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PubMed2003

Prognostic significance of the deleted in colorectal cancer gene protein expression in high-risk resected gastric carcinoma.

The deleted in colorectal cancer (DCC) gene is a candidate tumor suppressor gene that may be associated with differentiation and proliferation of normal cells. Loss of heterozygosity (LOH) of 18q, where the gene is located, and absence of DCC protein expression have been associated with worse prognosis in certain subgroups of patients with colorectal adenocarcinoma. We studied the prognostic significance of loss-of-protein expression in 66 patients with resected gastric cancer with a high probability of relapse (T3, T4, N+). The DCC protein was detected with immunohistochemistry using an anti-DCC monoclonal antibody on paraffin-embedded sections. The DCC protein expression was present in 51 cases (77.3%) and absent in 15 cases (22.7%). Poorly differentiated and signet ring carcinomas had significantly lower expression than more differentiated tumors (p < 0.05) as did diffuse-type tumors compared to intestinal and mixed (p < 0.01). There was no correlation with proliferation rate, estimated immunohistochemically using an anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody. Absence of DCC protein was an independent favorable prognostic factor (median survival 57 months vs. 18 months, p = 0.0176). The DCC protein expression was correlated with relapse site: all patients with distant metastases were positive for DCC staining, while one-third of patients with local/peritoneal relapse were negative (p < 0.01). In conclusion, DCC protein expression seems to be a significant prognostic factor in high-risk resected gastric cancer. Our results support previous data associating the DCC gene with differentiation and indicate that this gene may play a role in the metastatic potential of these tumors. These findings need to be confirmed by future larger studies.

Adenocarcinoma↗

PubMedDate not supplied

Clinicopathologic and carcinogenetic appraisal of DNA replication error in sporadic T3N0M0 stage colorectal cancer after curative resection.

BACKGROUND/AIMS: DNA replication error (RER) was found to play a role in the carcinogenesis of a subset of sporadic colorectal cancers. This study was conducted to evaluate the clinicopathologic implications of RER in T3N0M0 stage colorectal cancers. To better understand the carcinogenesis of sporadic colorectal cancer, the RER status was further correlated with the alterations of K-ras, p53 and deleted in colorectal cancer (DCC) genes which were frequently involved in the adenoma-carcinoma sequence. METHODOLOGY: Seventy-eight patients with curatively resected T3N0M0 stage sporadic colorectal cancer were accumulated. The stored frozen tissues were retrieved for analyses of 1) microsatellite instability at 7 distinct chromosomal loci, 2) loss of heterozygosity at DCC gene, 3) K-ras gene mutation, 4) p53 expression, and 5) DNA content. The RER status was correlated with various clinicopathologic and molecular genetic factors. The survival of patients stratified by RER status was analyzed by Kaplan-Meier estimator. RESULTS: The RER-positive tumor was detected in 32.1% (25/78) of patients. The RER-positive cancer patients presented with distinct clinicopathologic features including young age of tumor onset, proximal tumor location, mucin production in histology, a higher rate of synchronous and metachronous colorectal cancers, and an increased incidence of extracolonic primary cancer. Patients with RER-positive tumor were found to have an improved prognosis with the 5-year survival probability of 76% and 45% in RER-positive and RER-negative groups, respectively (p < 0.05). The RER-positive tumors tended to have normal p53 expression, DNA diploidy, and a lower DNA index. The rate for the loss of heterozygosity of DCC gene was significantly lower in RER-positive tumors. RER status was not associated with K-ras mutation. CONCLUSIONS: The clinicopathologic features and carcinogenesis of RER-positive sporadic colorectal cancers were considered different from those of RER-negative tumors. The presence of RER may identify a subset of less aggressive tumors with good prognosis in T3N0M0 stage colorectal cancers.

Adenocarcinoma↗

PubMed1993

[Genetic alterations and transformations in development and establishment of uterine endometrial carcinomas].

The recent advances in molecular biology have led to a concept that carcinomas arise from the accumulation of a series of genetic alterations involving activation of protooncogenes and inactivation of tumor suppressor genes. The present study was designed to elucidate that such processes take place in the tumorigenesis of the uterine endometrium as well. The incidence of ras gene mutation, which were mostly composed of the point mutations of k-ras codons 12 and 13, was higher in carcinomas (31%) than atypical hyperplasias (15%), with marginal significance, but has not been associated with aggressiveness of the carcinomas. Thus, k-ras activations may occur as an early event in tumorigenesis. Mutations of tumor suppressor gene, p53, were detected in 24% of carcinomas and 8% of atypical hyperplasia, while they are not statistically different. The p53 mutations were associated with poorly differentiated adenocarcinomas. The most common pattern of the base change detected in endometrial carcinomas was the transition from G:C to A:T. The p53 mutations at CpG sites were frequent, especially at codon 248. Loss of heterozygosity (LOH) was more frequently detected than the mutations and most cases with LOH harbored the mutations, suggesting that allelic loss may precede the mutation in the tumorigenesis of endometrium. Expression of p53 was well correlated with type of the p53 mutation and its overexpression is associated with aggressive clinical behavior, suggesting the possible application of p53 as a prognostic indicator. The other tumor suppressor genes, Retinoblastoma gene (RB) and DCC gene, were also involved in the endometrial carcinogenesis. LOH and abnormal m-RNA of RB were detected in 15% and 33% of carcinomas, respectively, and associated with advanced clinical stage and poorly differentiated adenocarcinomas. LOH of DCC was also detected in some cases while that of APC was not detected. Thus, tumor suppressor genes may also play an important role as later events in carcinogenesis by inactivation mechanism consisting of the loss of one chromosomal allele and/or mutation of the gene in the remaining allele. Human papillomavirus (HPV) DNA type 16 was curiously detected in 5% of cases by both Southern blot and in situ hybridization analyses. Consequently, two third of endometrial carcinomas examined in the present study for ras, p53, RB, DCC, APC and HPV showed abnormality of at least one of these genes. The abnormality of multiple genes may contribute as an etiologic role to multisteps in carcinogenesis of the endometrium.

Adenocarcinoma↗

PubMed1998

Prognostic significance of allelic lost at chromosome 18q21 for stage II colorectal cancer.

BACKGROUND & AIMS: Allelic loss of a portion of chromosome 18q and lack of expression of deleted in colorectal cancer (DCC) protein has been reported as an adverse prognostic indicator for stage II (i.e., Dukes' B2) colorectal cancer. Our aim was to assess whether the DCC gene locus was responsible. METHODS: We amplified five DNA microsatellite markers located on chromosome 18q21 surrounding or within the DCC gene locus, including a DCC intragenic (TA)n microsatellite, from DNA microdissected and isolated from paraffin-embedded, formalin-fixed specimens of 70 patients with stage II colorectal cancer. Epidemiological and survival data were blinded from the microsatellite analysis to avoid bias. RESULTS: The average follow-up time was 63.3 months for all patients. Eleven patients died of colorectal cancer by the end of the study. Loss of heterozygosity of 18q21 was present in 30 of 70 (43%) tumors. After adjustment for all other evaluated factors, 18q21 allelic loss was not a predictor of survival (hazard ratio, 1.17; 95% confidence interval, 0.27-5.10; P = 0.84). CONCLUSIONS: Loss of heterozygosity of 18q21 does not seem to predict a survival disadvantage in stage II colorectal cancer in our patient population, and its proposed use as a prognosticator of survival or chemotherapy stratification marker for stage II tumors is not substantiated.

Aged↗

PubMed1995

Low frequency and late occurrence of p53 and dcc aberrations in colorectal tumours.

Whilst p53 aberrations have been documented in numerous malignancies, reports of alterations to the deleted in colorectal cancer (dcc) gene are infrequent, and studies investigating the status of both genes in the same colon tumour are rare. In this study we have analysed a panel of 35 pairs of normal and neoplastic human colorectal tissues for abnormalities in these tumour-suppressor genes. In contrast to previous studies we have found only a low incidence of mutations and deletions. p53 point mutations were identified in 8/35 tumours (22%). All were G.C to A.T transitions, with 7/8 occurring at CpG dinucleotides. p53 allelic loss was detected in 4/11 informative cases (36%). Although not quite attaining statistical significance, p53 alteration correlated with the adenoma/carcinoma transition. Gross dcc alterations were identified by Southern blotting in 7/35 (20%) tumours. Microsatellite analysis using two markers, one within and one proximal to the dcc gene, detected a low frequency of deletion overall (41% informative cases). 18q/dcc aberrations were associated with the progression of early to late carcinoma, rather than with increasing adenoma size, as has been previously reported. Both p53 alterations and dcc deletions were detected at a higher frequency in distal tumours than in proximal malignancies. Two tumours exhibiting microsatellite instability in both markers were each of proximal origin.

Adult↗

PubMed1996

[A study on the loss of heterozygosity at the APC/MCC and DCC genetic loci in colorectal cancers].

To evaluate the role of APC, MCC and DCC genes in the development and progression of colorectal cancers, loss of heterozygosity (LOH) at these genetic loci was investigated in 41 surgically resected specimens of colorectal cancer by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. LOH at APC or/and MCC was detected in 38.9% (14/38) of the informative cases; at the APC in 28.0% (7/25) and at MCC locus in 36.4% (8/22). LOH at DCC genetic locus was detected in 55.3% (21/38) of the informative cases. LOH rates DCC gene in the cancer specimens with lymphnode metastasis (80.0%) and in Dukes' stage III and IV (71.4%) were significantly higher than that in specimens without lymphnode metastasis (39.1%) and in Dukes' stage I and II (35.3%) (P < 0.05). Our results suggest that LOH at APC/MCC and DCC is the common genetic alterations in colorectal cancer and DCC genetic LOH assay may be useful in predicting the prognosis of patients with colorectal cancer.

Adenocarcinoma↗

PubMed1999

[A study on the loss of heterozygosity of multiple tumor suppressor genes in gastrointestinal metaplasia].

OBJECTIVE: To investigate the role of multiple tumor suppressor gene abnormality in gastrointestinal metaplasia (IM). METHODS: The loss of heterozygosity (LOH) of YNZ22, APC, MCC and DCC genes was examined by PCR-RFLP technique in 60 IM cases. RESULTS: LOH of YNZ22, APC, MCC and DCC genes were found in 19.4% (6/31), 12.0% (3/25), 13.0% (3/23) and 4.3% (2/47) respectively. IM was classified into types I, II and III. It was found that the LOH rates of each tumor suppressor gene of type III IM were higher than those of types I & II IM, but the difference was not significant (P > 0.05). Two cases of type III IM were found to also have 2 gene alterations (APC, MCC or YNZ22, MCC) respectively. All LOH were found in IM of adjacent carcinoma. None were found in IM of cancer-free patients. CONCLUSION: The alteration of tumor suppressor gene may play a role in the development and carcinogenesis of IM.

DNA↗

PubMed2001

Telomere erosion is independent of microsatellite instability but related to loss of heterozygosity in gastric cancer.

AIM: To correlate the length of the telomere to microsatellite instability (MSI) and loss of heterozygosity (LOH) of APC, MCC and DCC genes in gastric carcinomas. METHODS: Telomeric restriction fragment (TRF) length of gastric cancer was measured with Southern blot. LOH of APC, MCC and DCC genes, microsatellite instability (MSI) and frameshift mutation of hMSH6, TGF-betaRII and BAX genes were analyzed by PCR-based methods. RESULTS: Sixty-eight cases of sporadic gastric carcinoma were studied for MSI using five microsatellite markers. MSI in at least one locus was detected in 17 (25%) of 68 tumors analyzed. Frameshift mutations of hMSH6, TGF-betaRII and BAX were detected in 2,6 and 3 of gastric carcinomas respectively showing high MSI (> or = 2 loci, n = 8), but none was found in those showing low MSI (only one locus, n = 9) or MSS (tumor lacking MSI or stable, n = 51). Thirty-five cases, including all high MSI and low MSI, were studied for TRF. The mean TRF length was not correlated with clinicopathological parameters. No association was observed between TRF length and MSI or frameshift mutation. On the contrary, LOH at the DCC locus was related to telomere shortening (P<0.01). This tendency was also observed in APC and MCC genes, although there was no statistical significance. CONCLUSION: The development of gastric cancer can arise through two different genetic pathways. In high MSI gastric cancers, defective mismatch repair allows mutations to accumulate and generate the high MSI phenotype. In gastric cancers showing either low MSI or MSS, multiple deletions may represent the LOH pathway. Telomere erosion is independent of high MSI phenotype but related to the LOH pathway in gastric cancer.

Adult↗

PubMed1996

[Structure and function of DCC (deleted in colorectal cancer) gene and its product].

The DCC gene is one of several genes altered during tumorigenesis. Recent studies demonstrate the existence of 29 exons and it spans 1.4 Mb. DCC gene is a candidate tumor-suppressor gene encoding a protein with a sequence similarity to cell adhesion molecule. Although the mutation of DCC gene was few, high incidence of LOH and decreased mRNA expression in colorectal cancer especially with hepatic metastasis was observed. These DCC gene abnormalities possibly be related to predictive marker for liver metastasis.

Amino Acid Sequence↗

PubMedDate not supplied

State of p53, Rb and DCC tumor suppressor genes in human oral cancer cell lines.

The tumor suppressor genes p53, Rb, and DCC were studied in five human oral cancer cell lines (FaDu, SCC-4, HEp-2, 1483, and OEC-M1) and in primary normal human oral keratinocytes (NHOK). All tested cancer lines had similar amount of p53 messages to normal cells, but the cancer lines FaDu and SCC-4 contained significantly higher p53 protein levels than did the normal counterpart. Sequencing p53 cDNA for these cancer cells showed point mutations: In the FaDu cell line, a mutation of CGG to CTG occurred at codon 248; and in the SCC-4 cell line, a mutation of CCC to TCC occurred at codon 151. The HEp-2 and 1483 cancer lines translated very low levels of p53 protein compared to the normal counterpart. Sequencing of p53 cDNA for HEp-2 and 1483 lines showed no mutations. Southern and Northern analyses revealed that these cell lines harbored HPV-18 DNA and expressed the viral E6/E7 protein. The OEC-M1 line showed different restriction fragment length polymorphism for the p53 gene compared with other cells, and did not express p53. All oral cancer cell lines except the OEC-M1 cells expressed both phosphorylated and hypophosphorylated Rb proteins. Further, the OEC-M1 line expressed smaller sized hypophosphorylated Rb proteins compared with normal cells. Unlike the other cancer lines, the HEp-2 and OEC-M1 lines also did not contain DCC mRNAs. These data indicate that "high risk" HPV infections and mutations of p53, Rb, and DCC genes are frequently found in oral cancer cells and may be associated with oral cancer.

Base Sequence↗

PubMed1992

Frequent loss of heterozygosity on chromosome 18 in ovarian adenocarcinoma which does not always include the DCC locus.

Inactivation of the DCC gene on chromosome 18 owing to loss of heterozygosity is a common finding in colorectal cancer. Because both ovarian and colon cancer are features of Lynch syndrome II, which has been provisionally mapped to chromosome 18, we hypothesized that loss of heterozygosity at the DCC locus may also occur in ovarian neoplasia. Fifty-two sporadic ovarian adenocarcinoma tumours were analysed by Southern blotting for loss of heterozygosity (LOH) at six chromosome 18 loci. Overall, tumours from 31 patients (60%) showed allelic loss at one or more of these loci. A similarly high level of LOH, 66%, was found at D17S5 (17p13.3). In contrast, moderate levels of LOH, of 31%, 39% and 33%, were found at MYCL1 (1p32), D1S57 (1p) and D14S20 (14q32.33) respectively. However, analysis of partial chromosome deletions in 11 patients indicates that the smallest region of overlap appears to exclude the DCC gene but to be between the D18S5 and D18S11 loci. This suggests that another locus, as well as or apart from DCC, may be involved.

Adenocarcinoma↗

PubMed2003

Folic acid mediated attenuation of loss of heterozygosity of DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas.

Loss of heterozygosity (LOH) and/or inactivation of tumor suppressor genes are implicated in the initiation and progression of many malignancies, including colorectal cancer. Although accumulating evidence suggests a chemopreventive role for folate in colorectal cancer, regulatory mechanisms are poorly understood. The primary objective of the current investigation was to determine whether folic acid would prevent LOH of the three tumor suppressor genes, deleted in colorectal cancer (DCC), adenomatous polyposis coli (APC) and p53 in macroscopically normal appearing rectal mucosa of patients with adenomatous polyps. In addition, the effect of folic acid on rectal mucosal proliferation was determined. Twenty patients were randomized in a double-blind study to receive either folic acid 5mg once daily or identical placebo tablets for 1 year. Genomic DNA and total protein were extracted from the rectal mucosa at baseline and after 1 year of treatment and analyzed for LOH and protein levels of APC, DCC and p53 genes. In addition, paraffin-embedded mucosal specimens were analyzed for proliferating cell nuclear antigen (PCNA) immunoreactivity, as a measure of cellular proliferative activity. Folate supplementation prevented LOH of DCC gene in five out of five (100%) patients who demonstrated baseline heterozygosity, whereas two out of four (50%) placebo-treated patients with baseline heterozygosity demonstrated allelic loss. Mucosal protein levels of DCC were also reduced in 7 of 10 (70%) placebo-treated patients compared to only 2 of 10 (20%) of patients treated with folate. Levels increased, however, in eight and three patients in the folic acid and placebo groups, respectively (P<0.02). Folic acid caused no change in allelic status of either APC or p53 gene. Folate supplementation caused a small, but not statistically significant, 16% reduction in mucosal proliferation, whereas placebo treatment resulted in a 88% (P<0.05) increase in this parameter, when compared with the corresponding baseline values. Our results indicate that folic acid prevents an increase in proliferation and arrests LOH of DCC gene and also stabilizes its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Taken together, our data suggest that one of the ways folate may exert its chemopreventive effect is by stabilizing certain tumor suppressor gene(s) and preventing further increases in proliferation.

Adenoma↗

PubMed2000

Genetic aberrations common in gastric high-grade large B-cell lymphoma.

Genetic aberrations associated with the development of extranodal high-grade large B-cell lymphoma originating in the stomach have not been fully identified yet. We analyzed 31 such lymphomas using 73 microsatellite markers for allelic imbalance and microsatellite instability. The highest frequency (42%) of loss of heterozygosity (LOH) was found on the long arm of chromosome 6. We identified 2 LOH hot spots on 6q21-22.1 and 6q23.3-25, flanked by markers D6S246-D6S261 and D6S310-D6S441, respectively, containing putative tumor suppressor genes (TSGs). These 6q aberrations were found to be the sole allelic imbalance in 1 patient only; they were mostly accompanied by additional abnormalities. Several known TSGs, namely, the APC, p15/p16, p53, and DCC genes, were found to suffer frequent LOH during lymphomagenesis. LOH was also detected in regions containing putative TSGs on 7q and 13q14. Frequent amplification of genomic material was found in the 2p, 3q27 at the BCL-6 gene locus, 6p, 7q, 11q23-24 at the MLL gene locus, and 18q regions. Analysis of the pattern of occurrence of these aberrations revealed an association of the amplification of the MLL gene region with LOH at the p53 locus (P =.02). Only low frequency of microsatellite instability (MSI) was detected in these lymphomas and MSI incidence increased with age (P =.01). Karyotypic instability thus plays the main role in the development of gastric high-grade large B-cell lymphoma. Common genetic aberrations responsible for lymphomagenesis are deletions of 6q, loss of p53, and amplification of the 3q27 and the MLL gene regions. (Blood. 2000;95:1180-1187)

Age Factors↗

PubMed2001

Multiple genetic alterations involved in the tumorigenesis of human cholangiocarcinoma: a molecular genetic and clinicopathological study.

PURPOSE: Cholangiocarcinoma (CC) is the second most common malignant tumor in the liver and the molecular genetic alterations involved in the tumorigenesis of CC have not been well studied. PATIENTS AND METHODS: The authors analyzed the loss of heterozygosity (LOH) in four tumor suppressor genes, including the adenomatous polyposis coli (APC) gene, the deleted in colon cancer (DCC) gene, the 8-hydroguanine-specific DNA glycosylase (OGG1) gene, and the p53 gene in 22 surgically resected primary CCs by using microdissection-based PCR amplification and direct DNA sequencing. RESULTS: A total of 19 (86.4%) out of 22 CCs exhibited genetic alterations, of which 11 (57.9%) and eight (42.1%) cases showed one and more than one gene alterations, respectively. The frequency of genetic alterations of the four genes studied ranged in order from high to low as APC (68.8%) > DCC (46.2%) > OGG1 (41.7%) > p53 (37.5%). Based on the pattern of altered genes and their correlation with clinical and pathological parameters, the genetic alterations were classified into three groups: group I: no detectable genetic alterations (n = 3, 13.6%); group II: LOH in APC and/or DCC (n = 9, 40.9%); and group III: LOH in OGG1 and/or p53 occurred separately or combined with LOH in APC and/or DCC (n = 10, 45.5%). The > or = 3-year survival rates between group II and group III are 88.9% and 30%, respectively (P < 0.05). No significant differences were found between genetic alterations and tumor size, tumor type, tumor invasion, TNM staging, and tumor differentiation (P > 0.05). CONCLUSION: Accumulation of multiple genetic alterations are involved in the tumorigenesis of CC, of which genetic alterations of APC and DCC occur at a relatively early stage, and of OGG1 and p53 occur at a relatively late stage during development of CC.

Aged↗

PubMed2002

High resolution analysis of chromosome 18 alterations in ulcerative colitis-related colorectal cancer.

We previously have demonstrated by comparative genomic hybridization that 80% of ulcerative colitis-related cancers show loss of all or part of chromosome 18, the site of at least three candidate tumor suppressor genes: DCC, SMAD2, and SMAD4. To determine whether these genes are targeted in colitis-related carcinogenesis, we performed a high-resolution analysis of chromosome 18 alteractions in 32 colitis-related colorectal cancers by assessing allelic imbalance at 11 microsatellite markers distributed along the chromosome, and by the quantitative polymerase chain reaction (PCR) method (TaqMan). TaqMan analysis was used to determine the relative copy number of five test genes on chromosome 18 (PACAP on 18p and DCC, SMAD2, SMAD4, and GALNR on 18q). We found allelic imbalance, as assessed by loss of heterozygosity, in at least one marker on chromosome 18 in 25 of the 29 tumors (86%) successfully tested. In 14 tumors, allelic imbalance was detected at all informative markers on 18q, while the other 11 tumors showed only partial loss. Allelic imbalance was most commonly detected at D18S363 (78% of informative cases). This marker is in closest proximity to SMAD4. By quantitative PCR analysis, a relative loss of copy number of SMAD2, SMAD4, and DCC were detected in 40%, 57%, and 53%, respectively, of the colitis-related cancers. SMAD2 was retained in four tumors having loss of SMAD4 and DCC. Loss of SMAD4 alone was seen in one tumor. The present data indicate that the loss of SMAD4 and DCC occurs in the majority of colitis-related cancers.

Adult↗

PubMed1993

Molecular events including p53 and k-ras alterations in the in vitro progression of a human colorectal adenoma cell line to an adenocarcinoma.

The aim of the current study was to identify genetic abnormalities in human colorectal adenoma and carcinoma derived cell lines, and to determine whether the genetic changes which occur in vitro are relevant to the in vivo situation. Loss of 1p(33-35) region was shown to be the most common chromosome 1 abnormality and loss of heterozygosity (LOH) of the DCC gene and/or adjacent sequences was detected in all adenoma derived cells as well as the carcinoma cell lines. The level of p53 protein was also investigated as increased cellular p53 protein had previously been associated with mutation of the p53 gene. A further aim was to investigate genetic changes in our in vitro model of tumour progression, where the adenoma derived PC/AA cell line has previously been converted in vitro to two distinct tumorigenic phenotypes, producing either an adenocarcinoma or a mucinous carcinoma in athymic nude mice. Progression to the adenocarcinoma phenotype was shown to involve a specific chromosome 1 rearrangement, loss of both normal copies of chromosome 18 (although DCC gene sequences were retained), loss of the remaining wild type allele of k-ras resulting in homozygosity for the k-ras codon 12 mutation and increased cellular p53 protein as detected by SDS-PAGE Western blotting. The increase in p53 protein was shown not to be due to the acquisition of a mutation in the p53 gene. Interestingly, progression of the adenoma derived PC/AA cell line to the mucinous malignant phenotype did not involve any of these molecular rearrangements, suggesting that different genetically distinct pathways are involved in colorectal carcinogenesis. These studies show that the genetic changes in our in vitro model of human colorectal tumour progression are similar to those observed in in vivo studies.

Adenocarcinoma↗

PubMed1993

[Metastasis related genes and malignancy in human esophageal, gastric and colorectal cancers].

Alterations in multiple oncogenes and multiple tumor suppressor genes are observed in human gastro-intestinal cancer. Among them, the most frequently implicated in malignancy and metastasis of esophageal carcinoma may be amplification and overexpression of the human cyclin D gene. In gastric carcinoma, amplification and abnormal expression of the c-met gene encoding receptor for hepatocyte growth factor (HGF) may contribute to the tumor progression and metastasis. Interaction between cadherin in c-met overexpressed tumor cells and HGF from fibroblast may play an important role in morphogenesis of two histological types of stomach cancer. During stomach carcinogenesis the clone having critical p53 mutations may expand selectively to make up a finally advanced stage of malignancy and show metastasis. In colorectal cancer, loss of heterozygosity of the RB, p53 and DCC genes is frequently associated with liver metastasis. Overexpression of nm23 may participate in carcinogenesis and the reduction in nm23 expression is involved in metastasis in gastric and colorectal cancers.

Colorectal Neoplasms↗

PubMed1992

[Genetic analysis of adenomatous polyposis coli: analysis of alterations of oncogenes and tumor suppressor genes in colorectal tumors].

Adenomatous polyposis coli (APC) is a genetic disorder transmitted as an autosomal dominant trait. This syndrome is characterized by the development of numerous polyps during the first 20-30 years of life and classified into two phenotypes according to the number of polyps: the profuse and sparse types. If left untreated, most or all affected individuals are at a high risk of developing adenocarcinoma by as early as 40 years of age. Therefore, comparison of APC adenocarcinomas with non-polyposis colorectal carcinomas (NPCC) was thought to be useful for understanding genetically determined carcinogenesis. I investigated gene alterations in specimens obtained from 53 APC patients, of which 16 represented the profuse type and the others the sparse type, and from 15 NPCC patients. The results are summarized as follows: 1) K-ras gene mutations were detected more frequently in the profuse-type adenomas (43%) than in the sparse ones (14%) (p less than 0.05). 2) Loss of heterozygosity on the long arm of chromosome 5(5q), 18(18q) and the short arm of chromosome 17(17p) in the profuse-type adenomas was observed more frequently (22%) than in the sparse ones (7.3%) (p less than 0.05). 3) No significant differences were observed between APC adenocarcinomas and NPCCs regarding the allelic deletions on 5q, 17p and 18q in these tumors. 4) The alteration of the DCC gene, which is known to be involved in the formation of NPCC, was frequently detected in the APC adenocarcinomas, suggesting that similar genetic events are involved in the oncogenesis of adenocarcinomas from APC and NPCC.

Adenomatous Polyposis Coli↗