menses pattern. Two-locus (rs440960-rs1470579) haplotype analysis confirmed the positive association of TC, and negative association of GC and TA haplotypes with BC, while TC and GC haplotypes were negatively associated with TNBC. CONCLUSION: Whereas rs440960 was positively associated with BC, both rs4402960 and rs1470579 were negatively associated with TNBC, suggesting potential diagnostic/prognostic role in BC and its complications.

Unique ESR1 and ESR2 estrogen receptor gene variants associated with altered risk of triple-negative breast cancer: A case-control study.

BACKGROUND: We previously reported on the association between ESR1 and ESR2 gene variants and heightened risk of breast cancer (BC). Here we investigated the association of common ESR1 and ESR2 gene variants with triple negative BC (TNBC). METHODS: This retrospective case-control study involved 488 BC patients (130 TNBC, 358 non-TNBC patients). ESR1 (rs2234693, rs9340799, rs3020314, rs3798577) and ESR2 (rs928554, rs944459, rs4986938, rs1256049, rs1256030, rs1271572) genotyping was done by real-time PCR. RESULTS: While minor allele frequencies (MAF) of ESR1 variants were comparable between TNBC and non-TNBC subjects, significantly higher ESR2 rs1256049 MAF was seen in TNBC patients. Significantly higher frequency of ESR1 rs3798577 T/C and C/C genotypes were noted in TNBC cases, and significant differences were seen in ESR2 rs928554, rs1256049, and rs1271572 genotype distribution. Increased TNBC risk was associated with ESR1 rs3798577 T/C and C/C genotypes according to codominant and dominant models, while positive association of ESR2 rs928554 with TNBC was seen according to codominant and recessive models, and positive association of ESR2 rs1256049 with TNBC was seen according to codominant and dominant models. Positive interactions were noted between ESR2 rs1271572-ESR1 rs3020314, ESR2 rs1271572-ESR1 rs9340799, and ESR2 rs1271572-ESR1 rs2234693, ESR2 rs4986938-ESR1 rs2234693, and ESR2 rs928554-ESR1 rs9340799. Haplotype analysis confirmed the positive association of ESR1 CATT with TNBC, while ACGGCTC and ACGGTT ESR2 haplotypes were positively associated with TNBC. CONCLUSION: Results of this study confirmed the association of unique ESR1 and ESR2 genetic variants with altered risk of TNBC. This suggests possible diagnostic and prognostic role of these variants with TNBC independent of their association with BC.

Progesterone Receptor (PGR) Gene Variants Associated with Breast Cancer and Associated Features: a Case-Control Study.

Insofar as altered estrogen receptor-progesterone receptor (PR) expression contribute to breast cancer pathogenesis, previous studies examined the association of genetic variation in PR gene (PGR) with breast cancer, but with mixed outcome. We evaluated the association between PGR variants, and breast cancer and associated features. A retrospective case-control study involving 183 female breast cancer patients, and 222 control women. PGR genotyping was done by real-time PCR. Minor allele frequencies of rs1042838, rs590688, and rs10895068 PGR gene polymorphisms were significantly higher in breast cancer patients compared to controls. Patients carrying rs1042838 G/T, rs590688 C/C, and rs10895068 G/A genotypes had higher risk of breast cancer, while carriage of rs3740753 G/G genotype was associated with marginal reduction in breast cancer risk. In addition, carriage of rs1042839, rs3740753, and rs10895068 minor allele was associated with Her2 status, while rs3740753 and rs10895068 were associated with effective hormone replacement therapy. Furthermore, carriage of rs10895068 minor allele in breast cancer women were also associated with age at first pregnancy, hormone receptor (RH) status, and previous use of oral contraceptives. PGR haploview analysis documented moderate-strong linkage disequilibrium (non-random association of alleles at different loci) between 7 of the 8 tested PGR SNPs, thus allowing construction of 7-locus PGR haplotypes. Two haplotypes, ATGCCGA and GTGCCGA, both containing rs590688, were positively associated with breast cancer, thus assigning a breast cancer-susceptible nature to these haplotypes. PGR rs1042838, rs590688, and rs10895068, and ATGCCGA and GTGCCGA haplotypes are related with increased breast cancer susceptibility in Tunisian women.

IKZF1 genetic variants rs4132601 and rs11978267 and acute lymphoblastic leukemia risk in Tunisian children: a case-control study.

BACKGROUND: Associations between IKZF1 gene variants and Acute Lymphoblastic Leukemia (ALL) was recently reported. We examined whether the common IKZF1 polymorphisms rs4132601 T/G and rs111978267 A/G are associated with ALL among a Tunisian pediatric cohort. METHODS: This case-control study involved 170 patients with ALL and 150 control subjects. SNP genotyping was performed by TaqMan® SNP Genotyping Assay. RESULTS: The minor allele G of IKZF1 gene polymorphism rs4132601 T/G was significantly higher in ALL cases than in control subjects (P = 0.029), with 1.54-fold increased risk of ALL. The association of rs4132601 with ALL was seen under co-dominant (P = 0.009), recessive (P = 0.006), and additive (P = 0.027) genetic models, of which the co-dominant (P = 0.027) and recessive (P = 0.027) association remained significant after adjusting for covariates, and False Discovery Rate correction. In contrast, no association was noted for rs111978267 variant. Two-locus (rs4132601-rs11978267) IKZF1 haplotype analysis demonstrated association of GA (P = 0.053), with increased ALL risk [OR (95% CI) = 1.58 (1.00-2.51)], which remained significant after controlling for key covariates [aP = 0.046; aOR (95% CI) = 1.61 (1.01-2.57)]. CONCLUSION: We demonstrated the association of IKZF1 polymorphism rs4132601 T/G with increased risk of ALL among Tunisian pediatric cohort, with altered phenotypic changes among ALL patients.

Transforming growth factor beta 1 polymorphisms and haplotypes associated with breast cancer susceptibility: A case-control study in Tunisian women.

Variable association of transforming growth factor beta 1 (TGFß1) in breast cancer (BC) pathogenesis was documented, and the contribution of specific TGFB1 polymorphisms to the progression of BC and associated features remains poorly understood. We investigated the contribution of TGFB1 rs1800469, rs1800470, rs1800471, and rs1800472 variants and 4-locus TGFB1 haplotypes on BC susceptibility, and pathological presentation of BC subtypes. Study subjects comprised 430 female BC cases, and 498 cancer-free control women. BC-associated pathological parameters were also evaluated for correlation with TGFB1 variants. Results obtained showed that the minor allele frequency (MAF) of rs1800471 (+74G>C) was higher seen in BC cases than in control subjects, and was associated with increased risk of BC. Significant differences in rs1800471 and rs1800469 (-509C>T) genotype distribution were noted between BC cases and controls, which persisted after controlling for key covariates. TGFB1 rs1800472 was positively, while rs1800470 was negatively associated with triple negativity, while rs1800470 positively correlated with menarche, but negatively with tumor size and molecular type, and rs1800469 correlated positively with menstrual irregularity, distant metastasis, nodal status, and hormonotherapy. Heterogeneity in LD pattern was noted between the tested TGFB1 variants. Four-locus (rs1800472-rs1800471-rs1800470-rs1800469) Haploview analysis identified haplotype TGCT to be negatively associated, and haplotypes CGTT and CCCC to be positively associated with BC. This association of CGTT and CCCC, but not TGCT, with BC remained significant after controlling for key covariates. In conclusion, TGFB1 alleles and specific genotypes, and 4-locus TGFB1 haplotypes influence BC susceptibility, suggesting dual association imparted by specific SNP, consistent with dual role for TGFB1 in BC pathogenesis.

Common matrix metalloproteinase-2 gene variants and altered susceptibility to breast cancer and associated features in Tunisian women.

A role for matrix metalloproteinase polymorphisms in breast cancer development and progression was proposed, but with inconclusive results. We assessed the relation of matrix metalloproteinase-2 variants with breast cancer and related phenotypes in Tunisians. This case-control retrospective study involved 430 women with breast cancer and 498 healthy controls. Genotyping of matrix metalloproteinase-2 rs243866, rs243865, rs243864, and rs2285053 was analyzed by allelic exclusion. The minor allele frequency of rs2285053 was significantly lower in women with breast cancer cases as compared to control women; minor allele frequencies of the remaining single-nucleotide polymorphisms were similar between cases and control women. The distribution of rs243865 and rs2285053 genotypes was significantly different between breast cancer patients and control subjects. This persisted when key covariates were controlled for. None of the matrix metalloproteinase-2 variants were associated with estrogen receptor positivity, progesterone receptor positivity, or with double estrogen receptor-progesterone receptor positivity in breast cancer patients. Matrix metalloproteinase-2 rs243866, rs243865, and rs243864 were positively associated with menstrual irregularity and histological type, while rs243866 and rs2285053 were negatively associated with menarche and nodal status. In addition, rs2285053 was negatively associated with triple negativity, tumor size, distance metastasis, molecular type, and chemotherapy. Haploview analysis revealed high linkage disequilibrium between matrix metalloproteinase-2 variants. Four-locus Haploview analysis identified haplotypes GCTT and GTTC to be negatively associated with breast cancer, which remained statistically after controlling for key covariates. Matrix metalloproteinase-2 alleles and genotypes, along with four-locus haplotypes, are related to reduced susceptibility to breast cancer in Tunisian women, suggesting a protective effect.

Association of Genetic Variants in NF-kB with Susceptibility to Breast Cancer: a Case Control Study.

Insofar as altered NF-κB signaling stemming from the presence of specific genetic variants in NF-κB gene contribute to cancer pathogenesis, this study evaluated the association between NF-κB rs147574894/I552V, rs148626207/M860T rs3774937 and rs1598859 variants and breast cancer and associated features and complications. This was a retrospective case-control study, which involved 207 women with breast cancer, and 214 cancer-free women who served as controls. NF-κB genotyping was done by real-time PCR. Significantly higher rs3774937 minor allele frequencies (MAF), and lower rs147574894 MAF were seen among breast cancer patients, thereby imparting disease susceptibility and protective nature to these variants, respectively. Significant association of rs3774937 and rs147574894 genotypes with breast cancer was seen under the dominant model. Histological type and grade, molecular type, Her2 positivity and ER+/Her2- correlated positively, while distant metastasis negatively correlated with rs3774937. On the other hand, rs147574894 negatively correlated with histological type and grade, tumor size, Her2 positivity, molecular type, and ER+/Her2-, while rs148626207 correlated positively with histological grade, but negatively with distant metastasis and triple-negative status. Breast cancer-susceptible and -protective 4-locus haplotypes were also identified. This is the first report that addresses the contribution of NF-κB variants to the pathogenesis of breast cancer in Middle Eastern-North African population, and the first to document positive association of rs3774937 with breast cancer.

Differential association of ESR1 and ESR2 gene variants with the risk of breast cancer and associated features: A case-control study.

BACKGROUND: Estrogen is key to breast cancer pathogenesis, and acts by binding its receptor (ER), which exists as ERα and ERß, encoded by ESR1 and ESR2 genes, respectively. Studies that investigated the association of ESR1 and ESR2 variants with breast cancer yielded mixed outcome, and ethnic contribution was proposed. We evaluated the association between ESR1 and ESR2 variants and breast cancer and associated features in Tunisian women. METHODS: Retrospective case-control study involving 207 female breast cancer patients, and 284 control women. Genotyping was done by real-time PCR. RESULTS: Minor allele frequencies (MAF) of tagging SNPs rs2234693 and rs3798577 (ESR1) were significantly higher, while MAF of rs1256049 (ESR2) was significantly lower in breast cancer patients vs. CONTROLS: Patients carrying rs3798577 genotypes had higher risk, while rs1256049 genotype carriers had reduced risk of breast cancer. The association of ESR1 and ESR2 gene variants with breast cancer depended on ER and Her-2 status. ESR1 rs3798577 and ESR2 rs1256049 were associated with breast cancer in ER-positive cases, and ESR1 rs2234693, and rs3798577 were associated with breast cancer in Her-2-negative cases, while the association of ESR2 rs1256049 with breast cancer was seen in Her-2 positive cases. Haploview analysis identified 4-locus ESR1 haplotypes that were positively (CGTT, TACC, and TACT), and negatively (CGTC) associated with breast cancer. No ESR2 haplotypes associated with breast cancer were identified. CONCLUSION: ESR1 alleles and genotypes, and specific 3-locus ESR1 haplotypes are related with increased breast cancer susceptibility in Tunisian women. However, ESR2 variant and specific 1-locus ESR1 haplotype have a protective effect.