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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between diet and colorectal cancer has been previously demonstrated and supported with strong epidemiological evidence. The role of genetic polymorphisms has, however, been less well elaborated upon. We conducted a hospital-based case-control study including 727 cases and 736 healthy controls to evaluate the associations of the polymorphic phase-I and -II biotransformations (CYP1A1, CYP1A2, GSTM1, GSTT1, GSTP1, NAT1 and NAT2) and DNA-repair enzymes (XRCC1, XRCC3 and XPD) with the risk of contracting colorectal cancer. We found that men featuring the CYP1A1*2C G/G genotype, the GSTT1 null genotype and XPD 751 with the Gln allele were associated with an elevated risk of colorectal cancer than were men who did not exhibit such genetic features. Multivariate logistic regression analysis revealed that individuals featuring more than two high-risk genotypes increased the colorectal-cancer risk 3.1-fold (OR = 3.1, 95% CI = 1.8-5.2). For women, subjects featuring the CYP1A1*2C G/G genotype and the XRCC3 Thr/Thr genotype faced a 3.1-fold greater risk (95% CI = 1.3-7.0) of colorectal cancer when compared to those featuring the CYP1A1*2C A allele and the XRCC3 Met allele. Taken together, this study suggests that polymorphisms of genes involved in biotransformation and DNA repair could modulate colorectal-cancer risk in Taiwan.
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PMID:Association between polymorphisms of biotransformation and DNA-repair genes and risk of colorectal cancer in Taiwan. 1719 Oct 90

This work focuses on the main DNA repair pathways, highlighting their role in gastrointestinal carcinogenesis and the role of mitochondrial DNA (mtDNA), mutations being described in several tumor types, including those of the gastrointestinal tract. The mismatch repair (MMR) system is inherently altered in patients with hereditary non-polyposis colorectal cancer, and plays a role in carcinogenesis in a subset of sporadic colorectal, gastric and esophageal cancers. Alterations in homologous recombination (HR) and non-homologous end-joining (NHEJ) also contribute to the development of pancreatic cancer. Gene polymorphisms of some X-ray cross-complementing (XRCCs), cofactor proteins involved in the base excision repair pathway, have been investigated in relation to gastric, colorectal and pancreatic cancer. Yet only one polymorphism, XRCC1 Arg194Trp, appears to be involved in smoking-related cancers and in early onset pancreatic cancer. Although evidence in the literature indicates that mtDNA somatic mutations play a role in gastric and colorectal carcinogenesis, no sound conclusions have yet been drawn regarding this issue in pancreatic cancer, although an mtDNA variant at 16519 is believed to worsen the outcome of pancreatic cancer patients, possibly because it is involved in altering cellular metabolism.
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PMID:DNA repair pathways and mitochondrial DNA mutations in gastrointestinal carcinogenesis. 1739 16

Mutations in one of the DNA repair genes are one of the most common reasons for cancer, and it may be assumed that the individual genetic background modulating the DNA repair capacity may affect the susceptibility to cancer. Numerous polymorphisms (mainly SNPs) have been identified for DNA repair genes, although their functional outcome and phenotypic effect is often unknown. The aim of the present review is to evaluate the studies investigating a possible influence of DNA repair polymorphisms in the risk of sporadic colorectal cancer and/or adenoma. Overall, no relevant common findings emerge among the studies, except for some statistically significant associations between polymorphisms in the XRCC1 and XPD genes, mainly for colorectal adenoma risk. Other individual associations remain to be confirmed. This inconclusive data may suggest that the modulation of cancer risk depends not only on a single gene/SNP, but also on a joint effect of multiple polymorphisms (or haplotypes) within different genes or pathways, in close interaction with environmental factors. The relevance of many low-penetrance genes in cancer susceptibility is supposed to be very subtle. Several reviewed association studies revealed weaknesses in their design. However, there has been a progressive improvement over the years in aspects such as simultaneous genotyping and combined analyses of different polymorphisms in larger numbers of patients and controls, as well as stratification of results by ethnicity, gender, and tumor localization. This gained experience shows that only carefully designed studies of a sufficient statistical power may resolve the relationships between polymorphisms and colorectal cancer risk.
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PMID:Sporadic colorectal cancer and individual susceptibility: a review of the association studies investigating the role of DNA repair genetic polymorphisms. 1741 91

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair genes: XRCC1 (Arg(194)Trp and Arg(399)Gln), PARP (Val(762)Ala, Lys(940)Arg), XPD (Asp(312)Asn, Lys(751)Gln), OGG1 (Ser(326)Cys), and MGMT (Leu(84)Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P=0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P=0.012). The effect of smoking among carriers of the Arg(194)-Gln(399) haplotype was OR=0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp(194)-Arg(399) haplotype, it was OR=1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P=0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.6-1.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk.
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PMID:DNA repair single-nucleotide polymorphisms in colorectal cancer and their role as modifiers of the effect of cigarette smoking and alcohol in the Singapore Chinese Health Study. 1800 25

We studied the role of TS (5'VNTR, 5'SNP and 3'UTR), XRCC1-399, XPD-751, ERCC1-118 and XRCC3-241 genetic polymorphisms in tailoring fluroropyrimidine/oxaliplatin treatment. For this purpose, 110 XELOX (capecitabine/oxaliplatin)- or FUOX (fluorouracil/oxaliplatin)-treated metastatic colorectal cancer patients were selected prospectively for genotyping. In the FUOX group, TS-3'UTR +6bp/+6bp (hazards ratio, HR=2.62, p=0.007) and ERCC1-118C/T or C/C (HR=1.96, p=0.050) genotypes correlated with a shorter progression-free survival (PFS). When analysed jointly, the higher the number of favourable genotypes (FG) the longer the PFS (6.8m, 9.6m and 25.8m for 0, 1 or 2 FG; p=0.005). Disease-control rate was 100% in patients with 2 FG (87% and 38.5% for 1 or 0 FG; p=0.001). In the multivariate analysis, ERCC1-118 (HR=2.12, p=0.0037) and TS-3'UTR (HR=2.68, p=0.006) were strong independent prognostic factors. According to this, patients harbouring TS-3'UTR +6bp/+6bp and ERCC1-118C/T or C/C genotypes may better receive capecitabine instead of 5FU in an oxaliplatin-based first-line treatment.
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PMID:Pharmacogenetic approach for capecitabine or 5-fluorouracil selection to be combined with oxaliplatin as first-line chemotherapy in advanced colorectal cancer. 1844 28

To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms were determined by real-time PCR on an ABI PRISM 7000, using DNA from peripheral blood. Clinical response (CR), progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. In the univariate analysis for CR, ERCC1-118 and XPD 751 polymorphisms were significant (P=0.02 and P=0.05, respectively). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance (P=0.008). In the univariate analysis for PFS, ERCC1-118 and XPD 751 were significant (P=0.003 and P=0.009, respectively). In the multivariant analysis, only the XPD 751 was significant for PFS (P=0.02). Finally, ERCC1-118 and XPD 751 polymorphisms were significant in the univariate analysis for OS (P=0.006 and P=0.015, respectively). Both genetic variables remained significant in the multivariate Cox survival analysis (P=0.022 and P=0.03). Our data support the hypothesis that enhanced DNA repair diminishes the benefit of platinum-based treatments.
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PMID:Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy. 1879 64

Although in recent years, chemotherapeutic options for colorectal carcinoma have expanded, overall response rates are still too low, with high rates of toxicity. Pharmacogenetics aim at predicting both treatment response and adverse effects in individual patients. This review describes the current knowledge of pharmacogenetic markers in the systemic treatment of colorectal cancer. UGT1A1*28 leads to reduced conjugation of SN-38, the active metabolite of irinotecan, resulting in an increased rate of adverse effects, especially neutropenia. To a lesser extent, increased 5-FU toxicity is predicted by DPYD*2A. A variable number of tandem repeats polymorphism in the thymidylate synthase enhancer region, in combination with a single nucleotide polymorphism C>G, may predict poorer response to 5-FU. Efficacy of oxaliplatin is influenced by polymorphisms in components of DNA repair systems, such as ERCC1 and XRCC1. Polymorphic changes in the endothelial growth factor receptor probably predict cetuximab efficacy. Furthermore, the antibody-depended cell-mediated cytotoxic effect of cetuximab may be reduced by polymorphisms in the immunoglobin G fragment C receptors. Bevacizumab efficacy is suspected to be influenced by polymorphisms in the VEGF gene and the hypoxia inducible factor 1alpha gene. Although the interpretation of pharmacogenetic studies is complicated, results imply a promising way of pretreatment prediction of chemotherapy efficacy and toxicity.
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PMID:Pharmacogenetics in chemotherapy of colorectal cancer. 1941 51

Colorectal cancer is the second most frequent cause of death among malignant diseases. The mortality of head and neck cancer in Hungary increased by 265 percent in the last thirty years. Both malignancies belong to the most current public health problems in Hungary. The influence of two allelic polymorphisms of GSTM1 and GSTT1, and that of p53 gene codon 72 on colon cancer was investigated. In case of head and neck cancer the effects of the Arg194Trp and Arg399Gln polymorphisms of XRCC1 gene were analyzed. Intraoperative removed tissue samples were processed and cancer free human samples were used as matched controls. The formalin fixed samples were deparaffinized and digested with proteinase K. Genotyping was performed by PCR amplification, and in case of head and neck cancer a PCR-RFLP method was applied. No significant difference was found between tumor patients and controls in the investigated polymorphisms. A significant difference in survival was found between the GSTM1 and p53 gene variants in Dukes'B stage colorectal patients. The survival difference among the XRCC1 194 alleles by head and neck patients in clinical stage III proved to be also significant. The complex analysis of this type of genetic variants may be the future way of the personal risk assessment and the real chance for personal therapy.
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PMID:[Genetic polymorphism in patients with colorectal and with head and neck cancer]. 1964 19

DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a 2-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (odds ratio, 2.2; 95% confidence interval, 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG island methylator phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (odds ratio, 1.4; 95% confidence interval, 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer.
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PMID:Assessing tumor mutations to gain insight into base excision repair sequence polymorphisms and smoking in colon cancer. 1995 86

Animal and in vitrostudies support a role for polyunsaturated fatty acids (PUFAs) in colon carcinogenesis; however, the epidemiological evidence is inconclusive. Recently, we investigated their role within the Singapore Chinese Health Study, a population-based cohort of Singapore Chinese men and women. We reported that a high intake of marine n-3 PUFAs was associated with an increased risk of colorectal cancer (CRC). Oxidation of PUFAs incorporated into cell membranes generates lipid hydroperoxides, which can be mutagenic. In this report, we investigated whether single nucleotide polymorphisms (SNPs) in DNA repair genes modified the effect of PUFAs on CRC risk using a nested case-control study within the Singapore Chinese Health Study. We genotyped 1,181 controls and 311 cases (180 colon and 131 rectal cancer) for SNPs in the XRCC1 (Arg194Trp, Arg399Gln), OGG1 (Ser326Cys), PARP (Val762Ala, Lys940Arg), and XPD (Asp312Asn, Lys751Gln) genes. We observed that the PARP Val762Ala SNP modified the association between marine n-3 PUFA and rectal cancer risk, with no evidence of interaction among colon cancer (heterogeneity test p=0.003). Our results suggest a positive association between high intake of marine n-3 PUFA and rectal cancer risk among carriers of at least one PARP codon 762 Ala allele (odds ratio=1.7, 95% confidence interval=1.1-2.7).
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PMID:Polyunsaturated fatty acids, DNA repair single nucleotide polymorphisms and colorectal cancer in the Singapore Chinese Health Study. 2055 12


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