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.

Assessing serum cytokine profiles in inflammatory breast cancer patients using Luminex® technology.

BACKGROUND: Inflammatory breast cancer (IBC), accounts for the majority of deaths associated with breast tumors. Because this form is aggressive from its appearance and has a strong metastatic potential. The majority of patients are not diagnosed until late stages, highlighting the need for the development of novel diagnostic biomarkers. Immune mediators may affect IBC progression and metastasis installation. AIM OF THE STUDY: Analysis of serum proteins to identify a panel of prognostic biomarkers for IBC. PATIENTS AND METHODS: Serum levels of 65 analytes were determined in IBC and Non-IBC patients with the ProcartaPlex Human Immune Monitoring 65-Plex Panel. RESULTS: Fifteen analytes: 5 cytokines (IL-8, IL-16, IL-21, IL-22 and MIF), 7 chemokines (Eotaxin, eotaxin-3, Fractalkine, IP-10, MIP-1α, MIP-1ß and SDF-1α), One growth factors (FGF-2) and 2 soluble receptors (TNFRII and Tweak); were significantly differentially expressed between the two groups. ROC curves showed that twelve of them (IL-8, IL-16, IL-21, IL-22, MIF, MIP-1α, MIP-1ß, SDF-1α, TNFRII, FGF-2, Eotaxin-3, and Fractalkine) had AUC values greater than 0.70 and thus had potential clinical utility. Moreover, seven cytokines: IL-8, IL-16, MIF, Eotaxin-3, MIP-1α, MIP-1ß, and CD-30 are positively associated with patients who developed distant metastasis. Ten analytes: Eotaxin-3, Fractalkine, IL-16, IL-1α, IL-22, IL-8, MIF, MIP-1α, MIP-1ß, and TNFRII are positively associated with patients who had Lymph-Nodes invasion. CONCLUSION: This study has uncovered a set of 8 analytes (Eotaxin-3, Fractalkine, IL-16, IL-8, IL-22, MIF, MIP-1α, MIP-1ß) that can be used as biomarkers of IBC, and can be utilized for early detection of IBC, preventing metastasis and lymph-Nodes invasion.

Immune checkpoints as potential theragnostic biomarkers for epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. EOC is asymptomatic in early stages, so most patients are not diagnosed until late stages, highlighting the need to develop new diagnostic biomarkers. Mediators of the tumoral microenvironment may influence EOC progression and resistance to treatment. AIM: To analyze immune checkpoints to evaluate them as theranostic biomarkers for EOC. PATIENTS AND METHODS: Serum levels of 16 immune checkpoints were determined in EOC patients and healthy controls using the MILLIPLEX MAP® Human Immuno-Oncology Checkpoint Protein Magnetic Bead Panel. RESULTS: Seven receptors: BTLA, CD40, CD80/B7-1, GITRL, LAG-3, TIM-3, TLR-2 are differentially expressed between EOC and healthy controls. Serum levels of immune checkpoints in EOC patients are positively significantly correlated with levels of their ligands, with a higher significant correlation between CD80 and CTLA4 than between CD28 and CD80. Four receptors, CD40, HVEM, PD-1, and PD-L1, are positively associated with the development of resistance to Taxol-platinum-based chemotherapy. All of them have an acceptable area under the curve (>0.7). CONCLUSION: This study has yielded a first panel of seven immune checkpoints (BTLA, CD40, CD80/B7-1, GITRL, LAG-3, TIM-3, TLR-2) associated with a higher risk of EOC and a second panel of four immune checkpoints (CD40, HVEM, PD-1, PD-L1) that may help physicians to identify EOC patients who are at high risk of developing resistance to EOC chemotherapy.

Identification of two theranostic biomarker panels for epithelial ovarian cancer.

BACKGROUND: Epithelial Ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. Because the disease is asymptomatic in early-stage, the majority of patients are not diagnosed until late stages, highlighting the need for the development of novel diagnostic biomarkers. Mediators of tumoral microenvironment may affect EOC progression and resistance to treatment. AIM OF THE STUDY: Analysis of serum proteins to identify a panel of theranostic biomarkers for EOC. PATIENTS AND METHODS: Serum levels of 65 analytes were determined in EOC patients, and healthy controls with the ProcartaPlex Human Immune Monitoring 65-Plex Panel. RESULTS: Twenty-one analytes: 7 cytokines (IFN-γ, IL-12p70, IL-13, IL-18 and TSLP), 7 chemokines (Eotaxin, eotaxin-2, IP-10, BLC, I-TAC, SDF-1α, and fractalkine), 2 growth factors (MMP-1, VEGF-α), and 5 soluble receptors (APRIL, CD40L, TWEAK, CD30 and TNFRII; were significantly differentially expressed between the two groups. ROC curves showed that only seven of them (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine, and Tweak) had AUC values greater than 0.70 and thus had potential clinical utility. Moreover, five cytokines: IFN-γ, IL-1 ß, IL-8, MIP-1ß, and TNF-α are positively associated with patients who developed resistance to taxol-platinum-based chemotherapy (CT). CONCLUSION: This study has revealed a first panel of 7 analytes (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine and Tweak) that can be used for early detection of EOC and a second panel of five cytokines (IFN-γ, IL-1ß, IL-8, MIP-1ß, TNF-α) that can help clinicians to identify EOC patients who are at higher risk to develop resistance to CT of EOC.

Sensitive electrochemical detection of polymorphisms in IL6 and TGFß1 genes from ovarian cancer DNA patients using EcoRI and DNA hairpin-modified gold electrodes.

Two electrochemical bioplatforms were prepared based on thiolated hairpin DNA probes tethered to AuNP-modified screen-printed electrodes to detect T > G and T > C polymorphisms, namely rs1880269 and rs1800469, present the interleukin-6 (IL6) and transforming growth factor ß1 (TGFß1) genes. The electrochemical readout was ensured by the detection of the double-stranded DNA using methylene blue as a redox probe after treatment by EcoRI restrictase. The main parameters influencing the analytical response such as the thiolated DNA probe concentration, incubation time with electrode, DNA hybridization time, EcoRI enzyme load, and its cleavage time were optimized based on the current intensity and signal-to-blank (S/B) ratio as selection criteria. Using spiked buffer solutions, the IL6 and TGFß1 E-bioplatforms display wide ranges of linearity (1 × 102-1 × 108 fM and 5 × 101-1 × 105 fM, respectively) and limits of detection (47.9 fM and 16.6 fM, respectively). The two bioelectrodes have also good discrimination toward 1-mismatched, two mismatched, and non-complementary sequences, when they were used 30-fold higher than the target sequences. More importantly, the two bioplatforms successfully detected the single nucleotide polymorphisms (SNPs) in scarcely diluted genomic DNA, collected from 52 donors, and showed they can reliably distinguish between heterozygous (TG and TC genotypes) and homozygous (GG and CC genotypes) patients with  respect to the control subjects (TT genotype), where the differences are statistically highly significant (p-value < 0.0001). Thus, the designed devices could be used to conduct large cohort studies targeting these mutations or extended to other SNPs.

A comparative study of the self-assembly of achiral and chiral hairy nanoparticles with polystyrene cores and poly(2-hydroxyethylmethacrylate) hairs.

Hairy nanoparticles with polystyrene cores (PS cores) and poly(2-hydroxyethylmethacrylate) (PHEMA) shells were synthesized by combining living anionic polymerization and atom transfer radical polymerization (ATRP). The structural characterization was carried out by FT-IR and NMR spectroscopy (1H NMR, 13C NMR, APT 13C NMR and 1H 13C HMQC). The thermal stability of the PS cores was not affected by grafting PHEMA on their surfaces. A differential scanning calorimetry (DSC) thermogram of the HNPs showed two distinct transition temperatures indicating microphase separation. Chiral HNPs were prepared by inducing chirality in the achiral HNPs by complexation with R- or S-mandelic acid. The circular dichroism (CD) spectroscopy of complexes of the HNPs/R- or S-mandelic acid indicated the formation of enantiomeric chiral structures. The self-assembled structures formed from the achiral HNPs show different surface morphologies, porous and zigzag, dependent on the solvents used. Blends of polystyrene functionalized with hydroxyl groups and PHEMA show different morphology and thermal properties compared with the core-shell HNP system. The chiral HNPs self-assembled into donut like structures or toroids with sizes in the range between 200 to 5000 nm. The study suggests that chirality can be utilized to develop interesting self-assembled structures.

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.