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PubMed1994

Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors.

Mutation of the adenomatous polyposis coli (APC) gene was analyzed in 500 colorectal tumors from 70 familial adenomatous polyposis (FAP) and 102 non-FAP patients and in normal tissues from 119 FAP patients, using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing methods. These tumors were histopathologically diagnosed. Sixty-eight germ line mutations (62% deletion, 9% insertion, and 29% single-base substitution) and 241 somatic mutations (56% deletion, 12% insertion, and 32% single-base substitution) were detected. All mutations formed stop codons resulting in truncated APC proteins, except for one germ line mutation. Differences were found between somatic and germ line mutations, including 3 new hot spots of mutation at codons 1378, 1450, and 1487-1490, which frequently occurred in somatic mutations but not in germ lines. The frequency of mutation in each histopathological type of FAP tumor was 53% in moderate adenoma, 64% in severe adenoma, 52% in intramucosal carcinoma, and 33% in invasive carcinoma, whereas the loss of heterozygosity including the APC gene increased with development to each histopathological type. A similar tendency was observed in non-FAP tumors. Additionally, we found 10 FAP tumors that had both somatic mutation and loss of heterozygosity. These tumors were assumed to have developed from moderate adenomas with germ line and somatic mutations, followed by deletion of the allele with germ line mutation. These results suggest that inactivation of the APC gene by two mutations is involved in the development of moderate adenoma, and loss of heterozygosity of the APC gene is associated with further development to carcinoma. It was also observed that the distribution of 75 somatic mutations from one FAP patient on the APC sequence was similar to the distribution of 159 somatic mutations from 83 patients with FAP and non-FAP, which suggests that the position of somatic mutation is mostly due to the APC sequence itself.

Adenoma↗

PubMed2001

Expression of the E-cadherin-catenin complex in lung neuroendocrine tumours.

Neuroendocrine tumours (NETs) of the lung represent a wide spectrum of phenotypically distinct entities, with differences in tumour progression and aggressiveness. The redistribution and/or the loss of various cell adhesion molecules, such as the E-cadherin-catenin complex, play a predominant role in carcinogenesis and in tumour invasion. Moreover, mutations in exon 3 of the beta-catenin gene, the adenomatous polyposis coli (APC) gene or the E-cadherin genes were previously found to result in intracytoplasmic and/or nuclear beta-catenin protein accumulation, activating nuclear transcription of target genes involved in tumour progression. In the present study, the distribution of the components of this E-cadherin-catenin complex has been investigated by immunohistochemistry and an attempt has been made to correlate the abnormal expression pattern with the eventual detection of mutations in the corresponding genes. This study included 27 primary NETs of the lung, with nine typical carcinoids (TCs), three atypical carcinoids (ACs), and 15 large cell neuroendocrine carcinomas (LCNECs). The E-cadherin-catenin complex remained expressed in most of these lung tumours, but with a cytoplasmic and/or nuclear redistribution of beta-catenin, E-cadherin, and alpha-catenin; abnormal positive immunoreactivity was observed in 24 (88.9%), in 21 (80.8%), and in 20 (76.9%) NETs, respectively. In the great majority of cases, there was a good correlation between the expression of these three proteins, but no significant association with histological classification or TNM stage. Thus, E-cadherin-complex redistribution cannot be considered a prognostic marker in NET of the lung. Of particular interest was the frequent focal beta-catenin nuclear immunostaining (55.5% in total), which was also unrelated to histological type or TNM stage. However, this study failed to detect any mutation in exon 3 of the beta-catenin gene, in the APC gene or in the E-cadherin gene. These data suggest another mechanism of regulation of beta-catenin in these tumours.

Adult↗

PubMed1997

Molecular analysis of the adenomatous polyposis coli gene in sarcomas, hematological malignancies and noncolonic, neoplastic tissues.

Somatic mutations of the adenomatous polyposis coli (APC) gene have been frequently found in sporadic colorectal tumors, and the frequency of such mutations remain constant as tumors progress from benign adenomas to malignant cancers. Thus the mutations of the APC gene may have a major role in the early development of sporadic colorectal tumors. Whether inactivation of the APC gene accounts for other types of primary tumors is still being investigated. We investigated for APC mutations within the mutation cluster region (a 684-bp region containing most of the mutations found in colorectal tumors) in 317 samples from a wide variety of human malignant and premalignant tissues, including 40 lung cancers, 47 renal cell carcinomas, 41 osteosarcomas and 21 other types of sarcomas, 45 acute lymphoid leukemias/lymphomas, 33 acute myeloid leukemias, 27 myelodysplastic syndrome samples, and 20 chronic colitis (ulcerative colitis and Crohn's disease) associated cancers and dysplasias, and 43 human malignant cell lines. We used single-strand conformation polymorphism assay following polymerase chain reaction. Samples with abnormal assay results were reamplified and analyzed by the direct DNA sequencing method. We detected a total of two cases with a base substitution. A silent mutation was detected in a case of myelodysplastic syndrome, and a novel nonsense mutation was discovered in a colorectal cancer cell line, SW837. In summary, we did not detect any functional mutations of the APC gene in a wide variety of tumors except for a colon cancer cell line, suggesting that alterations of the APC gene do not have a major role in the development of lung and renal cancers, various types of sarcomas, or hematological malignancies.

Colonic Neoplasms↗

PubMed2000

[Development of a detection system (APC yeast color assay) of APC mutations by color change of yeast].

The author developed a sensitive yeast-based color assay which expresses APC-ADE2 (reporter) fusion protein in yeast and can screen almost the entire coding region of the APC gene. In this assay, the wild-type APC coding sequence of 8.5 kb is divided into 5 overlapping regions which are respectively ligated in-frame with an ADE2 open reading frame. The resulting five constructs containing a part of wild-type APC gene preserve the ADE2(+) phenotype (white yeast colony) when introduced into the yeast, whereas the yeast transfected with plasmids containing frameshift mutations of the APC gene shows an ADE2(-) phenotype (red yeast colony). Six human colon cancer cell lines were analyzed by this yeast color assay. HCT116 cells with wild-type APC and normal colonic mucosa gave low percentages of red colonies (0-9.9%) in all the regions. On the other hand, more than 96% red colonies were observed in one of the five regions in SW480, Colo201 and Colo320DM cells. Sequence analysis demonstrated the clonal APC mutations at codon 1,338 in SW480, 1,554 in Colo201 and 811 in Colo320DM. Moreover, the assay detected a germline mutation of the APC gene in polyps of a familial adenomatous polyposis (FAP) patient which gave about 50% red colonies. For testing the assay for clinical utilization, 18 colon cancer tissues were subjected to the assay. Eleven cancers (61%) gave more than 10% red colonies (17-57%) and clonal mutations were detected in all these samples. The same mutations were demonstrated in both DNA and RNA samples derived from idendical tissues. These results suggest that this APC yeast color assay is powerful means for detection of APC mutations in clinical samples.

Adenomatous Polyposis Coli↗

PubMed1996

Genetic alterations in rat colon tumors induced by heterocyclic amines.

BACKGROUND: In rat colon tumors induced by the cooked food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), ras and p53 alterations are rarely detected. To investigate the roles of the APC gene and microsatellite instability (MI) in PhIP-induced colon carcinogenesis, mutations of the APC gene and alterations of microsatellites were examined. METHODS: Complimentary DNA sequence of the rat APC gene were determined by polymerase chain reaction (PCR) using primers based on the human APC sequence. PCR-single strand conformation polymorphism (SSCP) analysis was performed using primers based on sequences of flanking introns and exon 15. Microsatellite alterations were also analyzed using 85 microsatellite sequences dispersed through most of the rat chromosomes. RESULTS: Five mutations in the APC gene were detected in four of eight PhIP-induced rat colon tumors. All five mutations involved deletion of a guanine base in a 5'-GGGA-3' sequence. Only 2 of 13 IQ-induced colon tumors had mutations of the APC gene and these were base substitution mutations. Seven of eight PhIP-induced colon tumors had microsatellite alterations in at least one locus, whereas no alterations were observed in the IQ-induced colon tumors. CONCLUSIONS: The specific 5'-GGGA-3' to 5'-GGA-3' mutation and MI demonstrated in this study are strong evidence of a mutational fingerprint of PhIP.

Animals↗

PubMed2002

Familial adenomatous polyposis associated with multiple endocrine neoplasia type 1-related tumors and thyroid carcinoma: a case report with clinicopathologic and molecular analyses.

We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma. To clarify how mutations of the adenomatous polyposis coli ( APC ) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for beta-catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors. Immunohistochemical staining of beta-catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas. The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of beta-catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.

Adenomatous Polyposis Coli↗

PubMed1988

Structure and regulation of genes encoding phycocyanin and allophycocyanin from Anabaena variabilis ATCC 29413.

Gene clones encoding phycocyanin and allophycocyanin were isolated from an Anabaena variabilis ATCC 29413-Charon 30 library by using the phycocyanin (cpc) genes of Agmenellum quadruplicatum and the allophycocyanin (apc) genes of Cyanophora paradoxa as heterologous probes. The A. variabilis cpcA and cpcB genes occur together in the genome, as do the apcA and apcB genes; the two sets of genes are not closely linked, however. The cpc and apc genes appear to be present in only one copy per genome. DNA-RNA hybridization analysis showed that expression of the cpc and apc genes is greatly decreased during nitrogen starvation; within 1 h no cpc or apc mRNA could be detected. The source of nitrogen for growth did not influence expression of the genes; vegetative cells from nitrogen-fixing and ammonia-grown cultures had approximately the same levels of cpc and apc mRNAs. Heterocysts had less than 5% as much cpc mRNA as vegetative cells from nitrogen-fixing cultures. Northern hybridization (RNA blot) analysis showed that the cpc genes are transcribed to give an abundant 1.4-kilobase (kb) RNA as well as two less prominent 3.8- and 2.6-kb species. The apc genes gave rise to two transcripts, a 1.4-kb predominant RNA and a minor 1.75-kb form.

Cyanobacteria↗

PubMed1996

Effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine on intestinal polyp development in Apc delta 716 knockout mice.

Damage to the human adenomatous polyposis coli (APC) gene is responsible for not only familial adenomatous polyposis but also many sporadic cancers of the entire digestive tract. Using homologous recombination in embryonic stem cells, we recently constructed gene knockout mice with a truncation mutation in the Apc gene. These heterozygous mice developed intestinal polyps. We found that all microadenomas dissected from the earliest polyps had already lost the wild-type allele, indicating loss of heterozygosity (LOH) (Oshima et al., Proc. Natl. Acad. Sci. USA 92:4482-4486, 1995). Using these knockout mice, we investigated the effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), one of the most abundant heterocyclic amines found in cooked meat and fish. When PhIP was fed to these mice at 400 ppm for 8 wk, the polyp distribution shifted to a larger size range, although the total polyp number did not change significantly. Similar, but weaker, effects were observed with the other heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. On the other hand, intraperitoneal injections of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhlP) at a higher dose (50 mg/kg) for five consecutive days increased the polyp number significantly. This increment was not associated with mutations in the Apc gene; however, most polyps showed loss of the full-length Apc allele (LOH). These results suggest that PhIP affects intestinal polyp development by accelerating the growth rate of microadenomas. It is also possible that high doses of N-OH-PhIP increase the frequency of Apc gene LOH.

Age Factors↗

PubMed1997

Retinal pigment epithelium abnormalities in mice with adenomatous polyposis coli gene disruption.

OBJECTIVE: To examine eyes from mice with targeted adenomatous polyposis coli (APC) gene disruption to determine if retinal pigment epithelium (RPE) abnormalities replicate the human counterpart. METHODS: Thirty-two eyes from 16 mice heterozygous for APC gene disruption (chain-termination mutation in codon 1638 of exon 15) and 12 control eyes were examined by light microscopy. RESULTS: Fifteen of 32 eyes from 12 of 16 APC-disrupted mice demonstrated abnormalities of the RPE and retina. The RPE abnormalities included RPE coloboma, unifocal and multifocal RPE hypertrophy, RPE hyperplasia, and RPE duplication with invasion in the areas of outer and inner segments. Retinal abnormalities included outer nuclear layer duplication and outer nuclear layer atrophy. There were no RPE and retinal abnormalities seen in the control eyes. CONCLUSIONS: This study is consistent with the hypothesis that the APC gene is critical in the regulation of RPE proliferation and development. These findings also demonstrate that mutation of the APC gene in codon 1638, a location beyond the previously described critical region for human RPE abnormalities, leads to perturbation in the mouse RPE and retina. Further study of this murine model and the APC/RPE relationship may provide insight into regulatory mechanisms for RPE proliferation.

Adenomatous Polyposis Coli↗

PubMed1995

Molecular, cytogenetic, and phenotypic studies of a constitutional reciprocal translocation t(5;10)(q22;q25) responsible for familial adenomatous polyposis in a Dutch pedigree.

Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer caused by germline mutations in the adenomatous polyposis coli (APC) gene located on chromosome segment 5q21-q22. We detected a germline rearrangement of the APC gene in a Dutch FAP family by screening genomic DNA samples with APC cDNA probes. Subsequent molecular and cytogenetic studies revealed a constitutional reciprocal translocation t(5;10)(q22;q25) that resulted in the disruption of the APC gene. Southern blot and polymorphic marker analysis indicated that part of the APC gene had been deleted. Analysis of the APC protein product indicated that the translocation breakpoint did not lead to the formation of a detectable truncated APC protein but apparently resulted in a null allele. Evaluation of the clinical phenotypes in the patients suggested that they exhibited features of an unusual form of FAP characterized by a slightly delayed age of onset of colorectal cancer and a reduced number of colorectal polyps. The latter were mainly sessile and were located predominantly in the proximal colon. To our knowledge, this is the first description of FAP caused by a reciprocal translocation disrupting the APC gene.

Adenomatous Polyposis Coli↗

PubMedDate not supplied

APC, beta-catenin, and E-cadherin and the development of recurrent endometrial carcinoma.

Endometrial carcinoma, generally, has a good prognosis. However, in some patients, the tumor appears to behave very aggressively, a course that cannot be explained with histopathological characteristics. More insight into the molecular background can be valuable to clarify these differences in tumor behavior. The three components associated with the Wnt pathway--i.e., adenomatous polyposis coli (APC), beta-catenin, and E-cadherin--were evaluated in a case-control study of 28 patients with stage-I endometrial carcinomas to determine their involvement in the development of recurrent disease. Mutation analysis of the mutation cluster region of the APC gene, determination of gene promoter methylation status of the APC-1A and E-cadherin genes, and immunohistochemical analysis of APC, E-cadherin, and beta-catenin were performed using paraffin-embedded tumor tissue. Twenty-one APC gene mutations were detected in 12 of 28 (43%) patients. Only three mutations would result in a stopcodon in the APC gene. APC gene promoter methylation was assessed in 12 of 28 (43%) patients. APC immunostaining was absent in two of 24 (8.3%) patients. The occurrence of APC mutations, APC gene promoter methylation, and APC immunostaining were not predictive for recurrence. No E-cadherin expression was observed in four of 24 patients (17%). E-cadherin gene promoter methylation could not be detected in any of the patients. The absence of E-cadherin expression was predictive for distant metastases, but not for local recurrence. Nuclear localization of beta-catenin was present in nine of 24 (38%) patients and was not predictive for recurrent disease. Involvement of epigenetic and genetic aberrations in APC and beta-catenin genes seems to be of minor importance for the development of local recurrences and distant metastases. Although the number of patients is limited, E-cadherin expression appears to be predictive for the development of distant metastases in endometrial carcinoma.

Adenomatous Polyposis Coli↗

PubMed1998

Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor).

Aggressive fibromatosis is a monoclonal proliferation of spindle (fibroblast-like) cells. A subset of lesions contain somatic truncating adenomatous polyposis coli (APC) gene mutations, and all of the lesions contain an elevated beta-catenin protein level. A major function of APC is to regulate beta-catenin protein level. Beta-catenin has a dual function in the cell: it is a member of the adherens junction, and it binds transcription factors in the tcf-lef family, transactivating transcription. Cell cultures from aggressive fibromatoses containing an APC mutation were studied. Transient transfection of the full-length APC gene caused decreased proliferation and beta-catenin protein level in these cultures. To determine whether beta-catenin protein level was responsible for the change in proliferation rate, stable transfections of deltaN89beta-catenin (a stabilized form that is not degraded by APC, but retains all other functions) were achieved in half of the cultures derived from each tumor, whereas the other half were transfected with an empty vector. Transfection of the full-length APC gene in cultures that were stably transfected with deltaN89beta-catenin did not result in a change in proliferation. The type I promotor of p56lck contains an HMG consensus region, to which members of the tcf-lef family can bind. p56lck was expressed in cultures not transfected with the full-length APC gene and in cultures transfected with the full-length APC gene and deltaN89beta-catenin, but not in cultures transfected with only the full-length APC gene. These data show that APC truncating mutations give aggressive fibromatosis cells a proliferative advantage through beta-catenin and suggest that beta-catenin acts to transactivate transcription.

Apoptosis↗

PubMed2004

In vitro model for liposome-mediated adenomatous polyposis coli gene transfer in a duodenal model.

PURPOSE: Duodenal adenomas arise in more than 90 percent of patients with familial adenomatous polyposis (FAP). Management of severe duodenal disease remains difficult and controversial. This study investigates transfer of functional wild-type adenomatous polyposis coli (APC) gene under conditions of varying pH and bile concentrations into a somatic duodenal cancer cell line (HUTU-80) as a prelude to in vivo gene therapy in the management of severe duodenal disease. METHODS: In vitro transfection of human APC gene was performed on a human duodenal adenocarcinoma cell line (HUTU-80) by use of a liposomal vector. Different concentrations (5 percent and 10 percent) of human bile and varying pH (6 percent and 8 percent) were used during APC gene transfer to assess their effects on transfection efficiency. The effect of bile on the proliferation of HUTU-80 cells was evaluated by means of a colorimetric chemosensitivity assay with sulforhodamine B (SRB). The duration of APC transgene expression was analyzed by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Exogenous APC transgene was expressed in HUTU-80 cell line for 6 days after transfection. Differing pH did not affect APC gene transfer into the duodenal cell line with similar transgene expression to controls, but APC transfection efficiency was reduced semiquantitatively in the presence of bile. Coculturing with human bile (5 percent and 10 percent) did not affect the proliferation of HUTU-80. CONCLUSION: This study demonstrates transfer of APC gene into a duodenal epithelial cell line with prolonged transgene expression. Liposome-mediated APC gene transfer to the duodenum is feasible even in the presence of bile and varying pH, raising the potential of future gene therapy for this extremely difficult to treat condition.

Adenomatous Polyposis Coli↗

PubMed2000

Ultrastructural and ERG findings in mice with adenomatous polyposis coli gene disruption.

PURPOSE: In order to continue the previous morphological studies of eyes from mice with adenomatous polyposis coli (APC) gene mutation at codon 1638, we determined the ultrastructural and electrophysiologic characteristics of these eyes. METHODS: Thirty-eight eyes from 20 mice heterozygous for APC gene mutation and 22 eyes from 11 wild-type mice were examined by light microscopy. Six APC-modified eyes without light microscopic abnormalities, four APC-modified eyes with focal light microscopic abnormalities, and four wild-type eyes were examined by electron microscopy. Electroretinograms were recorded from four APC-modified and three wild-type mice. RESULTS: Four of 38 APC-modified eyes demonstrated ultrastructural evidence of focal RPE cells with increased melanosome production and atrophy. Other areas of the RPE in these four eyes demonstrated no ultrastructural abnormalities. Three APC-modified eyes demonstrated electron and light microscopic evidence of RPE hyperplasia. Electron microscopic examination of APC-modified eyes without light microscopic evidence of abnormalities demonstrated no ultrastructural differences from age-matched controls. Electroretinography demonstrated no differences in the b-wave or c-wave amplitudes between APC-modified and wild-type mice. CONCLUSIONS: While light microscopic RPE alterations are observed in these APC-modified mice, the absence of a generalized, ultrastructural murine RPE defect is in contradistinction to observations in electron microscopic investigations of humans with colonic polyposis, pigmented ocular fundus lesions, and APC gene mutations between codons 463 and 1444. Our results in mice with APC mutation at codon 1638, however, are consistent with a previously identified association between the expression of pigmented ocular fundus lesions and region-specific mutation in the human APC gene. The APC protein may possess a physiologic function for both retinal and RPE development.

Adenomatous Polyposis Coli↗

PubMed1994

Aberrations of tumor-suppressor genes (p53, apc, mcc and Rb) in esophageal squamous-cell carcinoma.

Loss of heterozygosity at 4 tumor-suppressor gene loci (p53, apc, mcc and Rb) was investigated using polymerase chain reactions, in 49 esophageal squamous-cell carcinoma specimens from patients who had undergone curative resection. Mutations in the p53 gene within exons 5 to 8 were also examined. LOH was detected in 9 (43%) of 21 p53 genes, 16 (55%) of 29 apc genes, 10 (48%) of 21 mcc genes, and 13 (52%) of 25 Rb genes for which heterozygosity could be determined. Mutations in the p53 gene were detected in 18 (36%) of 49 cases and were significantly more frequent in stage-III tumors and in tumors exhibiting DNA aneuploidy. In 5 cases where heterozygosity could be determined for all the loci, all had 2 or more aberrations. Additionally, a heterozygous deletion of p53 gene was associated with a mutation of the remaining allele in 8 (89%) of 9 cases. Short-term relapse within 3 to 12 months occurred significantly more frequently in patients having tumors with both p53 aberrations (p < 0.05). Thus, aberration of tumor-suppressor genes was a frequent occurrence in esophageal squamous-cell carcinoma and inactivation of the p53 gene may contribute to the progression of this tumor.

Aged↗

PubMed2001

Frequent beta-catenin mutations in juvenile nasopharyngeal angiofibromas.

Juvenile nasopharyngeal angiofibromas (JNAs) are locally aggressive vascular tumors occurring predominantly in adolescent males. The pathogenesis of JNAs is unknown. Recently, JNAs have been reported to occur at increased frequency among patients with familial adenomatous polyposis, suggesting that alterations of the adenomatous polyposis coli (APC)/beta-catenin pathway might also be involved in the pathogenesis of sporadic JNAs. We analyzed somatic beta-catenin and APC gene mutations in 16 sporadic JNAs from nonfamilial adenomatous polyposis patients using immunohistochemistry for beta-catenin, and direct DNA sequencing for exon 3 of the beta-catenin gene and the mutation cluster region of the APC gene. Nuclear accumulation of beta-catenin was diffusely present in the stromal cells but not in the endothelial cells of all 16 JNAs. Activating beta-catenin gene mutations were present in 75% (12 of 16) of JNAs. Six JNA patients also had recurrent tumors after surgery, and in all cases the beta-catenin gene status of the recurrent JNA was identical to the initial tumor. No mutations in the mutation cluster region of the APC gene were detected in the four JNAs without beta-catenin mutations. The high frequency of beta-catenin mutations in sporadic JNAs and the presence of identical beta-catenin gene mutations in recurrent tumors indicates that activating beta-catenin gene mutations are important in the pathogenesis of JNAs. The immunohistochemical localization of beta-catenin only to the nuclei of stromal cells further suggests that the stromal cells, rather than endothelial cells, are the neoplastic cells of JNAs.

Adolescent↗

PubMed2000

The Caenorhabditis elegans APC-related gene apr-1 is required for epithelial cell migration and Hox gene expression.

Inactivation of the Caenorhabditis elegans APC-related gene (apr-1) has pointed at two separate functions of apr-1. First, apr-1 is required for the migration of epithelial cells during morphogenesis of the embryo. In this process, APR-1 may act in a Cadherin/alpha-Catenin/beta-Catenin complex as a component of adherens junctions. Second, apr-1 is required for Hox gene expression, most likely by positively regulating the activity of the Wingless signaling pathway. During embryogenesis, apr-1 is required for the expression of ceh-13 labial in anterior seam and muscle cells and during larval development, apr-1 is necessary for the expression of lin-39 deformed in the vulval precursor cells. Thus, APR-1 may positively regulate the activity of the beta-Catenin/Armadillo-related proteins HMP-2 in migrating epithelial cells and BAR-1 in the vulval precursor cells.

Animals↗

PubMed1998

Genetic alterations in a patient with Turcot's syndrome.

Turcot's syndrome (TS) is a rare disorder associated with the development of both brain and colon neoplasms. Because of the very low incidence of the disease, its molecular basis remains unclear. Presented is a TS case of a 30-year-old Japanese male with a histopathologically confirmed diagnosis of both brain tumor (glioblastoma multiforme) and colon tumor (well-differentiated adenocarcinoma). Germline mutations of the p53 gene, somatic mutations of the Ki-ras, p53 and APC genes, and microsatellite instability (MSI) was examined using polymerase chain reaction (PCR)-single strand conformation polymorphism analysis, followed by PCR-direct sequencing, and sequencing after subcloning. No germline mutations of the p53 gene were found. Somatic mutations of Ki-ras and APC genes were found in the colon adenocarcinoma but not in the brain tumor. No somatic mutation of the p53 gene was present in either colon or brain tumors. Microsatellite instability of both colon and brain tumors was positive in two of four loci. These results indicate that the colon tumor of the TS patient carries the Ki-ras and APC gene mutations. The finding of MSI in both the brain and the colon tumors may support the hypothesis that alterations of DNA repair genes are involved in the tumor development of the TS patient.

Adenomatous Polyposis Coli↗