cyclin-d1 and Colorectal-Neoplasms--Hereditary-Nonpolyposis

Studies of the association between the cyclin D1 (CCND1) G870A genetic polymorphism and risk of colorectal cancer (CRC) have generated conflicting results. In order to derive a more precise estimation, a meta-analysis was here performed.. An extensive search of relevant studies was carried out as a meta-analysis of twenty studies with 5,975 cases and 8,333 controls.. Overall, a significantly elevated colorectal cancer risk was associated with variant allele 870A when all studies were pooled (AA vs. GG: OR = 1.23, 95%CI = 1.04-1.44; GA vs. GG: OR = 1.13, 95% CI = 1.01-1.26; dominant model: OR = 1.16, 95%CI = 1.03-1.31). In the subgroup analysis by ethnicity, significantly increased risks were detected among Caucasians (AA vs. GG: OR = 1.27, 95%CI = 1.04-1.44; and dominant model: OR = 1.17, 95%CI = 1.02-1.34). With stratification into sporadic CRC and hereditary nonpolyposis colorectal cancer (HNPCC), the former demonstrated increased cancer susceptibility (AA vs. GG: OR = 1.24, 95%CI = 1.04-1.48; dominant model: OR = 1.17, 95%CI = 1.04-1.33). However, no significant associations were found in either Asians or HNPCC patients for any genetic model.. The results suggest that the cyclin D1 870A allele is a low-penetrant risk factor for development of sporadic colorectal cancer, especially among Caucasians.

Topics: Alleles; Case-Control Studies; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Cyclin D1; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide

Colorectal cancer (CRC) is one of the most frequent neoplasms worldwide, and up to 15% have a family history. Lynch syndrome (LS) is a hereditary cause of CRC and gastric (GC). Individuals with LS have mutations in mismatch genes repair. p53, cyclin D1, β-catenin, APC and c-myc proteins are involved in the cell cycle and carcinogenesis.. To study the expression of p53, Cyclin D1, β-catenin, APC and c-myc proteins in patients with CRC and GC with at least one of the Bethesda positive criteria. Compare the expression of these proteins with the presence or absence of expression of the DNA repair proteins.. We included 70 individuals with CRC or GC with at least one of the Bethesda positive criteria. Protein expression of MLH1, MSH2, MSH6, PMS2, p53, cyclin D1, β-catenin, APC and c-myc were analized by immunohistochemistry tumours tissues.. Deficient expression of MLH1, MSH2, MSH6 and PMS2 were respectively 38.7%; 17.7%; 26.22% and 48.38%. We found a negative association between deficiency of PMS2 and age, and positive association between PMS2 deficiency and APC positive. The positive imunoexpression of APC increases by 4 times the chance of having deficiency of PMS2.. Patients with loss of expression of PMS2 had a higher risk of mutation or deletion of APC and tumours with positive immunoexpression of cyclin D1 had an increased risk of loss of expression of MSH2. These results suggest that tumours with loss of expression of DNA repair proteins had a higher loss of cell control cycle.
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Topics: Adenomatous Polyposis Coli Protein; beta Catenin; Biomarkers, Tumor; Brazil; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Cyclin D1; DNA Repair Enzymes; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; Proto-Oncogene Proteins c-myc; Retrospective Studies; Stomach Neoplasms; Tumor Suppressor Protein p53

Polymorphisms in the 2 cell-cycle control genes Aurora A and Cyclin D1 have previously been associated with changes in the age of onset of colorectal cancer in persons harboring germline mutations in DNA mismatch repair genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). In this report, we have genotyped 312 individuals, who all harbored confirmed causative mutations in either hMSH2 or hMLH1, for 2 polymorphisms, one in Aurora A (T91A) and the other in Cyclin D1 (G870A). The results reveal that the previous association with the Aurora A polymorphism could not be confirmed in our larger group of HNPCC patients. The Cyclin D1 polymorphism, however, was associated with a significant difference in the age of disease onset on patients harboring hMSH2 mutations, which was not observed in hMLH1 mutation carriers. A combined analysis of the Aurora A and Cyclin D1 polymorphisms did not reveal any obvious association. In conclusion, it appears that the polymorphic variant of Aurora A does not appear to be associated with variation in colorectal cancer risk in HNPCC, whereas there is a more complex relationship between the Cyclin D1 polymorphism and disease risk in HNPCC.

Topics: Adult; Age of Onset; Aged; Aurora Kinases; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Cyclin D1; Disease Progression; Female; Gene Frequency; Heterozygote; Homozygote; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Survival Analysis

CCND1 encodes cyclin D1, which plays an important role in the G1 to S phase transition of the cell cycle. A common polymorphism (c.G870A) increases alternate splicing. Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in mismatch repair (MMR) genes, mainly MSH2 and MLH1, and shows a wide range in the age of its onset (AO), suggesting the existence of other modifying genetic factors. To date, two studies have investigated the association between CCND1 G/A variation and AO in HNPCC with contradictory results in 86 and 146 MMR mutation carriers, respectively. To clarify the role of the CCND1 G/A variation in HNPCC, we performed a study in 406 individuals carrying exclusively clear cut pathogenic mutations in MSH2 or MLH1. We did not observe a significant difference in genotype frequencies of affected and unaffected mutation carriers and healthy controls. A significant association between CCND1 genotypes and AO was found neither in the global comparison (log-rank, P = 0.2981; Wilcoxon, P = 0.2567) nor in a multivariate Cox regression analysis (hazard ratios 1.111, 95%CI 0.950-1.299, P = 0.188 and 1.090, 95%CI 0.868-1.369, P = 0.459 for the additive and dominant effect, respectively). We conclude, that the CCND1 G870A sequence variation is not a genetic modifier of the phenotype of HNPCC.

Topics: Adolescent; Adult; Age of Onset; Aged; Colorectal Neoplasms, Hereditary Nonpolyposis; Cyclin D1; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic

Hereditary nonpolyposis colorectal cancer is associated with inherited defects in DNA mismatch repair. Clinical variation even in cases with identical predisposing mutations suggests the existence of other factors contributing to the phenotype. We addressed the modifying role of the common A/G polymorphism in exon 4 and the alternatively spliced transcripts a and b of the CCND1 gene encoding cyclin D1 in a series of 146 affected carriers of 10 MLH1 and 3 MSH2 mutations. No correlation was observed between a particular allele (A versus G) and age at onset. However, the presence of the variant transcript b in blood/normal mucosa, by multiplex reverse transcription-PCR, was associated with a significantly lower age at onset of colon cancer as compared with individuals with transcript a only (35 versus 46 years; P = 0.02). Whereas our data do not support a modifying role of A versus G allele of CCND1, the results do suggest that the relative abundance of a and b transcripts may modify the age at onset of colon cancer in hereditary nonpolyposis colorectal cancer.

Topics: Adaptor Proteins, Signal Transducing; Adult; Age Factors; Aged; Alleles; Alternative Splicing; Carrier Proteins; Colorectal Neoplasms, Hereditary Nonpolyposis; Cyclin D1; DNA Repair; DNA-Binding Proteins; Female; Genes, bcl-1; Genotype; Humans; Loss of Heterozygosity; Male; Middle Aged; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Polymorphism, Genetic; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

A common polymorphism in the cyclin D1 gene enhances the gene's alternate splicing. The alternatively spliced product encodes an altered protein that does not contain sequences involved in the turnover of the protein. We found that hereditary nonpolyposis colorectal carcinoma patients who were homozygous or heterozygous for the mutant allele developed colorectal cancer an average of 11 years earlier than patients who were homozygous for the normal alleles. This is the first report indicating that the cyclin D1 polymorphism influences age of onset of cancer. Because cyclin D1 plays an important role in the G1 to S phase transition of the cell cycle, our findings suggest that cells with the mutant allele accumulate mutations as a result of defective mismatch repair and may also bypass the G1-S checkpoint of the cell cycle more easily than in cells not carrying the polymorphism. The polymorphism has a dominant phenotype.

Topics: Adaptor Proteins, Signal Transducing; Adult; Age of Onset; Aged; Aged, 80 and over; Base Pair Mismatch; Base Sequence; Carrier Proteins; Cell Cycle; Colorectal Neoplasms, Hereditary Nonpolyposis; Cyclin D1; DNA-Binding Proteins; Ethnicity; Female; Fungal Proteins; Genetic Carrier Screening; Homozygote; Humans; Male; Middle Aged; Mutation, Missense; MutL Protein Homolog 1; MutL Proteins; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Polymorphism, Genetic; Proto-Oncogene Proteins; Survival Analysis