GSTM1 and GSTT1 polymorphisms as modifiers of age at diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) in a homogeneous cohort of individuals carrying a single predisposing mutation

Felix, Rebecca; Bodmer, W F; Fearnhead, Nicola; Merwe, Lize van der; Goldberg, P. A.; Ramesar, Raj

doi:10.1016/j.mrfmmm.2006.09.004

Cited by 33 publications

(32 citation statements)

References 23 publications

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“…It could be the case that common and rare variants in the same gene or in different genes along the same pathway interact and modify each other's effects to produce the phenotype. 19,36 A search for possible combined effects of the common variant rs9344 and one or more of the rare or low-frequency variants is almost certainly likely to be confounded by weak LD between rs9344 and these variants, and so would require a much larger sample size. This is indicated by the very significant, but low level of LD between rs9344 and the CCND1-10/13/20 haplotype.…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients

et al. 2010

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We examined the influence that rare variants and low-frequency polymorphisms in the cancer candidate gene CCND1 have on the development of multiple intestinal adenomas and the early onset of colorectal cancer. Individuals with o100 multiple polyps and patients with colorectal cancer diagnosed before 50 years of age were recruited in UK, and screened for sequence changes in the coding and regulatory regions of CCND1. A set of about 800 UK control individuals was genotyped for the variants discovered in the cases. Variants in the promoter, intron-exon boundaries and untranslated regions of the CCND1 gene had higher frequencies in cases than in controls. Five of these variants were typed in a set of French multiple adenoma and early-onset patients, who also showed higher allele frequencies than UK controls. When pooled together, variants with frequencies lower than 1% conferred an increased risk of disease that was significant in the multiple adenoma group (odds ratio (OR) 2.2; 95% confidence interval, 1.1-4.4; P¼0.03). Most variants had a putative functional effect when assessed in silico. We conclude that rare variants of CCND1 are risk factors for colorectal cancer, with considerably larger effects than common polymorphisms, and as such should be systematically evaluated in susceptibility studies.

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Section: Discussionmentioning

confidence: 99%

Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients

et al. 2010

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“…In 129 subjects of South African origin and harbouring the same MLH1 missense mutation, males harbouring the null genotype for the GSTT1 and GSTM1 genes developed cancer earlier than the males harbouring the other genotypes. 7 This effect of the GSTT1 and GSTM1 null genotypes was not confirmed in a second study including 257 MMR mutation carriers from 130 families. 8 Nevertheless, the authors reported that subjects heterozygous for the CYP1A1 rs1048943 SNP (c.1384A4G; p.Ile462Val) developed CRC earlier than individuals with the homozygous wild-type genotype and that subjects heterozygous for this polymorphism and an additional SNP rs4646903 (Msp1; g.6235T4C) had an increased CRC risk.…”

Section: Introductionmentioning

confidence: 91%

Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers

et al. 2011

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Several studies have reported that, in Lynch syndrome resulting from mutations of the mismatch repair (MMR) genes, a CA repeat r17 within the IGF1 promoter, SNPs within the xenobiotic metabolizing enzyme gene CYP1A1 and SNPs on 8q23.3 and 11q23.1 modify colorectal cancer (CRC) risk in MMR mutation carriers. We analysed the impact of these polymorphisms on CRC risk in 748 French MMR mutation carriers derived from 359 families. We also analysed the effect of the Novel 1 SNP (18q21), which has recently been shown to increase CRC risk in the general population. We observed a significant difference in the CRC-free survival time between males and females, between MSH2 and MSH6 mutation carriers and between MLH1 and MSH6, indicating that this series is representative of Lynch syndrome. In contrast, the univariate log-rank test, as well as multivariate Cox model analysis controlling for familial aggregation and mutated MMR gene, year of birth and gender showed that the polymorphic alleles tested were not associated with a significant CRC risk increase, neither on the entire sample nor among males and females. This discrepancy with previous reports might be explained both by the genetic heterogeneity between the different populations analysed and the allelic heterogeneity of the MMR mutations. We conclude that genotyping of these polymorphisms is not useful to evaluate CRC risk in MMR mutation carriers and to optimize their clinical follow-up.

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“…The considerable variation in disease expression (age of onset and tumor site) in these disorders cannot entirely be explained by the type and position of the mutation in the respective genes (11). Several reports have shown that genetic polymorphisms may be contributing factors to disease in HNPCC and sporadic cases of CRC (12)(13)(14)(15)(16)(17). MicroRNAs (miRNAs) are endogenously expressed RNAs 18-24 nucleotides in length that regulate gene expression through translational repression by binding to a target mRNA.…”

Section: Introductionmentioning

confidence: 99%

A Functional Variant of IC53 Correlates with the Late Onset of Colorectal Cancer

Chen

Shi

et al. 2011

Mol Med

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The IC53 gene was reported to be upregulated in the colon adenocarcinoma cell line SW480. Here, we show that the expression level of IC53 is positively correlated with the grade and depth of invasion in adenocarcinoma of the colon. Injection of IC53 stably transfected HCT-116 cells into athymic nude mice promoted tumor growth. Furthermore, overexpression of IC53 increased cell invasive growth, which could be dramatically prevented by knocking down IC53 with siRNA. The effects of IC53 on cellinvasive growth were mediated by upregulation of integrins, activation of phosphatidylinositol 3-kinase and phosphorylation of Akt. A single-nucleotide polymorphism rs2737 in the IC53 gene created a potential microRNA379 target site, and microRNA379 expression inhibited IC53 translation. Among 222 patients with colorectal cancer, the C/C rs2737 genotype was associated with late onset of colorectal cancer (median age 63.0 versus 55.3 years, P = 0.003). The frequency of the C/C rs2737 genotype was much lower in patients who developed colorectal cancer below the age of 45 years than in individuals over age 45 years (10.8% versus 26.6%, P = 0.039). These data indicated that IC53 is a positive mediator for colon cancer progression, and IC53-rs2737 may serve as protection from the onset of colorectal cancer.

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GSTM1 and GSTT1 polymorphisms as modifiers of age at diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) in a homogeneous cohort of individuals carrying a single predisposing mutation

Cited by 33 publications

References 23 publications

Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients

Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients

Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers

A Functional Variant of IC53 Correlates with the Late Onset of Colorectal Cancer

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