Variants of SMAD1 gene increase the risk of colorectal cancer in the Bangladeshi population.

Colorectal cancer is the fourth most common type of malignancy worldwide that may develop due to the accumulation of several genetic variations. Different single nucleotide polymorphisms of SMAD1 gene are assumed to be linked with increased colorectal cancer risk. The current case-control study was conducted to verify the association of genetic polymorphisms of SMAD1 (rs11100883 and rs7661162) with colorectal cancer in the Bangladeshi population. This study was performed on 275 colorectal cancer patients and 300 healthy volunteers using polymerase chain reaction-restriction fragment length polymorphism method. The odds ratios were adjusted for age and sex with logistic regression analysis. In case of SMAD1 rs11100883 polymorphism, GA heterozygous genotype, GA + AA (dominant model), and minor allele "A" were significantly associated with colorectal cancer (adjusted odds ratio = 1.55, 95% confidence interval = 1.09-2.20, p = 0.014; adjusted odds ratio = 1.59, 95% confidence interval = 1.13-2.23, p = 0.008; and odds ratio = 1.35, 95% confidence interval = 1.06-1.73, p = 0.015, respectively) and the significance exists after the Bonferroni correction. Again, single nucleotide polymorphism rs7661162 showed significant association with an elevated colorectal cancer risk for AG heterozygous genotype, AG + GG (dominant model), AG versus AA + GG (overdominant model), and minor allele "G" (adjusted odds ratio = 1.78, 95% confidence interval = 1.24-2.56, p = 0.002; adjusted odds ratio = 1.68, 95% confidence interval = 1.18-2.39, p = 0.004; adjusted odds ratio = 1.76, 95% confidence interval = 1.23-2.53, p = 0.002; and odds ratio = 1.47, 95% confidence interval = 1.08-2.00, p = 0.014, respectively) and significance withstands after the Bonferroni correction. No significant age and gender differences between cases and controls were observed. In silico, gene expression analysis showed that the SMAD1 mRNA level was downregulated in the colon and rectal cancer tissues compared to healthy tissues. In conclusion, our findings indicate that SMAD1 rs11100883 and rs7661162 polymorphisms are responsible for increasing the susceptibility of colorectal cancer development in the Bangladeshi population.

Breast cancer risk in relation to TP53 codon 72 and CDH1 gene polymorphisms in the Bangladeshi women.

Pharmacogenomic studies play a significant role in understanding the risk of breast cancer where genetic abnormalities are implicated as the etiology of cancer. Various polymorphisms of tumor suppressor gene TP53 and E-cadherin (CDH1) have been found to be associated with increased breast cancer risk worldwide. This study aimed to analyze the contribution of TP53 and CDH1 gene anomalies in breast cancer risk in the Bangladeshi breast cancer patients. For risk determination, 310 patients with breast cancer and 250 controls from Bangladeshi women were recruited who are matched up with age and use of contraceptives with patients. Genetic polymorphisms were detected by using polymerase chain reaction restriction fragment length polymorphism. A significant association was found between TP53Arg72Pro (rs1042522) and CDH1 -160 C/A (rs16260) polymorphisms and breast cancer risk. In case of P53rs1042522 polymorphism, Arg/Pro (P = 0.0053, odds ratio (OR) = 1.69) and Pro/Pro (P = 0.018, OR = 1.83) genotypes were associated with increased risk of breast cancer in comparison to the Arg/Arg genotype. Arg/Pro + Pro/Pro genotype and Pro allele also increased the risk of breast cancer (P = 0.002, OR = 1.73; P = 0.004, OR = 1.43, respectively). In case of CDH1rs16260 polymorphism, C/A heterozygote and combined C/A + A/A genotypes were found to be strongly associated (P = 0.005, OR = 1.67; P = 0.0037, OR = 1.68) with increased risk of breast cancer. The variant A allele also increased the breast cancer risk (P = 0.0058, OR = 1.52). The present study demonstrates that P53Arg72Pro and CDH1rs16260 polymorphisms are associated with elevated breast cancer risk in the Bangladeshi population.

Metabolomic signatures of carfilzomib-related cardiotoxicity in patients with multiple myeloma.

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies.

A frequent CYP2D6 variant promotes skipping of exon 3 and reduces CYP2D6 protein expression in human liver samples.

CYP2D6 is one of the most polymorphic drug-metabolizing enzymes in the liver. While genetic CYP2D6 variants serve as clinical biomarkers to predict CYP2D6 activity, large inter-person variability in CYP2D6 expression remains unaccounted for. Previous results suggest that there is variable expression of a CYP2D6 splice isoform with an in-frame deletion of exon 3 (CYP2D6ΔE3) encoding a protein lacking numerous active site residues. Here, using fragment analysis and RT-qPCR, we revealed that rs1058164 G (MAF = 27%-43%) is associated with increased formation of CYP2D6∆E3 in human liver samples (1.4-2.5-fold) and transfected cells. Furthermore, western blots showed that rs1058164 G was associated with a 50% decrease in full-length hepatic CYP2D6 protein expression. In addition, by studying a larger liver cohort, we confirmed our previous results that rs16947 (CYP2D6*2) reduces full-length CYP2D6 mRNA by increasing the production of an unstable splice isoform lacking exon 6 (CYP2D6ΔE6) and that the impact of CYP2D6ΔE6 is offset in carriers of the downstream enhancer variant rs5758550. The three frequent SNPs (rs1058164, rs16947, and rs5758550) form various 3-SNP-haplotypes, each with distinct CYP2D6 expression characteristics. Using an expression score (ES) system, we tested the impact of the 3-SNP-haplotype on improving the standard model to predict hepatic CYP2D6 protein expression based on genotype. A model that incorporates the 3-SNP-haplotype provided the best fit for CYP2D6 expression and also accounted for more variability in CYP2D6 protein levels (59%) than a model based on the accepted standard (36%) or one that only adds rs16947 and rs5758550 (42%). Clinical studies are needed to determine whether including the 3-SNP-haplotype alongside current standard CYP2D6 models improves the predictive value of CYP2D6 panels.

Association of RAD51 and XRCC2 Gene Polymorphisms with Cervical Cancer Risk in the Bangladeshi Women.

OBJECTIVE: Alterations in common DNA repair genes (RAD51 and XRCC2) may lead to cervical cancer (CC) development. In the present study, we analyzed the association between RAD51 rs1801320 and XRCC2 rs3218536 polymorphisms and CC. METHODS: Variants were selected based on their associations with some cancers in several ethnicities and the risk allele frequency (>0.05) in different populations. The variants were detected using the PCR-RFLP method. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were determined by logistic regression models. RESULT: Significantly increased risk (p <0.05) were detected for both SNPs with CC (rs1801320- GC vs. GG: aOR=2.21, 95% CI=1.43-3.42; CC vs. GG: aOR=4.48, 95% CI=1.76-11.42; dominant model: aOR=2.49, 95% CI=1.65-3.76; recessive model: aOR=3.52, 95% CI=1.40-8.88; allele model: OR=2.30, 95% CI=1.63-3.26, and rs3218536- GA vs. GG: aOR=2.77, 95% CI=1.85-4.17; AA vs. GG: aOR=5.86, 95% CI=2.08-16.50; dominant model: aOR=2.97, 95% CI=1.99-4.42; recessive model: aOR=3.56, 95% CI=1.30-9.73; and allele model: aOR=2.21, 95% CI=1.62-3.00). Besides, older patients (>60 years) with rs1801320 showed significantly reduced risk (OR=0.53, 95% CI=0.29-0.96, p=0.04) but with rs3218536 depicted significantly increased risk (aOR=2.44, 95% CI=1.20-4.96, p=0.01) for CC. CONCLUSION: This study indicates an association of rs1801320 and rs3218536 polymorphisms with CC and confirms that patients older than 60 years are more likely to develop CC for rs3218536 polymorphism.

The ECCR1 rs11615, ERCC4 rs2276466, XPC rs2228000 and XPC rs2228001 polymorphisms increase the cervical cancer risk and aggressiveness in the Bangladeshi population.

BACKGROUND: Multiple studies around the world revealed that genetic polymorphism in different genes of the DNA repair system might affect the DNA repair capabilities and accelerate the chances of cervical cancer (CC) development. Therefore, we aimed to evaluate the association of DNA repair gene- ECCR1 rs11615, ERCC4 rs2276466, XPC rs2228000 and rs2228001 polymorphisms and CC susceptibility in the Bangladeshi population. METHODS: A case-control genetic association study was conducted among 210 patients with diagnostically confirmed CC and 200 healthy volunteers. The p-value and OR (odds ratios) with 95% CI (confidence interval) were evaluated to get the level of association. RESULTS: After the individual analysis of all SNPs, we noticed that ECCR1 rs11615 possessed a significantly lower risk, whereas ERCC4 rs2276466 possessed a significantly elevated risk of CC in all genetic models (p < 0.05). XPC rs2228000 showed a significantly lower risk of CC in TC, TC + CC genotypes and allele model (OR = 0.61, p = 0.025; OR = 0.61, p = 0.019 and OR = 0.67, p = 0.027, respectively), whereas XPC rs2228001 possessed a significantly elevated risk of CC in CA, CA + AA genotypes and allele model (OR = 1.67, p = 0.012; OR = 1.69, p = 0.009 and OR = 1.42, p = 0.022). Besides, ERCC4 rs2276466 (Grade III vs. I + II: OR = 4.01, p = 0.003) and XPC rs2228001 (Grade III vs. I + II: OR = 3.38, p = 0.003) were connected with high tumor aggressiveness and ERCC4 rs2276466 was also showed a lower risk of CC development in the younger population (<45 years). CONCLUSION: The findings supported that rs2276466 and rs2228001 polymorphisms increase CC development and aggressiveness, whereas rs11615 and rs2228000 lower the CC risk in the studied population.

Genetic Variations of RAD51 and XRCC2 Genes Increase the Risk of Colorectal Cancer in Bangladeshi Population.

OBJECTIVES: In case of Bangladeshi population, no report is observed till now showing the genetic variations of RAD51 (rs1801320) and XRCC2 (rs3218536) genes polymorphism having association with colorectal cancer risk. For this reason the aim of this study is to ascertain their interrelation with colorectal cancer occurrence in Bangladeshi population. MATERIALS AND METHODS: A case control study was conducted where 200 colorectal cancer patients and 200 healthy volunteers were figured for this research using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). RESULTS: Here, in case of RAD51 (rs1801320), G/C heterozygous genotype was found significant (p=0.037; OR=1.64; 95% CI=1.03 to 2.6). On the other hand, G/G genotype was not found statistically significant (p=0.423; OR=1.61; 95% CI=0.49 to 5.22) and significance was observed for GC+GG (p=0.030; OR=1.63; 95% CI=1.05 to 2.55). In case of XRCC2 (rs3218536), C/T heterozygous genotype was remarked statistically significant (p=0.033; OR=1.60; 95% CI=1.04 to 2.46). The T/T genotype was not recorded statistically significant (p=0.237; OR=1.65; 95% CI=0.72 to 3.76) but significance found for CT+TT (p=0.027; OR=1.61; 95% CI=1.05 to 2.45). Moreover, it is found that the risk factor of developing CRC is observed in G/C, C/T heterozygote and GC+GG, CT+TT (heterozygote+ mutant) in RAD51 (rs1801320) and XRCC2 (rs3218536) respectively although no significance is observed in case of G/G and T/T mutant. CONCLUSIONS: So, the association of RAD51 (rs1801320) and XRCC2 (rs3218536) genes polymorphism with colorectal cancer risk is observed in Bangladeshi population.

DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer.

BACKGROUND: Significant inter-individual variation in the sensitivity to 5-fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5-fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients. METHODS: Colorectal cancer patients (n = 161) receiving 5-FU-based chemotherapy were prospectively enrolled. DPYD and MTHFR polymorphisms were assessed in peripheral leukocytes. Multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity and efficacy. RESULTS: Multivariate analyses showed that DPYD*2A polymorphism was a predictive factor (P = 0.023) for grade 3 and grade 4 5-fluorouracil-related toxicities. Although MTHFR C677T polymorphism might act as forecasters for grade 3 or grade 4 neutropenia, diarrhea, and mucositis, this polymorphism was found to increase significantly (P = 0.006) the response of 5-FU. CONCLUSION: DPYD*2A and MTHFR C677T polymorphisms could explain 5-FU toxicity or clinical outcome in Bangladeshi colorectal patients.

Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population.

Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160C