Genotypes In Cancer Patients Research Articles

Effect of opioid-related gene polymorphisms on patients with high-dose opioid-tolerant cancer pain

Objective: To investigate the relationship between single nucleotide polymorphisms of opioid-related genes and high-dose opioid tolerance in patients with cancer pain. Methods: Twenty patients (high-dose opioid tolerance group, group A) who were hospitalized in Henan Cancer Hospital from June 2016 to June 2018 and who received high-dose opioid for pain control for more than 1 week were selected as case groups (group A). Thirty patients with stage Ⅳ tumors who were hospitalized in Henan Cancer Hospital and did not have opioid tolerance were randomly selected as the control group (group B). The peripheral blood samples of two groups were taken for DNA extraction. Gene polymorphisms were detected in 15 single nucleotide polymorphisms (SNP) (rs1799971, rs754891060, rs200637194, rs1045642, rs7438135, rs7439366, rs2242480, rs1080985, rs529520, rs581111, rs2234918, rs4680, rs6276, rs3732765, rs9859538) of the nine opioid receptor-related genes (OPRM1,ABCB1,UGT2B7,CYP3A4,CYP2D6,OPRD1, COMT,DRD2,P2RY12) which most likely to affect high-dose opioid tolerance in patients with cancer pain. Results: The distribution of different genotypes of rs7438135 locus in UGT2B7 gene were statistically significant between the two groups (χ(2)=9.68, P=0.004). The difference in the distribution of the different genotypes of the rs3732765 locus of the P2RY12 gene in the two groups were at the significant edge (χ(2)=5.57, P=0.05). A correlation analysis between the relevant SNP locus and the risk of high-dose opioid tolerance in cancer patients indicated that individuals with rs7438135 GA genotype in cancer patients were at 6.19 times more likely to have high doses of opioid tolerance than individuals with AA genotypes. Conclusions: The rs7438135 locus gene polymorphism of UGT2B7 gene may be a risk predictor for high-dose opioid tolerance. The rs3732765 site of the P2RY12 gene may be a potential predictor of high-dose opioid tolerance.

XPC intron11 C/A polymorphism as a risk factor for prostate cancer.

DNA repair genes play an important role in protection against environmental and endogenous DNA damage, and constitute the first line of defense against cancer. Xeroderma pigmentosum complementation group C (XPC) is involved in the damage recognition step during nucleotide excision repair. The relationship between XPC intron11 C/A polymorphism and cancer risk has not been widely studied. Hence, this study evaluated the relationship between the XPC intron11 C/A polymorphism and prostate cancer risk. This hospital-based cohort consisted of 152 patients with prostate cancer and 142 male controls. The XPC intron11 C/A genotype was determined using the PCR-RFLP method. Medical, occupational, and cigarette-smoking history was obtained from each participant using questionnaires. Logistic regression analysis revealed that compared to controls, the frequencies of the A/A and C/A genotypes were significantly higher than those of the C/C genotype in cancer patients (OR = 2.03, 95% confidence interval (CI) 1.03-3.98 and OR = 1.91, 95% CI 1.13-3.24, respectively). We also found that the frequency of the A/A genotype was significantly higher in cancer cases than in controls among non-smokers (OR = 7.7, 95% CI 1.38-42.88, compared to the C/C genotype). We found that the XPC intron11 C/A polymorphism was associated with an increased risk of prostate cancer. Among non-smokers, the A/A genotype was significantly more prevalent in prostate cancer patients than in controls.

Polymorphisms in RAD51 and their relation with breast cancer in Saudi females.

The present study aimed at investigating the relationship between rs1801320 (G>C), rs1801321 (G>T), and rs2619681 (C>T) RAD51 gene polymorphisms and the risk of breast cancer development in Saudi females. The genotypes were analyzed using TaqMan genotyping assay and polymerase chain reaction-restriction fragment length polymorphism. The genotype and allele frequencies were computed using chi-square or Fisher’s exact test (two-tailed) by SPSS 21 software. The results showed that rs1801321G>T GG genotype and G allele frequency were strongly (P<0.0001) related to an elevated risk of breast cancer, while the mutant T allele appeared to provide protection against breast cancer development as observed from the significantly lower (P<0.0001) frequencies of the TT and GT genotypes in cancer patients compared to the healthy controls. The variant rs1801320G>C showed no significant differences in the frequencies of the genotypes and alleles in the patients and the control groups. The CC genotype and C allele frequency of rs2619681 (C>T) variant were significantly (P=0.012) higher in cancer patients, whereas the T allele showed a protective effect against cancer development. The frequencies of the three single-nucleotide polymorphisms did not differ in cancer patients with different tumor grades and human epidermal growth factor receptor 2 status (+ or −). However, the genotype frequency of rs1801320 (135G>C) differed in the patients with estrogen receptor (ER)+ and ER−, where CC genotype showed a significantly higher prevalence in the females with ER− who were suffering from breast cancer. In addition, the frequency of C allele of rs2619681 (C>T) was also significantly higher in the breast cancer patients who were ER+ and progesterone receptor (PR)+ compared to those with ER− and PR−. In the Saudi females, rs1801320 did not show an association with risk of breast cancer. Taken together, the results suggest that RAD51 rs1801321 polymorphism may be involved in the etiology of breast cancer in the Saudi females; however, further studies are necessary to confirm this relation.

The protective role of the −1306C&gt;T functional polymorphism in matrix metalloproteinase-2 gene is associated with cervical cancer: implication of human papillomavirus infection

Cervical cancer is the major reproductive health problem among women caused by persistent infection of high-risk human papillomavirus (HR-HPV). Metalloproteinase-2 (MMP-2) is an endopeptidase highly expressed in cervical cancer; however, the genetic link between aberrant expression of MMP-2 and cervical carcinogenesis is not known. The genotypic distribution, expression pattern of MMP-2 and HPV infection, was analyzed in a total of 300 fresh surgically resected cervical tissue biopsies. The MMP-2 C1306T (rs243865) promoter polymorphism dominant model (CC v/s CT + CT + TT) revealed that the CC genotype had a 4.33-fold significant increased risk for development of cervical cancer (OR = 4.33; 95% CI = 2.36-4.02, p = 0.0001) compared to those with variant genotypes (-1306 CT + TT). The C allele was associated with 3-fold significant increased risk (OR = 2.95; 95% CI = 1.90-4.60, p = 0.0002) compared to T allele. Interestingly, a significant correlation was found between high expression of MMP-2 protein and CC genotype in cancer patients (p = 0.001) compared to normal controls (p = 0.012). Further analysis showed that the risk of cancer was extremely pronounced in HPV positive patients (OR = 9.33; 95% CI = 2.88-30.20, p = 0.0001) compared to HPV negative ones, implicating the possible interaction between -1306CC genotype and HPV infection in increasing the cancer risk (p = 0.0001). The leads from the present study suggest the protective role of gene variant -1306C>T at the promoter region of the MMP-2 against HPV-mediated cervical cancer. These findings substantiate the functional role of MMP-2 C1306T polymorphism in a significant downregulation of MMP-2 protein in women with variant genotype (CT/TT) compared to the normal wild CC genotype.

Relationship between serotonin transporter gene polymorphism and constipation in cancer patients.

IntroductionTo assess the potential association between serotonin transporter gene insertion/deletion polymorphism and the cancer-related constipation phenotype.Material and methodsA total of 120 patients diagnosed with malignant solid tumors were subjected to genotyping. For the two groups – patients with constipation and constipation-free patients with non-gastrointestinal cancer, 60 cases in each group – we collected the peripheral venous blood. We extracted genomic DNA, and used polymerase chain reaction (PCR) to analyze the serotonin transporter (5-HT) link polymorphic region (5-HTTLPR) polymorphism of the serotonin transporter gene.ResultsThe frequency of S/S genotype in cancer patients with constipation was 66.67% (40/60), and the frequency of the S allele was 79.17% (95/120); the frequency of S/S genotype in cancer patients without constipation was 48.33% (29/60), and the frequency of the S allele was 65.83% (79/120). There was a significant difference between the two groups (p < 0.05).ConclusionsThe presence of 5-HTTLPRS/S genotype and the S allele in patients with cancers probably carry an increased risk of constipation. However, its role as a cause of cancer-related constipation needs to be further investigated.

Variation of hepatitis C virus genotype distribution between geographically related patients: A retrospective multicenter study.

8052 Background: According to the nucleotide sequence of the viral genome, hepatitic C virus (HCV) shows considerable genetic heterogeneity. HCV genotypes vary geographically, with different distribution observed in various countries. In the United States, genotypes 1a and 1b are the most prevalent variants followed by genotypes 2 and 3. Despite the carcinogenetic role of HCV, the distribution of HCV genotypes in cancer patients as compared to non cancer patients has not been evaluated. Methods: A total of 636 patients with chronic HCV infection were evaluated at three academic institutions in Houston, (01/2008-12/2009). Demographic, epidemiological, and viral data were retrieved from medical records. Results: According to patients’ underlying disease, patients were classified into cancer patients (N=129), immunocompetent (N=333), and HCV-HIV coinfected (N=102). Overall, genotype 1 (G-1) was the predominant infecting type (82%); however, the distribution varied among the 3 patient groups. Only 66% of cancer patients had G-1 infection compared to 84% of immunocompetent (P = 0.00004) or 99% of HCV-HIV coinfected patients (P < .00001). More cancer patients had G-2 and G-3 infections compared to the other groups. Cancer types included 53 hematological malignancies and 76 solid tumors. Age, gender, risk factors for acquiring HCV infection, duration of infection, and place of residency were comparable between cancer and immunocompetent patients. G-1 predominated (84%) in immunocompetent as compared to patients with hepatocellular carcinoma (74%, P = .08) or lymphoma (59%, P = .001). G- 2 was more prevalent in patients with lymphoma (24%) compared to immunocompetent (8%), P = .003; yielding a three-fold increase in cancer risk among HCV-infected patients than other genotypes (OR: 3.72, 95% CI:1.38-9.76). Conclusions: This multicenter retrospective study provides initial evidence of the different distribution for HCV genotypes among geographically related infected patients and suggests a greater carcinogenic potential of some variants. Large-scale prospective studies are warranted to ascertain these findings in other geographical regions.

Polymorphism in ADH and MTHFR genes in oral squamous cell carcinoma of Indians

Alcohol consumption is known to increase the risk for several cellular disorders like oral cancer. The risk may be reinforced by polymorphism in genes like alcohol dehydrogenase. Therefore, this study is designed to asses the polymorphic status in ADH1B (formerly ADH2), ADH1C (formerly ADH3) and MTHFR genes in order to correlate the susceptibility to oral squamous cell carcinoma (OSCC). DNA from 126 OSCC samples were amplified using primers for ADH1B, ADH1C and MTHFR genes. The amplicons were analyzed for ADH1B*1, ADH1C*2 and MTHFR C677T allelic polymorphism by restriction digestion using appropriate enzymes. ADH1B*1/*1 genotype in cancer patients who were heavy drinkers showed a negligible risk association with an odds ratio of 1.62; 95% CI = 1.08-2.14. In OSCC patients, ADH1C*2/*2 genotypes showed a relatively higher risk (odds ratio 2.65; 95% CI = 1.78-3.53) in heavy drinkers and a less significant risk (1.6; 95% CI = 1.15-2.03) in moderate drinkers and negligible risk in light drinkers (1.23; 95% CI = 0.77-1.63). In contrast, MTHFR 677TT genotype showed a high risk association for OSCC in heavy drinkers (odds ratio 3.0; 95% CI = 2.02-4.0). Interestingly, the combination of ADH1B*1/*1/ MTHFR 677TT genotypes in alcoholic cancer patients showed a high risk (odds ratio 4.16; 95% CI = 2.78-5.53). A similar risk (odds ratio 4.16; 95% CI = 1.18-5.53) was shown by ADH1B*1/*2/*2/*2MTHFR 677TT genotype combination. The ADH1C*2/*2 /MTHFR 677TT genotype combination showed the maximum risk (odds ratio 20; 95% CI = 13.45-26.64) in the heavy drinker group. This combination showed a high risk in moderate drinkers (odds ratio 5.88; 95% CI = 4.24-7.50) and relatively lower risk in light drinkers (odds ratio 2.77; 95% CI = 1.74-3.68). The ADH1C*2/*2/MTHFR 677TT genotype combination appears to be more susceptible for OSCC, since it showed a 20-fold increase in risk in heavy drinkers and a 5.9- and 2.8-fold increase in risk respectively in moderate drinkers and light drinkers. This study suggests the association of ADH1C*2/*2/MTHFR 677TT genotype combination as a risk factor for OSCC in alcoholics.

Association of ECRG2 TCA short tandem repeat polymorphism with the risk of oesophageal cancer in a North Indian population

Oesophageal cancer-related gene (ECRG2) is a tumour suppressor gene and it has been suggested that a triplet TCA short tandem repeat (STR) in the noncoding region of exon 4 plays a role in genetic susceptibility to oesophageal cancer. In the present study, ECRG2 STR polymorphism was studied in 134 patients with oesophageal cancer and 194 controls, using PCR and polyacrylamide gel electrophoresis. The results showed a higher frequency of the ECRG2 TCA (3)/TCA (4) genotype in cancer patients than in controls (odds ratio 2.6, 95% CI 1.0-6.4, p = 0.03). The association of the ECRG2 TCA (3)/TCA (4) genotype with clinical characteristics showed an increased risk for squamous cell histology (2.8, 95% CI 1.1-7.1, p = 0.03), while no association with tumor location or lymph node involvement was observed. Interaction of tobacco, alcohol and occupational exposure with the ECRG2 genotypes did not show modulation of risk. In conclusion, the ECRG2 TCA (3)/TCA (4) genotype is associated with the risk of oesophageal carcinoma in a North Indian population.

Role of MTHFR polymorphisms and folate levels in different phenotypes of sporadic colorectal cancers

By altering both DNA methylation and nucleotide synthesis, folate metabolism is thought to contribute to colorectal carcinogenesis. We examined the role of folate metabolism in three different phenotypes of sporadic colorectal cancers (CRCs), phenotypes that were classified by the status of microsatellite instability (MSI) and chromosomal instability (CIN): MSI-H, microsatellite stability (MSS)/aneuploidy, and MSS/diploid. A total of 195 sporadic colorectal tumors and another 195 age- and gender-matched healthy volunteers in Taipei-Veteran General Hospital and Taipei City Hospital were collected. We analyzed for MTHFR (methylenetetrahydrofolate reductase) polymorphisms (C677T, A1297C), folate, and vitamin B(12) levels. We determined MSI status and DNA ploidy with fluorescent polymerase chain reaction and flow cytometry. Relations between clinicopathological variables and molecular variables were analyzed by chi (2) tests (with Yates' correction) for categorical variables and Student's t test for numerical variables. Folate levels (5.02+/-4.43 ng/ml) were significantly lower in cancer patients than in controls (7.22+/-4.46 ng/ml). Vitamin B(12) level was similar between cancer patients and controls. The frequency of the TT genotype of MTHFR C627T (12.3%) was slightly higher than controls (8.2%), but it did not reach statistical significance (p=0.174). Within the low-folate group (<5 ng/ml), the frequency of the TT genotype in cancer patients (14.4%) was significantly higher than in controls (4.6%). Sixteen patients who had MSI-H CRC (8.2%) had a significantly higher frequency of TT MTHFR (37.5%) and lower folate levels (3.56+/-2.41 ng/ml) than patients with MSS tumors (10.1%, 5.14+/-3.72 ng/ml). Patients with MSS/aneuploid tumors had significantly lower folate levels (4.50+/-3.06 ng/ml) than those with MSS/diploid tumors (6.69+/-4.73 ng/ml). Folate deficiency and the MTHFR genetic polymorphism play an important role in colorectal carcinogenesis, including MSI and CI. Folate metabolism plays an important role in colorectal carcinogenesis. We demonstrate that patients with MSI-H tumors had higher frequency of TT MTHFR C627T (37.5%), and patients with MSS/aneuploid tumor had lower folate level (4.50+/-3.06 ng/ml).

Interleukin-6 polymorphisms and the risk of cervical cancer

Recent data implicate that cytokine gene polymorphisms are important in pathogenesis of various neoplastic and nonneoplastic human diseases, and it was recently suggested that polymorphisms in interleukin (IL)-6 might increase the risk of gynecological malignancies, including cervical carcinomas. The aim of this case-control study is to compare the IL-6 polymorphisms in cervical cancer patients and healthy controls and to assess whether any of these polymorphisms would increase the risk of developing cervical cancer. The material in this case-control study consists of 56 patients with cervical carcinoma and 253 population-based control subjects, all ethnic Brazilian women. Control subjects were cancer-free women, following a negative cervical cytology and colposcopy. IL-6 genotyping was performed using a polymerase chain reaction-based restriction fragment length polymorphism. Distribution of the GG, GC, and CC genotypes in cases and controls was significantly different (P= 0.033). Compared with the GG genotype as reference, the adjusted odds ratio for the combined GC and CC genotypes in cancer patients was 1.90 (95% confidence interval, 1.1-3.4). These data suggest that women carrying at least one C genotype in their IL-6 promoter region (-174G-->C) are at higher risk of developing cervical cancer.

Interleukin-6 polymorphisms and the risk of cervical cancer

Recent data implicate that cytokine gene polymorphisms are important in pathogenesis of various neoplastic and nonneoplastic human diseases, and it was recently suggested that polymorphisms in interleukin (IL)-6 might increase the risk of gynecological malignancies, including cervical carcinomas. The aim of this case–control study is to compare the IL-6 polymorphisms in cervical cancer patients and healthy controls and to assess whether any of these polymorphisms would increase the risk of developing cervical cancer. The material in this case–control study consists of 56 patients with cervical carcinoma and 253 population-based control subjects, all ethnic Brazilian women. Control subjects were cancer-free women, following a negative cervical cytology and colposcopy. IL-6 genotyping was performed using a polymerase chain reaction–based restriction fragment length polymorphism. Distribution of the GG, GC, and CC genotypes in cases and controls was significantly different (P = 0.033). Compared with the GG genotype as reference, the adjusted odds ratio for the combined GC and CC genotypes in cancer patients was 1.90 (95% confidence interval, 1.1–3.4). These data suggest that women carrying at least one C genotype in their IL-6 promoter region (−174G→C) are at higher risk of developing cervical cancer.