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PubMed1997

Identification and characterization of neogenin, a DCC-related gene.

DCC (deleted in colorectal cancer), a candidate tumor suppressor gene located in chromosome band 18q21.2, encodes a transmembrane protein of 1447 amino acids. Neogenin, a protein with nearly 50% amino acid identity to DCC, was recently identified because of its dynamic expression in the developing nervous system and gastrointestinal tract of the chicken. To explore a role for the human neogenin (NGN) gene in cancer, we have isolated cDNAs for two alternatively spliced forms of NGN, encoding proteins of 1461 and 1408 amino acids. Fluorescence in situ hybridization studies (FISH) localized NGN in chromosome band 15q22, a region infrequently affected by alterations in cancer. NGN transcripts of about 7.5 and 5.5 kb were detected in all adult tissues studied. In contrast to the frequent loss of DCC expression, no alterations in NGN expression were observed in more than 50 cancers studied, including glioblastoma, medulloblastoma, neuroblastoma, colorectal, breast, cervical and pancreatic cancer cell lines and xenografts. Based on their sequence conservation and similar expression during development, DCC and NGN may have related functions. However, the chromosomal location and ubiquitous expression of NGN in various human tumors suggest it is infrequently altered in cancer.

Adult↗
PubMed2004

No association between the Arg201Gly polymorphism of the DCC gene and colorectal cancer.

BACKGROUND AND AIMS: In one small study, the DCC Arg201Gly polymorphism has been observed more frequently in colorectal cancer cases compared with controls. We wondered whether these results could be replicated in a much larger study. METHODOLOGY: The DCC Arg201 Gly polymorphism was genotyped in 625 unselected Caucasian colorectal cancer patients and 220 controls. Association analysis was used to search for a difference between patients and controls. Subgroup analyses were performed for site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification. RESULTS: The association analyses revealed no difference in Arg201Gly genotype frequency between patients and controls, neither overall nor for different subgroups according to site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification. CONCLUSION: No association was observed between the Arg201Gly polymorphism of DCC and colorectal cancer risk.

Adult↗
PubMed2006

[Growth inhibitory effects of lipofectamine-mediated DCC gene on ovarian epithelial carcinoma].

OBJECTIVE: To study the inhibitory effects of lipofectamine-mediated deleted colorectal carcinoma gene on ovarian epithelial carcinoma (ovarian cancer) cell line SKOV3. METHODS: We constructed a recombinant eukaryotic expression vector pcDNA3.1 (+)-DCC containing exogenous human DCC cDNA and vector with neomycin resistance gene, which were introduced by lipofectamine-mediated gene transfection into SKOV3 cell line that does not express DCC endogenously, thus forming SKOV3/DCC. Therefore, the experimental cells were classified into SKOV3/DCC, SKOV3/Neo and SKOV3. By using reverse transcriptase-polymerase chain reaction and immunocytochemistry, the expression of DCC mRNA and its protein were examined. RESULTS: Exogenous DCC had successfully been transferred into SKOV3 cells and obtained permanent expression. The growth speed of SKOV3/DCC was slower than the other two groups, there was significant difference between them (P < 0.01). SKOV3/DCC clones number was 38 +/- 8, while SKOV3 and SKOV3/Neo were 192 +/- 8 and 186 +/- 10, respectively, there was significant difference between them (P < 0.01). The percentage of G(1) phase cells increased to 78.0%, which that of S phase decreased to 5.3% by analyzing cell cycle, there was significant difference between them (20.0% and 3.2%, P < 0.01). The ultrastructural changes of the cells were observed under electron microscope, revealing growth retardation. CONCLUSION: DCC gene played an important role in generation and development of ovarian carcinomas.

Cell Cycle↗
PubMed1999

Infrequent loss of heterozygosity of APC/MCC and DCC genes in gastric cancer showing DNA microsatellite instability.

AIM: To investigate the role of DNA microsatellite instability (MSI) in gastric carcinogenesis by studying associations between MSI status, clinicopathological features, and loss of genetic loci. METHODS: Six microsatellite loci and loss of heterozygosity at APC, DCC, and MCC were analysed by polymerase chain reaction based methods in 53 cases of advanced gastric cancer. RESULTS: MSI was observed in 32.1% of gastric carcinomas (17/53) and 20% of foci of intestinal metaplasia (3/15). Seven gastric carcinomas (13.7%) were MSI-high (MSI-H) (three loci or more) and 10 (18.9%) were MSI-low (MSI-L) (one or two loci). The frequency of MSI-H was higher in intestinal (25.0%) than in diffuse carcinomas (3.7%) (p < 0.05). None of the MSI-H tumours showed loss of heterozygosity at APC, MCC, or DCC loci. CONCLUSIONS: MSI may have an important and early role in a subset of gastric cancers, particularly the intestinal type. The MSI-H subset of gastric cancer has features in common with its colorectal counterpart, whereas MSI-L and microsatellite stable cancers appear to develop through the loss of heterozygosity pathway.

Adult↗
PubMed2005

Hypermethylation of the putative tumor-suppressor genes DCC, p51/63 and O6-methylguanine-DNA methyltransferase (MGMT) and loss of their expressions in cell lines of hematological malignancies.

Alterations and defective expression of three putative tumor-suppressor genes, the deleted in colorectal cancer (DCC), p51, and O(6)-methylguanine-DNA methyltransferase (MGMT), have been demonstrated in many cancers. However, it is not known whether the defective expression of each of these genes is independent or whether it reflects a specific methylation abnormality. Here, we investigated the expression of the DCC, p51 and MGMT genes and the methylation status of the 5' flanking CpG region in 17 cell lines established from hematological malignancies. The reverse transcriptase-polymerase chain reaction method showed DCC expression to be absent in 13 of the 17 cell lines and showed expression of both p51 and MGMT to be absent in 5 of the 17 cell lines. The methylation patterns were analyzed with methylation-specific polymerase chain reaction (MSP) of the 5'flanking region of the DCC and p51 genes and the promoter region of the MGMT gene. Although unmethylated patterns of the CpG region in the DCC, p51, and MGMT genes were observed in all 11 normal controls, abnormal methylation patterns of these genes were found even in many cell lines expressing these genes. A hypermethylation pattern was detected for the CpG region of MGMT and p51 in cells that did not express these genes. In contrast, a hypermethylation pattern was not always detected for the CpG region of DCC in cells with reduced DCC expression. The results of this study indicate that in many hematological cell lines, the DCC, p51, and MGMT genes have been abnormally methylated in the CpG region. Hypermethylation of these three genes may be independent events in each cell line.

Cell Line, Tumor↗
PubMed1992

Persistent expression of the tumor suppressor gene DCC is essential for neuronal differentiation.

Cell differentiation is associated either with a complete loss of proliferative potential or with a change in growth requirements. Neoplastic transformation may result from the activation of oncogenes that support growth or from inactivation or loss of tumor suppressor genes, which are thought to regulate differentiation. To examine the relationship between tumor suppressor genes and cell differentiation, we chose the gene "deleted in colorectal cancer" (DCC) and studied its role in a pheochromocytoma cell line, PC-12, using antisense RNA as well as antisense oligonucleotides to DCC. When exposed to nerve growth factor for several days, PC-12 cells develop long dendrites. This morphological change follows the transient expression of immediate early genes and is associated with an up-regulation of DCC. Interestingly, if the up-regulation of DCC was counteracted using an antisense RNA technique, the morphological changes were prevented, but the other parameters of the nerve growth factor response were unaffected. Moreover, when DCC expression was inhibited by antisense oligonucleotides to DCC in nerve growth factor-differentiated cells, the neuron-like phenotype was reversed. Our results demonstrate that the gene DCC is involved in a distal segment of neural differentiation and provide the first direct evidence that a tumor suppressor gene plays a role in cell differentiation.

Animals↗
PubMed1993

Tumor suppressor gene allelic loss in human renal cancers.

It is now apparent that multiple genetic alterations, including oncogene activation and tumor suppressor gene inactivation, are necessary steps in carcinogenesis. We have studied this concept in renal cancers by looking at specific tumor suppressor genes implicated in several allelotyping studies. Primary, predominantly low stage renal tumors of varying grades and histologic subtypes were investigated for allelic loss of 3p, 17p and the p53 gene, the DCC gene and the Rb gene and its product. 3p loss occurred in 47% of tumors studied and was much more common in clear cell cancers (85%). 17p and p53 gene loss were relatively uncommon events with only 6 of 42 tumors demonstrating loss. None of the tumors with typical histologies had allelic loss of the DCC gene, though loss did occur in leiomyosarcoma and a collecting duct tumor. Allelic loss of the Rb gene occurred in one clear cell tumor, the leiomyosarcoma, and, interestingly, in both collecting duct tumors in this series. Allelic loss of the Rb gene was correlated with little or no RB protein expression as judged by immunohistochemistry. At all loci studied, allelic loss did not appear to correlate with tumor grade or stage. These results suggest that inactivation of the p53, Rb, and DCC genes by allelic loss are uncommon events in the early stages of renal carcinogenesis.

Blotting, Southern↗
PubMed1993

[Analysis of molecular mechanism in colorectal tumorigenesis].

Genetic alterations of Ki-ras gene, p53 gene, and DCC gene were analyzed in human colon cancer cell lines (HCCLs). On the basis of these analyses, a HCCL (HCT116)-human chromosome 18 hybrids, and targeted cell lines that were disrupted at the activated Ki-ras gene in HCCLs (HCT116 and DLD-1), were established. Tumorigenicity and expression of c-myc gene were investigated in these cell lines, respectively. 1. Point mutations of Ki-ras gene, p53 gene, and insertion mutations of DCC gene were detected in 10 out of 18 HCCLs, 8 out of 15 HCCLs, and 3 out of 16 HCCLs, respectively. 2. HCT116-chromosome 18 hybrids were morphologically similar to the parental line, and were not suppressed for tumorigenicity in vitro, but they produced slowly growing tumors in nude mice compared with the growth of the parental line. 3. The targeted cell lines that were disrupted at the activated Ki-ras gene were morphologically altered and lost neoplastic phenotypes, including tumorigenicity in nude mice and anchorage-independent growth. Furthermore, expression of c-myc gene in these clones was much reduced compared with findings in the parental line, regardless of their growth rates.

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↗
PubMed1997

Expression and mutational analysis of the DCC, DPC4, and MADR2/JV18-1 genes in neuroblastoma.

Loss of heterozygosity (LOH) on chromosome 18q21 is found frequently in various human cancers. Three candidate tumor suppressor genes, DCC (deleted in colorectal carcinomas), DPC4 (deleted in pancreatic carcinomas, locus 4), and MADR2/JV18-1 (MAD-related gene 2), have been cloned and identified from this chromosome region. We have reported recently that LOH on chromosome 18q is observed frequently in neuroblastoma. Alterations of DCC are involved in many human tumors. DPC4 and MADR2/JV18-1 are recently demonstrated to be altered in pancreatic and colorectal cancers, respectively. To confirm if inactivation of the DCC, DPC4, and MADR2/JV18-1 genes is involved in the pathogenesis of neuroblastoma and to clarify the mechanism of inactivation, we analyzed the expression of DCC, DPC4, and MADR2/JV18-1 in neuroblastoma cell lines and primary tumors by reverse transcription-PCR and investigated the mutations in the coding regions of these genes by PCR/reverse transcription-PCR single-strand conformation polymorphism. We found that 12 of 25 (48%) cell lines and 14 of 32 (44%) primary tumors, including 3 with 18q LOH, had absent or reduced expression of DCC mRNA. Expression was more likely to be reduced in advanced (67%) than in early stage neuroblastomas (24%) (P = 0.036), suggesting that inactivation of the DCC gene plays an important role in the progression of neuroblastoma. Altered expression of DPC4 was found in six (24%) cell lines and six (19%) tumors. MADR2/JV18-1 expression was reduced or absent only in four (16%) cell lines and three (9%) tumors. Mutations of the DCC genes were examined in 25 of 29 exons in neuroblastoma cell lines, and those exons in which mutations were found were further examined in primary tumors. We found missense mutations of AAC (Asn) to AGC (Ser) at DCC codon 176 in one cell line and ACC (Thr) to ATC (Ile) at codon 1105 in one cell line and tumor, respectively; polymorphisms of CGA (Arg) to GGA (Gly) at codon 201 and TTT (Phe) to TTG (Leu) at codon 951 in most of the cell lines and tumors; and a silent mutation of GAG (Glu) to GAA (Glu) at codon 118 in four cell lines and five primary tumors. We did not identify any mutations in the DPC4 and MADR2/JV18-1 genes in neuroblastoma. Our results suggested that mutations of the DCC gene may be involved in the pathogenesis of neuroblastomas but failed to account for the relatively high frequency of the altered expression, implying that other mechanisms are responsible for the inactivation of the DCC gene in neuroblastoma. Low frequency of reduced or absent mRNA expression and lack of mutations in DPC4 and MADR2/JV18-1 genes suggested a limited role for these two genes in neuroblastoma.

Cell Adhesion Molecules↗
PubMed2003

[Study on the expression of the gene deleted in colorectal carcinoma in ovarian carcinoma].

OBJECTIVE: The purpose of this study was to explore the relationship between the loss of the gene deleted in colorectal carcinoma (DCC) gene expression in ovarian carcinoma and the transformation, progression of the tumor and its clinicopathological factors. METHODS: DCC gene mRNA expression were examined by reverse transcription polymerase chain reaction (RT-PCR) in 34 malignant, 10 benign and 10 normal ovarian samples. To clarify the expression of DCC gene by the DNA cloning and the DNA sequencing analysis in normal ovarian sample. RESULTS: The expression of DCC gene was lost in no normal ovarian tissues, in 2 (2/10) benign lesions, while the loss of DCC gene expression was found in 19 (19/34, 56%) carcinomas (P < 0.05). Similar findings were also noted when subdivision was into serous (14/18) and mucinous (4/11) categories (P < 0.05). The percentage of the loss of DCC gene expression in stage III - IV was 68%, in stage I - II was 22%, as well as 42% in grade I - II and 90% in grade III. 61% of the carcinoma with metastasis presented the loss of DCC gene expression, then there was 33% in which without metastasis. CONCLUSIONS: In ovarian carcinomas, loss of DCC gene expression was significantly related to the serous phenotype, a high histological grade and a more advanced stage. The results indicated that loss of DCC gene expression may play an important role in ovarian carcinomas and its progression.

Cell Adhesion Molecules↗
PubMed1991

[Tumor-suppressor genes].

The existence of tumor-suppressor genes has been primarily suggested by three lines of evidences: 1) the suppression of transformed phenotypes of tumor cells by cell-cell hybridization with normal cells; 2) non-random chromosome deletions in a variety of tumors; 3) loss of heterozygosity in specific chromosomal regions in tumor cells. Results from monochromosome transfer experiments also suggest the existence of multiple, functionally distinct tumor-suppressor genes. Recently, several tumor-suppressor genes, which appeared to be functionally distinct, (i.e., Rb gene, WT gene and DCC gene) were isolated. Most recently, it was suggested that the inactivations of at least three different tumor-suppressor genes were required for the colorectal carcinogenesis at different steps. Thus, these findings support that losses or alterations in the dosage of multiple tumor-suppressor genes play crucial roles during initiation and/or progression of a wide variety of cancers.

Eye Neoplasms↗
PubMed1994

Somatic allelic loss at the DCC, APC, nm23-H1 and p53 tumor suppressor gene loci in human prostatic carcinoma.

We present a restriction fragment length polymorphism (RFLP) analysis of 29 benign and 30 malignant prostatic tumors, using polymorphic DNA probes to the putative tumor suppressor genes DCC (Deleted in Colorectal Carcinoma; chromosome 18q21.3), nm23-H1 (17q21.3), APC (Adenomatous Polyposis Coli; 5q21) and p53 (17p13). Six of 23 evaluable cancers (26%) showed loss of heterozygosity (LOH) at DCC; 5 were advanced stage and one was clinically localized (p < 0.05). Mapping 18q deletions, another (advanced) cancer showed LOH at a locus distal to DCC (18q22), but no LOH at DCC. Three of 15 evaluable cancers (20%), all advanced, showed LOH at APC. Three of eight (38%) cancers, of which 2 were advanced, showed LOH at p53. One high grade/stage cancer of 21 (5%) showed LOH at nm23-H1 (and also at DCC). Combining data, allelic losses at either DCC, APC, or p53 genes were seen in 13% of localized cancers, but in 71% of advanced cancers (p < 0.002). Allelic loss involving nm23-H1 is rare in prostatic carcinoma. We suggest that loss of tumor suppressor genes DCC and/or an unidentified gene located distally on chromosome 18q, APC, or p53 may influence progression in prostatic carcinoma.

Adenocarcinoma↗
PubMed1994

Studies of the deleted in colorectal cancer gene in normal and neoplastic tissues.

Chromosome 18q is among the chromosomal regions thought to harbor a tumor suppressor gene(s) that is frequently inactivated during the development of several cancer types, particularly those of the gastrointestinal tract. Moreover, preliminary data suggest that colorectal cancers with 18q LOH have a more aggressive clinical behavior than those cancers without 18q LOH. A candidate tumor suppressor gene from 18q, termed DCC for deleted in colorectal cancer, has been identified. The DCC gene is contained within the common region of LOH on 18q, its expression is markedly decreased or absent in colorectal cancers and cell lines, and a subset of colorectal cancers have been shown to have somatic mutations within the DCC gene. Thus, DCC represents the most promising candidate tumor suppressor gene from 18q. At present, however, many questions remain regarding the mechanisms underlying the inactivation of DCC in the majority of colorectal cancers. In addition, although studies of 18q LOH and DCC gene expression in other cancer types suggest that DCC inactivation may contribute to the pathogenesis of other tumor types, few studies have provided definitive data to demonstrate that DCC inactivation is a critical genetic event in these tumors. Moreover, little is known about the function of DCC in the regulation of normal cell growth and tumor suppression. The predicted structural similarity of DCC to the N-CAM family of cell-surface proteins suggests that it may function through cell-cell and/or cell-extracellular matrix interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Alterations in the deleted in colorectal carcinoma gene in human primary leukemia.

To evaluate the role of the deleted in colorectal carcinoma (DCC) gene in leukemogenesis, we examined loss of heterozygosity (LOH) in the DCC gene in 64 primary human leukemias using Southern blot analysis and examined the expression of the DCC gene using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Allelic loss in the DCC gene was observed in two patients (6%, 2 of 35 informative cases), and expression of the DCC gene was reduced or absent in 8 of 26 (31%) patients with acute myelogenous leukemia (AML), 3 of 9 (33%) patients with acute lymphocytic leukemia (ALL), and 7 of 29 (24%) patients with chronic myelogenous leukemia (CML). Moreover, in one ALL patient with absent DCC expression at diagnosis, its expression became normal after performing chemotherapy and achieving remission. These findings suggest that inactivation of the DCC gene contributes to some instances of leukemogenesis.

Alleles↗