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PubMed1991

A novel point mutation at codon 146 of the K-ras gene in a human colorectal cancer identified by the polymerase chain reaction.

In this report, point mutations of the K-ras gene at codon 146 were analyzed in 25 cases of colon cancer, 4 cases of lung cancer, and 41 cases of lymphoid malignancy. A codon 146 mutation substituting threonine (ACA) for alanine (GCA) was detected in the tumor tissue of a patient with colon cancer and was not detected in the normal tissue of the same patient. Any additional mutations of the ras gene family were not detected in this patient. These results suggest that the codon 146 mutation of the K-ras gene could be involved in the development of naturally occurring human malignancies.

Antisense Elements (Genetics)↗
PubMed2006

Association between polymorphisms of biotransformation and DNA-repair genes and risk of colorectal cancer in Taiwan.

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.

Biotransformation↗
PubMed2007

Partial duplications of the MSH2 and MLH1 genes in hereditary nonpolyposis colorectal cancer.

Numerous reports have highlighted the contribution of MSH2 and MLH1 genomic deletions to hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch's syndrome, but genomic duplications of these genes have been rarely reported. Using quantitative multiplex PCR of short fluorescent fragments (QMPSF), 962 and 611 index cases were, respectively, screened for MSH2 and MLH1 genomic rearrangements. This allowed us to detect, in 11 families, seven MSH2 duplications affecting exons 1-2-3, exons 4-5-6, exon 7, exons 7-8, exons 9-10, exon 11, and exon 15, and three MLH1 duplications affecting exons 2-3, exon 4 and exons 6-7-8. All duplications were confirmed by an independent method. The contribution of genomic duplications of MSH2 and MLH1 to HNPCC can therefore be estimated approximately to 1% of the HNPCC cases. Although this frequency is much lower than that of genomic deletions, the presence of MSH2 or MLH1 genomic duplications should be considered in HNPCC families without detectable point mutations.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Mutator genes and mosaicism in colorectal cancer.

Recent studies have shed light on the role of defective DNA mismatch repair in human cancer. An elevated mutation rate associated with mismatch repair deficiency has been demonstrated in the germline and normal tissue from patients with hereditary non-polyposis colorectal cancer and transgenic animals respectively. Thus mismatch repair deficiency may permit the accumulation of mutations in cancer genes that do not confer growth advantage. This represents one potential mechanism for the induction of mutational mosaicism in humans.

Animals↗
PubMed1990

Identification of a chromosome 18q gene that is altered in colorectal cancers.

Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5' end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.

Alleles↗
PubMed2000

Death from early colorectal cancer is predicted by the presence of transcripts of the REG gene family.

An intrinsic component of colorectal carcinogenesis may be the capacity to activate regenerative responses simultaneously with inhibition of apoptosis. Since apoptosis is known to be inhibited in colorectal cancer, this study sought evidence for the activation of the REG family of genes which are considered to be activated during regeneration of intestinal mucosa. Transcripts for the REG gene were found in 53% of colorectal cancers and for the PAP gene in 60% of colorectal cancers, by RT-PCR. Using in situ hybridization, the REG transcripts were found to be present in the tumour cells themselves rather than inflammatory or stromal cells. There were no significant correlations between the expression of these two genes and tumour stage, age or sex of the patient population or tumour site. However, in patients with non-metastatic disease who underwent ostensibly curative surgery, the expression of REG alone and co-expression of REG with PAP had a highly significantly adverse effect on survival. These data provide support for the concept that, in some tumours, carcinogenesis involves a regenerative process which co-exists with apoptotic inhibition and may provide a valuable selective indicator of the need for adjuvant therapy in those patients with early-stage colorectal cancer whose disease is destined to recur after curative surgery.

ADP-Ribosylation Factors↗
PubMed1996

[RB gene expression in gastrointestinal tract].

pRB, the retinoblastoma tumor suppressor gene product, regulates the cell cycle at G1/S transition negatively. Many cell cycle regulators modulate pRB function through its phosphorylation status. G1 cyclins (cyclin D, E)/cyclin-dependent kinases (cdk2, 4) inactivates pRB through its phosphorylation, while p21 (WAF1) and p16 inhibit cdks. In several kinds of cancer, Rb gene alteration or functional inactivation of pRB has been reported. In esophageal cancer, loss of heterozygosity of Rb gene and cyclin D gene amplification were frequently detected. But in gastric and colorectal cancer, Rb gene loss or deletion has been shown to be rare. In this study we investigated the expression of pRB, G1 cyclins, cdks and cdk-inhibitors in adenoma-carcinoma sequence of colorectum. And we compared the phosphorylation status of pRB in colorectal normal mucosa and cancer tissue. In adenoma only cyclin D and E were overexpressed but not cdks. In cancer in adenoma pRB and cdk2 were overexpressed with high frequency, and cdk4 overexpression was detected in advanced cancer. p16 overexpression was detected in almost all cancers, but in contrast p21 overexpression was rare event. Comparative study showed that pRB-positive cancer cells also expressed both cdc2/cdk2 and cyclin E. Densitometric analysis revealed that in advanced cancer pRB was hyperphosphorylated compared with normal mucosa. These results indicate that overexpression of cyclin D/cdk4 and cyclin E/cdk2 would phosphorylate pRB, and insufficient expression of p21 may accelerate pRB inactivation.

Cell Cycle↗
PubMed2005

Germline mutations in the MYH gene in Swedish familial and sporadic colorectal cancer.

Biallelic germline mutations in the base excision repair gene MYH have been shown to predispose to a proportion of multiple colorectal adenomas and cancer. To evaluate the contribution of MYH mutations to non- FAP, non-HNPCC familial colorectal cancer, 84 unrelated Swedish individuals affected with colorectal cancer from such families were screened for germline mutations in the coding sequence of the gene. None of the cases was found to carry any pathogenic sequence change. We then determined the prevalence of the two most common pathogenic MYH mutations found in Caucasians, Y165C and G382D, in 450 Swedish sporadic colorectal cancer cases and 480 Swedish healthy controls. The frequency of both variants in Swedish cases and controls was similar to those previously reported. In addition, we found that previously unknown sequence variations at the position of amino acid 423 (R423Q, R423P, and R423R) appear to occur more frequently in cases than in controls (p = 0.02), a finding that warrants future studies.

Amino Acid Substitution↗
PubMed2002

Frequent RASSF1A tumour suppressor gene promoter methylation in Wilms' tumour and colorectal cancer.

The 3p21.3 tumour suppressor gene (TSG) RASSF1A is inactivated predominantly by promoter methylation and rarely by somatic mutations. Recently we demonstrated that epigenetic inactivation of RASSF1A is frequent in both clear cell and papillary adult renal cell carcinomas (even though 3p21.3 allele loss is rare in papillary tumours). Wilms' tumour is the most common childhood kidney tumour, but relatively little is known about its molecular pathogenesis. Thus TSGs such as WT1, p16(CDKN2a) and p53 are inactivated in only a minority of cases. In view of the involvement of RASSF1A in adult renal cancers we investigated RASSF1A as a candidate Wilms' TSG. We detected RASSF1A hypermethylation in 21 of 39 (54%) primary Wilms' tumours. 3p21.3 allele loss was not detected in nine informative Wilms' tumours (five with RASSF1A methylation). In contrast to RASSF1A, only a minority (10.3%) of Wilms' tumours demonstrated p16 promoter methylation. As chromosome 3p allele loss is frequent in colorectal cancer, we proceeded to investigate RASSF1A promoter methylation in colorectal cancer and detected RASSF1A methylation in 80% (4/5) colorectal cancer cell lines and 45% (13/29) primary colorectal cancers. There was no correlation between RASSF1A and p16 methylation in colorectal cancer. We have demonstrated that RASSF1A inactivation is the most frequent genetic or epigenetic event yet reported in Wilms' tumourigenesis and that allelotyping studies may fail to identify regions containing important TSGs.

Colorectal Neoplasms↗
PubMed1999

beta-catenin expression in primary and metastatic colorectal carcinoma.

beta-catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also functions in growth signalling events, independently of the cadherin-catenin complex, and these signalling pathways are disturbed in colorectal cancer. Mutations in either the APC or beta-catenin genes in colorectal cancer cells result in up-regulation of protein expression and subsequent cytoplasmic and nuclear distribution of beta-catenin. In this study, we examined beta-catenin expression in 47 primary colorectal tumors and the corresponding liver metastases. Immunohistochemical studies demonstrated loss of membranous beta-catenin expression in 26% of primary tumors and 60% of liver metastases and a concomitant increase in cytoplasmic and nuclear staining. Widespread nuclear expression of beta-catenin was found in 64% of primary tumors and 21% of liver metastases. No associations were found between any form of beta-catenin expression and either tumor stage or tumor grade. Cellular distribution of beta-catenin was also examined by detergent extraction and Western blot analysis in 16 primary tumors and 23 liver metastases. This analysis showed that most tumors demonstrated reduced beta-catenin in the cytoskeletal fraction and increased beta-catenin in the cytosolic fraction. Furthermore, 3 liver metastases were found to contain a truncated beta-catenin protein of approximately M(r) 80,000. Immunoprecipitation studies showed that the truncated beta-catenin proteins only bound weakly to E-cadherin and beta-catenin compared with non-truncated beta-catenin. These results demonstrate gross alterations in the cellular distribution of beta-catenin in primary colorectal cancers with metastatic potential, as well as in the metastatic tumors. These changes may be the consequence of APC or beta-catenin gene mutations, or possibly result from a post-translational modification of the E-cadherin-catenin complex.

Adult↗
PubMed2003

Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas.

Colorectal cancer is a multi-step process characterized by a sequence of genetic alterations in cell growth regulatory genes, such as the adenomatous polyposis coli, KRAS, p53 and DCC genes. In the present study mutation analysis was performed with SSCA/direct sequencing of the hot-spot regions in exons 11 and 15 for the BRAF gene and exons 1-2 for the KRAS gene in 130 primary colorectal cancer tumors and correlated with clinico-pathological and mutational data. We also performed mutation analysis of the corresponding conserved regions in the ARAF and RAF-1 genes. Mutations in the BRAF and KRAS genes were found in 11.5 and 40% of the tumors, respectively. One germline exonic and nine germline intronic genetic variants were found in the ARAF and RAF-1 genes. All of the BRAF mutations were located in the kinase domain of the conserved region 3 in exon 15 of the BRAF gene. One novel somatic mutation was also identified in the BRAF gene. The majority of the BRAF mutations were found in colon compared with rectal tumors (P = 0.014). In agreement with others, a statistically significant correlation between BRAF mutations and microsatellite instability could be found. A negative correlation was also evident between mutations in the BRAF and KRAS genes, which supports earlier studies where somatic mutations in these genes are mutually exclusive. Collectively, our results provide support for the idea that activation of the MAP kinase pathway, especially via BRAF and KRAS mutations, is of critical importance for the development of colorectal cancer.

Adenocarcinoma↗
PubMed1995

Gene tests and counseling for colorectal cancer risk: lessons from familial polyposis.

Familial adenomatous polyposis (FAP) is a well-defined, inherited colorectal cancer syndrome due to mutations in the APC gene. Genetic counseling and predictive gene tests for FAP will likely be incorporated as a first step in risk assessment for this condition. Our experience with predictive gene testing for FAP sheds important light on the impact of such tests for families at risk for FAP or colorectal cancer. We counseled and tested 47 adults and 36 minors at risk for FAP. Gene test results changed the risk of FAP for a given individual from a priori 50% to essentially zero or 100%. These individuals and their family members were interviewed before and after disclosures of APC gene test results to examine issues related to patients' knowledge about FAP, risk perception, reasons for seeking gene testing, and anticipated meaning of the results. We found that the gene test is imbued with meaning beyond determination of gene status in families who choose gene testing. The at-risk patient has preformed, well-entrenched conceptions of what having FAP or colorectal cancer entails, and family relationships and identity may be strongly linked with disease or gene status. We have found that genetic testing of minors requires additional counseling considerations and effort to ensure their understanding of FAP and the gene test. Importantly, their understanding of the clinical and social meaning of the gene test result must be elicited. For all patients, the value of counseling includes reduction of uncertainty and adjustment of misperceptions. Genetic counseling guidelines for this emerging clinical service are presented.

Adenomatous Polyposis Coli↗
PubMed2004

Inactivation of 14-3-3sigma by hypermethylation is a rare event in colorectal cancers and its expression may correlate with cell cycle maintenance at the invasion front.

In many kinds of cancers, 14-3-3sigma, one of the cell cycle negative regulator, is inactivated by hypermethylation of the gene. In colorectal cancers, this study revealed that the hypermethylation of the 14-3-3sigma gene was an uncommon event and 14-3-3sigma expression was kept even in established colorectal cancer cell lines. Immunohistochemical study using surgical materials showed the expression of 14-3-3sigma was localized at the deep peripheral area of the tumor, so-called invasion front. According to the results of Ki-67 and cyclin B1 immunohistochemistry, 14-3-3sigma-positive cases maintained higher proliferative activity compared to 14-3-3sigma-negative cases at IF. However, a significant correlation between 14-3-3sigma expression and proliferative activity in CRC cells remains to be unsolved.

14-3-3 Proteins↗
PubMed1996

DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.

About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.

Alleles↗
PubMed2001

A phosphatase associated with metastasis of colorectal cancer.

To gain insights into the molecular basis for metastasis, we compared the global gene expression profile of metastatic colorectal cancer with that of primary cancers, benign colorectal tumors, and normal colorectal epithelium. Among the genes identified, the PRL-3 protein tyrosine phosphatase gene was of particular interest. It was expressed at high levels in each of 18 cancer metastases studied but at lower levels in nonmetastatic tumors and normal colorectal epithelium. In 3 of 12 metastases examined, multiple copies of the PRL-3 gene were found within a small amplicon located at chromosome 8q24.3. These data suggest that the PRL-3 gene is important for colorectal cancer metastasis and provide a new therapeutic target for these intractable lesions.

Adenoma↗
PubMed2005

Human FK506 binding protein 65 is associated with colorectal cancer.

We initiated the present study to identify new genes associated with colorectal cancer. In a previously published microarray study an EST (W80763), later identified as the gene hFKBP10 (NM_021939), was found to be strongly expressed in tumors while absent in the normal mucosa. Here we describe this gene hFKBP10 together with its encoded protein hFKBP65 as a novel marker associated with colorectal cancer. Analysis of 31 colorectal adenocarcinomas and 14 normal colorectal mucosa by RealTime PCR for hFKBP10 showed a significant up-regulation in tumors, when compared with normal mucosa. Immunohistochemical analysis of 26 adenocarcinomas and matching normal mucosa, as well as benign hyperplastic polyps and adenomas, using a monoclonal anti-hFKBP65 antibody, showed that the protein was not present in normal colorectal epithelial cells, but strongly expressed in the tumor cells of colorectal cancer. The protein was also expressed in fibroblasts of both normal mucosa and tumor tissue. Western blot analysis of matched tumors and normal mucosa supported the finding of increased hFKBP65 expression in tumors compared with normal mucosa, in addition to identifying the molecular mass of hFKBP65 to approximately 72 kDa. Cellular localization and glycosylation studies revealed the hFKBP65 protein to be localized in the endoplasmic reticulum, and to be N-glycosylated. In conclusion, the protein hFKBP65 is associated with colorectal cancer, and we hypothesize the protein to be involved in fibroblast and transformed epithelial cell-specific protein synthesis in the endoplasmic reticulum.

Adenocarcinoma↗
PubMedDate not supplied

Aberrant methylation of the CHFR gene is frequently detected in non-invasive colorectal cancer.

BACKGROUND: Aberrant methylation of the CHFR gene associated with gene silencing has been reported in several primary tumors. In order to define the role of CHFR in the tumorigenic pathway of the colorectum, the methylation of CHFR was examined in tumors from colorectal cancer patients. MATERIALS AND METHODS: Ninety-eight colorectal cancer patients were examined using a methylation-specific PCR (MSP) for CHFR CpG island in primary tumors. RESULTS: An aberrant methylation of the CHFR gene was detected in 25 out of 98 (26%) primary colorectal cancers. No methylation was detected in the corresponding normal tissue specimens. This finding suggested that an aberrant methylation of the CHFR gene occurs frequently in colorectal cancers. After a methylation analysis of all samples, the clinicopathological data were correlated with these results. A significant difference was found in the tumor (p = 0.035), thus, indicating that in early colorectal cancer the CHFR gene was more frequently methylated than in advanced cases. CONCLUSION: These findings suggest that CHFR might act as a tumor suppressor in at least some colorectal cancers and that CHFR methylation might, therefore, be a particular phenomenon of early colorectal cancer.

Base Sequence↗