NME1 and DCC variants are associated with susceptibility and tumor characteristics in Mexican patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) ranks third in cancer incidence globally and is the second leading cause of cancer-related mortality. The nucleoside diphosphate kinase 1 (NME1) and netrin 1 receptor (DCC) genes have been associated with resistance against tumorigenesis and tumor metastasis. This study investigates the potential association between NME1 (rs34214448 G > T and rs2302254 C > T) and DCC (rs2229080 G > C and rs714 A > G) variants and susceptibility to colorectal cancer development. METHODS: Samples from 232 colorectal cancer patients and 232 healthy blood donors underwent analysis. Variants were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Associations were assessed using odds ratios (OR), and the p values were adjusted with Bonferroni test. RESULTS: Individuals carrying the G/T and T/T genotypes for the NME1 rs34214448 variant exhibited a higher susceptibility for develop colorectal cancer (OR = 2.68, 95% CI: 1.76-4.09, P = 0.001 and OR = 2.47, 95% CI: 1.37-4.47, P = 0.001, respectively). These genotypes showed significant associations in patients over 50 years (OR = 2.87, 95% CI: 1.81-4.54, P = 0.001 and OR = 2.99, 95% CI: 1.54-5.79, P = 0.001 respectively) and with early Tumor-Nodule-Metastasis (TNM) stage (P = 0.001), and tumor location in the rectum (P = 0.001). Furthermore, the DCC rs2229080 variant revealed that carriers of the G/C genotype had an increased risk for develop colorectal cancer (OR = 2.00, 95% CI: 1.28-3.11, P = 0.002) and were associated with age over 50 years, sex, and advanced TNM stages (P = 0.001). CONCLUSIONS: These findings suggest that the NME1 rs34214448 and DCC rs2229080 variants play a significant role in colorectal cancer development.

Expression of ornithine decarboxylase in peripheral blood mononuclear cells from patients with pancreatic adenocarcinoma: A preliminary report.

Ductal adenocarcinoma represents 90-95% of pancreatic cancer (PC) cases and it is an aggressive disease with asymptomatic evolution at early stages, non-specific symptoms and a typical late diagnosis with a 5-year survival rate estimated to be 8%. A window of opportunity lies in early diagnosis as there are currently no reliable biomarkers. CA 19-9 is one of the most frequently used biomarkers of PC, with 75 and 77.6% sensitivity (Se) and specificity (Sp), respectively, and the carcinoembryonic antigen (CEA) shows 39.5 and 81.3% of Se and Sp, respectively. A case-control study was conducted including adult patients with a histological diagnosis of PC (n=11) without previous treatment at the Oncology Service of the CMNO-IMSS between 2019 and 2020, and a control group of adult volunteers (n=11) who were clinically healthy or with controlled disease including hypertension, hypothyroidism and diabetes. Clinical, laboratory and sociodemographic data as well as blood, urine and saliva samples were collected following patient consent. Polyamines were quantified using high-performance liquid chromatography with fluorescence detection, CA 19-9 and CEA were evaluated using enzyme-linked immunosorbent assay, and the protein expression of ornithine decarboxylase (ODC) was evaluated using western blotting. Polyamine metabolism and modulation by means of ODC were increased in the serum and saliva of patients with PC, and the expression of ODC alone was increased in peripheral blood mononuclear cells (PBMCs). The present study focused on the evaluation of putrescine, spermine, spermidine and ODC in PBMCs associated with CA 19-9 and CEA as an auxiliary tool in PC diagnosis.

Functional Variants in MicroRNAs (rs895819, rs11614913 and rs2910164) Are Associated with Susceptibility and Clinicopathological Features in Mexican Patients with Colorectal Cancer.

BACKGROUND: miRNAs are non-coding RNAs participating actively in the post-translational regulation of oncogenes, tumor suppressor, and DNA repair genes implicated in colorectal cancer (CRC). This study aims to examine the association of the variants miR-27a (rs895819 A>G), miR-196a2 (rs11614913 T>G) and miR-146a (rs2910164 C>G) in Mexican CRC patients. METHODS: DNA samples from 183 patients and 186 healthy Mexican subjects were analyzed. Variants were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) and adjusted by the Bonferroni test. RESULTS: Patients carrying the G/G genotype of the rs895819 variant in the miR-27a gene showed an increased risk of CRC (19% vs 12%, P=0.013). A similar tendency was noticed for patients younger than 50 years carrying A/G (48% vs 41%, P=0.014). The A/G genotype in TNM stages I+II (55.7% vs 40.8%, P=0.011) and tumor location in the colon (69.5 vs 40.8%, P=0.001) were also increased. For the variant rs11614913 of the miR-196a2 gene, carriers of the C/C genotype showed an increased risk of CRC (32% vs 22%, P=0.009). This genotype was more frequent in TNM stage III+IV (36.8% vs 22.5%, P=0.007) and the tumor had a more recurrent location in the rectum (31.6% vs 22.5%, P=0.013). The rs2910164 variant of the miR-146a gene was found to have no significant risk associations. CONCLUSION: Our results reveal that the rs895819 variant in miR-27a and rs11614913 in miR-196a2 have a substantial impact on the development of CRC.

Circulating cell-free-DNA concentration is a good biomarker for diagnosis of colorectal cancer in Mexican patients.

Colorectal cancer (CRC) is the third most common cancer in the world. Overall survival is related to clinical stage: more advanced stages show lower survival rates; therefore, they need to be monitored regularly with new, less invasive and more specific biomarkers. The concentration and integrity index of circulating cell-free DNA (ccfDNA) have been proposed as potential diagnostic and prognostic biomarkers for CRC, however, inconsistent results are still observed in different reports. Here we analyze these potential CRC biomarkers in a Mexican population. In this study, 124 patients with sporadic CRC and 37 healthy individuals were examined as a reference group. The ccfDNA was isolated from plasma samples of all included subjects. The ccfDNA concentration was determined by fluorometry and the integrity index (ALU247/ALU115 ratio) by quantitative PCR amplification (qPCR) of ALU sequences. The results show that ccfDNA concentration was higher in CRC patients than in the reference group (P=0.001). The integrity index showed no significant differences between these groups (P=0.258), except for histological type (P=0.012). A higher ccfDNA concentration was also associated with patients younger than 50 years (P=0.030). The ccfDNA concentration showed significant discriminatory power (AUC: 0.854, C.I.: 0.78-0.92, P=0.001) between patients and the reference group and between tumor-node-metastasis (TNM) stages. In conclusion, ccfDNA concentration proves to be a good diagnostic biomarker for CRC patients, whereas the integrity index did not show diagnostic utility.

RECK Variants are Associated with Clinicopathological Features and Decreased Susceptibility in Mexican Patients with Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death worldwide. Down-regulation of the cysteine-rich reversion-inducing protein with Kazal motifs (RECK) has been confirmed in numerous human cancers and is clinically associated with metastasis. This study aims to explore, for the first time, the possible association of the RECK variants rs11788747 and rs10972727 with CRC susceptibility and clinicopathological features. DNA from 130 CRC patients and 130 healthy blood donors was analyzed. Identification of genetic variants was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated using the odds ratio (OR) test and P values were adjusted using the Bonferroni test. Individuals carrying the G/G genotype for the rs11788747 variant showed a lower risk of colorectal cancer (OR 0.33; 95% CI 0.16-0.70; P = 0.006). Patients older than 50 years who carry the G/G genotype have a lower risk of CRC (OR 0.26; 95% CI 0.09-0.73; P = 0.019) and of developing advanced tumor-nodule-metastasis (TNM) stages (OR 0.23; 95% CI 0.09-0.54; P = 0.001). Individuals carrying the A/A genotype of the rs10972727 variant also showed decreased risk of CRC (OR 0.38; 95% CI 0.19-0.77; P = 0.011), and were associated with age (over 50 years), sex, advanced TNM stages, and tumor location in the colon. Our results suggest that the RECK variants studied here (rs11788747 and rs10972727) are associated with decreased CRC risk, TNM stages and tumor location.

MKK4 variants rs3826392 and rs3809728 are associated with susceptibility and clinicopathological features in colorectal cancer patients.

OBJECTIVES: The mitogen-activated protein kinase kinase 4 (MKK4) plays a key role in several processes like inflammation, apoptosis, and tumorigenesis. Several authors have proposed that genetic variations in these genes may alter their expression with subsequent cancer risk. This study aimed to examine the possible association of MKK4 rs3826392 and rs3809728 variants in Mexican patients with colorectal cancer (CRC). These variants were also compared with clinical features as sex, age, TNM stage, and tumor location. MATERIALS AND METHODS: The study included genomic DNA from 218 control subjects and 250 patients. Genotyping of the MKK4 variants was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) procedure. RESULTS: Individuals with A/T and T/T genotypes for the rs3809728 (-1044 A>T) variant showed a significantly increased risk for CRC (P=0.012 and 0.007, respectively); while individuals with the G/G genotype for the rs3826392 (-1304 T>G) variant showed a decreased risk for CRC (P=0.012). Genotypes of the MKK4 rs3809728 variant were also significantly related to colon localization and advanced TNM stage in CRC patients. T-T haplotype (rs3826392 and rs3809728) of the MKK4 gene was associated with risk in patients with CRC. CONCLUSION: The rs3826392 variant in the MKK4 gene could be a cancer protective factor, while the rs3809728 variant could be a risk factor. These variants play a significant role in CRC risk.

CD44 Genotypes Are Associated with Susceptibility and Tumor Characteristics in Colorectal Cancer Patients.

Colorectal cancer is the third cause of cancer and the second leading cause of death worldwide. The CD44 gene plays a key role in malignant processes, including growth, survival, epithelial to mesenchymal transition and metastasis. It is also known that some variants as rs187116 (c.67+4883G>A) and rs7116432 (c.2024+779A>G) can modulate the function of the CD44 gene and malignant transformation in several neoplasms. This study aims to explore, for the first time, the association of the CD44 rs187116 and rs7116432 variants in patients with colorectal cancer. Genomic DNA from 250 patients and 250 healthy blood donors were analyzed. The identification of variants was made by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) test and multivariate analysis. Individuals carrying the G/A and A/A genotypes for the rs187116 polymorphism showed an increased risk for colorectal cancer (OR = 3.11, 95% CI: 1.87-5.16, P = 0.001 and OR = 3.59, 95% CI: 2.06-6.25, P = 0.001, respectively). After adjusting for age and gender, these same genotypes and the G/G genotype of the rs7116432 polymorphism were associated with TNM stage and tumor location in the colon. Moreover, the A-G (rs187116 and rs7116432) haplotype was associated with increased risk; while, the haplotype G-A (rs187116 and rs7116432) was related with decreased risk. In conclusion, our results suggest that the here analyzed CD44 variants are involved with risk, TNM stage and tumor location in colorectal cancer.

GSK3ß Polymorphisms Are Associated with Tumor Site and TNM Stage in Colorectal Cancer.

BACKGROUND: Mutations and polymorphisms of the GSK3ß gene have been associated with several diseases including Alzheimer disease, diabetes and cancer; however, to date, no variants of this gene have been associated with colorectal cancer (CRC). This study aims to explore, for the first time, the association of the GSK3ß rs334558 and rs6438552 polymorphisms with CRC. METHODS: Genomic DNA from 330 CRC patients and healthy blood donors were analyzed. Identification of polymorphisms was made by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) test. RESULTS: Patients carrying the C/T genotype for the rs334558 (T>C) polymorphism showed an increased risk for CRC (OR = 1.71, 95% CI: 1.05-2.79, P = 0.039); this association was also observed for TNM stage and tumor location. For the rs6438552 (T>C) polymorphism, the OR analysis showed that patients carrying C/T and C/C genotypes have a decreased risk for CRC (OR = 0.44, 95% CI: 0.27-0.70, P = 0.001 and OR = 0.24, 95% CI: 0.10-0.64, P = 0.001, respectively); this decreased risk was also evident in the stratified analysis by TNM stage and tumor location. Haplotype analysis of these 2 loci of GSK3ß (rs334558 and rs6438552) showed differential distribution. The T-T and C-C haplotype was associated with a decreased risk of CRC, while the T-C haplotype was associated with an increased risk of CRC. CONCLUSION: Our results denote that GSK3ß gene polymorphisms play a significant role in promoting or preventing CRC. Additionally, variations in this gene are associated with the tumor site and the tumor-node-metastasis (TNM) stage in these patients.

Genetic Polymorphisms in APC, DVL2, and AXIN1 Are Associated with Susceptibility, Advanced TNM Stage or Tumor Location in Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death worldwide. The named "destruction complex" has a critical function in the Wnt/ß-catenin pathway regulating the level of ß-catenin in the cytoplasm and nucleus. Alterations in this complex lead to the cellular accumulation of ß-catenin, which participates in the development and progression of CRC. This study aims to determine the contribution of polymorphisms in the genes of the ß-catenin destruction complex to develop CRC, specifically adenomatous polyposis coli (APC) (rs11954856 G>T and rs459552 A>T), axis inhibition protein 1 (AXIN1) (rs9921222 C>T and rs1805105 C>T), AXIN2 (rs7224837 A>G), and dishevelled 2 (DVL2) (2074222 G>A and rs222836 C>T). Genomic DNA from 180 sporadic colorectal cancer patients and 150 healthy blood donors were analyzed. The identification of polymorphisms was made by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) test. Increased susceptibility to CRC was associated with the polymorphic variants rs11954856 (APC), rs222836 (DVL2), and rs9921222 (AXIN1). Decreased susceptibility was associated with the polymorphisms rs459552 (APC) and 2074222 (DVL2). Association was also observed with advanced Tumor-Node-Metastasis (TNM) stages and tumor location. The haplotypes G-T in APC (rs11954856-rs459552) and A-C in DVL2 (rs2074222-rs222836) were associated with decreased risk of CRC, while the G-T haplotype in the DVL2 gene was associated with increased CRC risk. In conclusion, our results suggest that variants in the destruction complex genes may be involved in the promotion or prevention of colorectal cancer.

Association of rs712 polymorphism in a let-7 microRNA-binding site of KRAS gene with colorectal cancer in a Mexican population.

OBJECTIVES: The rs712 polymorphism in a let-7 microRNA-binding site at KRAS gene has been associated with cancer. To examine its association with rs712 polymorphism, we analyzed Mexican individuals with colorectal cancer (CRC) and healthy subjects. MATERIALS AND METHODS: Genotyping of the rs712 polymorphism was performed by polymerase chain reaction in 281 controls and 336 CRC patients. RESULTS: The observed frequencies of rs712 polymorphism indicated an associated protective factor for CRC (P=0.032). An association between genotype and the disease was evident in: colon localization (allele T, odds ratio (OR) 3.82, 95% confidence Intervals (CI) 2.77-5.28, P=0.0001), node metastasis (genotype TT, OR 2.49, 95% CI 1.45-4.28, P=0.0009), poor differentiation (genotype GT, OR 2.35, 95% CI 1.35-4.1, P=0.0033), and poor chemotherapy response (genotype GT, OR 2.6, 95% CI 1.7-4.24, P=0.0001). CONCLUSION: Comparison of the data from patients with control group showed that polymorphism of rs712 in KRAS gene was protective factor, which was associated with susceptibility for CRC. However, the genotypes TT and GT of rs712 polymorphism in KRAS could contribute significantly to colon localization, node metastasis, poor differentiation and poor chemotherapy response in CRC patients in this sample population.