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PubMed1995

Chromosome 18: a possible site for a tumour suppressor gene deletion in squamous cell carcinoma of the head and neck.

The present study analyses tumour samples from 41 patients with squamous cell carcinoma of the head and neck (SCCHN) using the polymerase chain reaction (PCR) to detect genetic alterations on chromosome 18. Microsatellite markers were used to examine each sample for loss of heterozygosity (LOH) and microsatellite instability. Genetic alterations were most commonly noted on the long arm of chromosome 18 (18q). LOH/microsatellite instability occurred on 18q in 20/41 (49%) of patients. The highest single incidence of LOH was found at 18q21.1-21.3 using the microsatellite marker D18S35. LOH occurred in 10/30 (33%) informative cases while LOH/microsatellite instability occurred in 13/30 (43%) informative cases using this marker. Interestingly the tumour suppressor gene known as the 'deleted in colonic carcinoma' (DCC) gene is located in this region at 18q21.3 but is not commonly lost. This suggests that the marker D18S35 is mapping close to a second as yet unidentified tumour suppressor gene in this area.

Adult↗

PubMed1997

Evidence that loss of chromosome 18q is associated with tumor progression.

Four sets of cell lines (UM-SCC-14A, -14B, and -14C; UM-SCC-17A and -17B; UM-SCC-81A and -81B; and UM-SCC-83A and -83B), established from primary and metastatic or locally recurrent tumors from four patients with squamous cell carcinoma of the head and neck, were examined for loss of heterozygosity (LOH) on chromosome 18q. Metastatic or recurrent cell lines from all four exhibited 18q LOH. UM-SCC-14A, -14B, and -14C, which were derived from locally recurrent (14A and 14B) and metastatic (14C) tumors, lost all of 18q. However, in the other three cases, there was a partial loss of 18q in the recurrent or metastatic tumor cell lines but not in the primary tumor cell lines from the same patient. To determine whether the cell lines accurately reflect in vivo loss of 18q, we analyzed matched sets of normal, tumor, and tumor cell line DNA from eight patients with squamous cell carcinoma of the head and neck, including the tumor tissue corresponding to UM-SCC-81B. Three of the additional seven tumors and cell lines had 18q LOH. For all eight cases in which tumor and corresponding cell line DNAs were analyzed, there was complete concordance between allelic loss in the tumor and allelic loss in the corresponding cell line. The common region of loss established by tumors and cell lines with partial loss includes 18q21-18qter. This region contains the putative tumor suppressor gene DCC and two Mad (Mothers against dpp)-related genes, DPC4 and MADR2, which are both components in a transforming growth factor-beta-like signaling pathway. Loss of 18q in metastatic and locally recurrent tumors, but not in primary tumors from the same patients, suggests that a tumor suppressor gene in this region may be important in the progression of squamous cell carcinoma.

Carcinoma, Squamous Cell↗

PubMed1999

Novel homozygous deletions of chromosomal band 18q22 in pancreatic adenocarcinoma identified by STS marker scanning.

The identification of homozygous deletions in sporadic neoplasms has been pivotal in the positional cloning of several tumor suppressor genes. Chromosomal arm 18q harbors the DPC4, SMAD2, and DCC genes and is suspected on the basis of high frequencies of allelic loss to harbor additional tumor suppressor genes. We applied high-resolution sequence-tagged site (STS) marker scanning to a panel of 106 pancreatic adenocarcinomas to identify novel regions of homozygous deletions on 18q. Three homozygous deletions were identified. Physical mapping of these deletions showed them to be nonoverlapping, but clustered in an approximately 7- to 10-Mb region of chromosome band 18q22. Each deletion spanned physical distances of nearly 1.3 to 3 Mb. A number of transcribed genes map within these deletions. The identification of these homozygous deletions might aid in the identification of novel tumor suppressor genes on chromosomal arm 18q. Genes Chromosomes Cancer 25:370-375, 1999.

Adenocarcinoma↗

PubMed1999

Expression of DCC protein in colorectal tumors and its relationship to tumor progression and metastasis.

A loss of heterozygosity (LOH) at the DCC gene locus was detected in colorectal tumors, and this LOH might be related to metastasis. The aim of this study was to determine DCC protein expression in colorectal cancer and to evaluate its prognostic value. Allelic loss of the DCC locus was observed in 16 of the 23 patients (66.7%). In all 16 patients with LOH, DCC expression was decreased in the cancer tissue compared with the adjacent normal mucosa. All 23 colorectal tumors had decreased expression of this protein relative to the adjacent normal colonic mucosa in Western blot analysis. The levels of DCC protein were significantly lower in cancer tissues than in adenoma tissues. Decreased DCC protein expression was also observed by immunohistochemistry in the colorectal cancer cases. There were significant correlations between DCC protein expression and histologic type, venous invasion, and hematogenous metastasis. Patients with DCC-protein-negative tumors had a greater relative risk of recurrence compared with those whose tumors were DCC protein-positive. The 5-year survival rate was 91.0% in patients with DCC-protein-positive tumors, and 58.8% in those with DCC-protein-negative tumors; these differences between the two groups of patients were significant (p < 0.01). In multivariate analysis using the Cox regression model, DCC protein expression emerged as an independent prognostic indicator. These findings suggested that a decrease in DCC expression may have an important role in the progression of colorectal cancers and may be a biologic marker of prognostic significance.

Adenoma↗

PubMed1992

Mutations of the p53 gene and other genes involving in human colorectal carcinogenesis.

In this study, structural changes of the p53 gene in primary specimens of human colorectal carcinomas were analyzed by polymerase chain reaction mediated-DNA sequencing method. Point mutations of p53 gene, including an intronic mutation case, were detected in 8 of 14 carcinomas (57%). Point mutations of the gene were also observed in 2 of 2 adenomas, suggesting that mutations occur prior to the carcinoma stage. These results support that p53 gene plays an important role in the development of colorectal cancer. The frequency of Ki-ras oncogene mutations was also studied by polymerase chain reaction-single strand conformation polymorphism analysis (PCR-SSCP). This resulted in the rate of 42% (10/24), a quite similar value obtained by other methods. As PCR-SSCP analysis is a convenient method to detect point mutation, we have now examined 24 colorectal cancers for the p53 gene by this method, and detected the mutations. Furthermore, expression of the DCC gene, a candidate of tumor suppressor gene involved in colorectal carcinogenesis, was examined by reverse transcriptase-mediated PCR (RT-PCR) assay, resulting in significant reduction on the DCC expression in 8 of 14 carcinoma cases (57%).

Adenoma↗

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↗

PubMed1993

DCC tumor suppressor gene is inactivated in hematologic malignancies showing monosomy 18.

DCC (deleted in colorectal cancer) is a candidate tumor suppressor gene recently identified on chromosome band 18q21. Loss of one DCC allele or decreased DCC expression occurs in more than 70% of colorectal cancers, suggesting that DCC inactivation constitutes a critical event in the development of these tumors. Using polymerase chain reaction amplification of cDNA, we have studied DCC expression in bone marrow from 4 patients with leukemia (1 chronic myeloid leukemia-blastic crisis, case 1; 1 acute myeloid leukemia, case 2; 1 T-cell acute lymphoblastic leukemia [ALL], case 3; 1 B-cell ALL, case 4) showing loss of one DCC allele due to monosomy 18. We also studied DCC expression in multiple control samples, including normal lymphocytes, normal tonsillar tissue, and leukemias without 18q abnormalities. Four primer pairs consistently amplified the predicted DCC sequences from cDNA prepared from all control samples. However, in samples with monosomy 18, DCC transcripts were either not detected (case 1) or detected at a very low level (cases 2, 3, and 4). Southern analysis showed no structural rearrangement of the remaining DCC locus in all leukemia samples. Thus, loss of DCC expression was demonstrated in association with loss of one DCC allele in all cases tested. These results suggest that, as for colorectal tumors, the inactivation of DCC can have a role in the development of hematologic malignancies.

Adult↗

PubMed1999

Loss of heterozygosity of APC and DCC tumor suppressor genes in human sporadic colon cancer.

We examined 36 cases of human sporadic colon carcinoma and corresponding normal tissue samples to evaluate loss of heterozygosity at the APC and DCC tumor suppressor genes loci using restriction fragment length polymorphism polymerase chain reaction and variable nucleotide tandem repeat analysis. Observed informativity was 83% for APC and 75% for DCC. DNA from 6 (20%) of 30 informative tumors exhibited loss of heterozygosity at the APC locus. Loss of heterozygosity at the DCC locus was observed in 7 (26%) of 27 informative tumor DNAs. Our results support the view that malignant progression is a consequence of more than one genetic change and suggest that inactivation of APC and DCC genes plays a role in a multistep process of colon tumor progression.

Adenocarcinoma↗

PubMed2005

Cloning of full-length zebrafish dcc and expression analysis during embryonic and early larval development.

Members of the DCC family play key roles in axon guidance in vertebrates as well as invertebrates. In zebrafish, only a short partial sequence of the dcc gene has been reported to date. Here, we report the cloning of full-length zebrafish dcc. Zebrafish DCC shares the typical structure of the DCC subgroup of the immunoglobulin superfamily, consisting of four immunoglobulin and six fibronectin-type III repeats in the extracellular domain, a single transmembrane domain, and an intracellular domain with three conserved motifs. As a first step toward studying the function of dcc, we analyzed its sequence and characterized its expression pattern during embryonic and larval development. dcc is expressed highly in brain and spinal cord, but distinct staining was also observed in developing pectoral fins, pancreas, intestine, and heart. Thus, dcc may play roles not only in axon guidance, but in morphogenesis and functioning of these organs as well.

Amino Acid Sequence↗

PubMed1999

Expression of the deleted in colorectal cancer gene is related to prognosis in DNA diploid and low proliferative colorectal adenocarcinoma.

PURPOSE: Whether or not the deleted in colorectal cancer (DCC) gene is implicated in metastases or in predicting prognosis in patients with colorectal cancer has not previously been substantiated. Our aims were to investigate DCC expression in primary colorectal cancers and in metastases to identify any prognostic significance. PATIENTS AND METHODS: DCC expression was examined immunohistochemically in 195 primary colorectal adenocarcinomas and in 23 paired primary tumors and lymph node metastases. DNA content and S-phase fraction were measured by flow cytometry. RESULTS: The absence of DCC expression was observed in 55 primary tumors (28%). DCC negativity was significantly related to poor prognosis in patients with DNA diploid tumors (P =.03) and those with a low S-phase fraction (< 5%, P =.02) but not in patients with nondiploid tumors or those with a higher S-phase fraction. Furthermore, DCC expression retained its prognostic significance in the diploid subgroup after adjusting for sex, age, site, stage, growth pattern, and differentiation (P =.01). DCC expression was similar in primary tumors and their metastases. CONCLUSION: The absence of DCC predicted a poor outcome in the patients with diploid tumors and those tumors with a low S-phase fraction. Immunohistochemistry may be considered as a practical test to assess prognosis in this subgroup of patients.

Adenocarcinoma↗

PubMed2000

No SMAD4 hypermethylation in colorectal cancer.

The chromosome region 18q21 is frequently deleted in colorectal cancers. Three candidate tumour suppressor genes, DCC, SMAD4 and SMAD2, map to this region. The SMAD4(DPC4) gene was recently identified as a candidate pancreatic cancer suppressor gene. It is also a gene for juvenile polyposis tumour predisposition syndrome. Somatic SMAD4 mutations have been detected in some colorectal carcinomas. However, the frequency of these mutations is relatively low, and whether SMAD4 plays a key role in colorectal tumorigenesis is still unclear. In addition to loss of chromosomal material and intragenic mutations there is a third mechanism, DNA methylation, which may have an important role in gene inactivation. In the present study, we examined whether promoter hypermethylation could be a mechanism for SMAD4 inactivation. In total, 42 colorectal tumours were selected for the methylation analysis and no evidence of promoter hypermethylation was found. Our result suggests that hypermethylation of the SMAD4 promoter region is not a frequent event in colorectal tumorigenesis.

Adenocarcinoma↗

PubMed1992

Suppressor gene alterations in the colorectal adenoma-carcinoma sequence.

Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate to bring about the neoplastic phenotype. Colorectal tumors appear to arise as a result of the mutational activation of oncogenes coupled with the inactivation of several tumor suppressor genes. We have found frequent allelic deletions of specific portions of chromosomes 5, 17, and 18 which presumably harbor suppressor genes. The target of allelic loss events on chromosome 17 has been shown to be the p53 gene, which is frequently mutated not only in colon cancer but in several other tumor types as well. Candidate suppressor genes have also recently been identified on chromosomes 18 and 5. The DCC gene on chromosome 18q encodes a protein with significant sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. Alterations of this gene may interfere with normal cell growth and differentiation by disrupting cell-cell or cell-substrate interactions. Two genes (MCC and APC) on chromosome 5q have also recently been identified and partially cloned. These genes are located in a region tightly linked to familial adenomatous polyposis (FAP). While MCC mutations have been found only in sporadic colon tumors, APC mutations have been identified in sporadic tumors as well as the germline of patients with FAP. Studies are currently in progress to increase our understanding of how alterations of these genes affect colorectal tumor cell growth.

Adenoma↗

PubMed1999

In vitro analysis of the role of DCC in mucus-secreting intestinal differentiation.

The deleted in colorectal cancer (DCC) gene was initially described as a colon cancer-associated tumor suppressor gene and subsequently proposed to be involved in goblet cell differentiation, but its precise role in normal intestine physiology and in cancer remains to be established. We have analyzed DCC mRNA expression in a panel of human colorectal cancer cell lines with a variety of differentiation phenotypes by reverse transcription-polymerase chain reaction (RT-PCR) and have shown that (1) most cell lines showed lower levels of DCC mRNA than normal colonic tissue; (2) only 1 cell line lacked detectable levels of DCC mRNA expression; (3) a discrepancy was found between the detectability of RT-PCR products corresponding to the extracellular and intracellular domains of DCC; and (4) there was no association between the presence of DCC transcripts and the differentiation phenotype. Specifically, DCC was not exclusively associated with the mucus-secreting phenotype, as determined by Alcian blue staining and Northern blotting with mucin gene probes. This was further supported by immunohistochemical results on DCC product and mucins in normal colon: DCC was detected in both goblet and absorptive cells. The introduction of full-length DCC cDNA in undifferentiated HT-29 cells did not have any effect on their differentiation phenotype, as shown by morphological studies and analysis of markers for this process in colon, such as mucins, dipeptidylpeptidase IV, villin and sucrase-isomaltase. There were no effects on cell proliferation in vitro. Our results indicate that DCC is not selectively involved in the mucosecretory differentiation pathway and that it is neither sufficient nor essential for normal intestinal differentiation.

Cell Adhesion Molecules↗

PubMed2000

Allelic imbalance on chromosome 18 in neuroblastoma.

We previously demonstrated that chromosome 18 is frequently deleted in neuroblastoma. To further elucidate the role of chromosome 18 deletions in the development of neuroblastomas we examined 82 cases of neuroblastomas for allelic imbalance (AI) at 17 loci on chromosome 18 to define the common region of AI in neuroblastoma. AI at one or more loci on chromosome 18 was detected in 18/82 (22%) cases. AI on 18q was detected in 17/82 (21%) cases, whereas AI on 18p was detected in 4/82 (5%) cases. There was a distinct common region of AI at 18q21.1 between the D18S363 and D18S858 loci. In addition, cases 16 and 53, which did not show AI at 18q21.1, showed AI at 18pter-q12.3 between the D18S52 and D18S36 loci, indicating that another common region of AI may exist on chromosome 18. AI on chromosome 18 did not significantly correlate with any clinicopathological findings of patients with neuroblastoma. The common region of AI at 18q21.1 includes the DCC gene but not the Smad2 and Smad4 genes. However, our previous studies together with the present study indicated that the incidence of DCC mutation is much less than that of AI at 18q21.1 in neuroblastoma. These results indicate that novel tumour suppressor genes involved in the development of neuroblastoma are present at 18q21.1, and possibly at 18pter-q12.3.

Blotting, Southern↗

PubMed1995

Genetic alterations of microsatellites on chromosome 18 in human breast carcinoma.

Allelic alterations of chromosome 18 microsatellites were determined using normal and tumor DNA pairs from 29 patients with infiltrating ductal carcinoma of the breast. Loss of heterozygosity was detected in 62% (18 of 29 patients) of the tumors at one or more of these microsatellites. Eight of the 18 patients exhibited deletions in the region at 18q21.1. This chromosomal band is known to contain a tumor suppressor gene (DCC) whose expression is frequently inactivated in several types of cancer. Ten other patients had deletions in regions not included in the DCC locus. Five of these patients revealed a common deletion at the D18S50 locus (18q23), and the other five patients had deletions in various other regions of the chromosome. No apparent correlation between loss of heterozygosity of chromosome 18 microsatellites and the clinical stage was found in this series. The results indicate that, in addition to the DCC locus, the 18q23 region is likely to contain a second tumor suppressor gene relevant to breast carcinogenesis. Four percent of all microsatellites tested in these patients showed allelic differences in the sizes of repeat units between tumor and the corresponding constitutional DNAs. The pattern of allele instability observed in breast carcinoma differed from that originally reported in a hereditary type of colorectal carcinoma. The observation suggests that this phenomenon is not a mechanism specific to neoplastic processes in breast carcinoma.

Alleles↗

PubMed1992

Characterization of murine cell lines from diethylstilbestrol-induced uterine endometrial adenocarcinomas.

Neonatal treatment with estrogens is associated with development of uterine adenocarcinomas in CD-1 mice. Treatment with the synthetic estrogen diethylstilbestrol (DES) on Days 1 to 5 after birth results in 90% incidence of these hormone-dependent lesions in 18-mo.-old mice. Three cell lines were established from these DES-associated tumors. Each of these cell lines exhibited morphologic and ultrastructural characteristics of transformed epithelial cells, including an increased nuclear:cytoplasmic ratio, enlarged and irregular nuclei with multiple nucleoli and areas of chromatin condensation, positive staining for cytokeratin, desmosomes, and microvilli. After subcutaneous injection into nude mice, all three cell lines formed solid tumors within 4 wk. Although the primary uterine tumors and tumor transplants in nude mice had been shown to be estrogen-dependent and estrogen-receptor positive, neither the monolayer growth nor the tumorigenicity of any of the three cell lines in this study was enhanced by or dependent on estrogen. Estrogen receptor levels were low in early and intermediate passage cells. Allele-specific oligonucleotide hybridization analysis of PCR-amplified cell line DNA revealed no point mutations in the 12th, 13th, or 61st codons of the K-ras or H-ras protooncogenes. Southern analysis revealed no changes in genomic organization of the putative tumor suppressor gene DCC, but demonstrated a three- to four-fold amplification of the c-myc gene in one cell line. Expression of c-myc RNA was concomitantly increased in the same cell line. These three transformed cell lines represent the end point in the process of hormone-associated tumorigenesis and as such should prove useful in investigating the molecular changes and the mechanisms involved in hormonal carcinogenesis.

Adenocarcinoma↗

PubMed1995

Decreased expression of DCC mRNA in gastric and colorectal cancer.

The deleted-in-colorectal-cancer (DCC) gene, located on chromosome 18q 21.3, is considered to be a tumor suppressor gene related to cellular adhesion receptors. A loss of heterozygosity (LOH) on chromosome 18q is frequently observed in adenomatous polyposis coli, as well as in sporadic colon carcinoma and its liver metastatic loci. In this study, we investigated the expression of DCC mRNA in the resected specimens of 38 gastric cancers and 28 colorectal cancers by a reverse transcription-polymerase chain reaction method. In the gastric cancer patients, the mean expression level of DCC mRNA in the tumors was significantly lower than that in normal tissues (p = 0.009), but no difference was observed in the colorectal cancer patients. DCC mRNA expression was decreased in 15 gastric cancers (40%) and 10 colorectal cancers (36%), and there was a significant correlation between the decreased expression of DCC mRNA and nodal metastasis in colorectal cancer (chi 2 = 7.049, DF = 1, P = 0.0079). Two of four gastric cancer patients and none of seven colorectal cancer patients whose cancers were confined to the muscularis propria without metastasis showed decreased expression of DCC mRNA. These findings demonstrate that decreased expression of DCC mRNA may occur at an early stage in gastric cancer and at a late stage in colorectal cancer and that this decreased expression correlates with the potential to develop nodal metastasis.

Cell Adhesion Molecules↗

PubMed1994

[Tumor suppressor genes. New perspectives for clinical investigations in cancer].

Tumor origin is viewed as comprising a series of specific genetic events in target cells and their clonal descendants. The development of molecular biology during the last decade has led to the recognition that these events fall into two distinct categories: the activation of protooncogenes and the inactivation of tumor suppressor genes. The latter are genes the inactivation of which is required for the malignant transformation of a cell. Loss of tumor suppressor genes plays an important role in the development of human tumors. Studies with somatic cell hybrids have shown that tumor suppression occurs in neoplastic cells and can be corrected by cell fusion with normal human chromosome. These experiments proved that tumorigenicity is a recessive phenotype controlled by specific chromosomes. Certain tumor suppressor genes, e.g. p53 and RB1, may be involved in a variety of malignancies whereas others, e.g. the DCC gene, may be restricted to a single type of cancer. The detection of germline mutations in tumor suppressor genes should allow the identification of subjects at high risk of developing cancer.

Cell Transformation, Neoplastic↗