Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Turcot's syndrome is a genetic disease characterized by the concurrence of primary brain tumors and colon cancers and/or multiple colorectal adenomas. We report a Turcot family with no parental consanguinity, in which two affected sisters, with no history of tumors in their parents, died of a brain tumor and of a colorectal tumor, respectively, at a very early age. The proband had a severe microsatellite instability (MIN) phenotype in both tumor and normal colon mucosa, and mutations in the TGFbeta-RII and APC genes in the colorectal tumor. We identified two germline mutations within the PMS2 gene: a G deletion (1221delG) in exon 11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which were inherited from the patient's unaffected parents. These results represent the first evidence that two germline frameshift mutations in PMS2, an MMR gene which is only rarely involved in HNPCC, are not pathogenic per se, but become so when occurring together in a compound heterozygote. The compound heterozygosity for two mutations in the PMS2 gene has implications for the role of protein PMS2 in the mismatch repair mechanism, as well as for the presymptomatic molecular diagnosis of at-risk family members. Furthermore, our data support and enlarge the notion that high DNA instability in normal tissues might trigger the development of cancer in this syndrome.
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PMID:Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene. 1076 29

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant primary tumor of the liver in Japan. Despite progress in operative techniques and adjuvant therapy, the prognosis of ICC remains very poor. Therefore, it is important to investigate the mechanism of carcinogenesis and progression of ICC. We screened allelic losses at 6 loci, including that of novel tumor-suppressor gene FEZ1 on chromosome 8p, and at 5 microsatellite loci to define the association with tumor-suppressor genes (HNPCC, APC, RB1, p53, DCC) in tumors from 18 unrelated ICC patients by PCR-loss of heterozygosity (LOH) assay and correlated the alterations with clinicopathological parameters. As a result, 61.1% (11 of 18) of patients showed LOH at 1 of the loci at least, and microsatellite instability was observed in 16.7% (3 of 18). At locus D8S258, relatively frequent LOH was detected (17.6%) compared with other loci on chromosome 8p. Among the other 5 chromosomal arms tested, the highest frequency of LOH (23.5%) was observed at D17S153. Fifty percent of cases with the mass-forming + periductal infiltrating type were frequently detected by LOH at D8S258 compared to cases of the mass-forming or intraductal growth type. In conclusion, we show that 1 putative tumor-suppressor gene on 8p22 may relate to progression of ICC and suggest that the p53 tumor-suppressor gene may be associated with carcinogenesis of ICC.
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PMID:Allelic loss in human intrahepatic cholangiocarcinoma: correlation between chromosome 8p22 and tumor progression. 1100 73

The spectrum of disease causing mutations is immense. It just so happens that the overwhelming majority of genetic alterations in the APC gene with leads to adenomatous polyposis coli generate truncated gene products. This observation lead to the development of the in vitro synthesis protein assay (protein truncation test) which is a sensitive method to detect these truncated gene products from patient samples. This article describes the assay to detect truncated proteins for the APC gene, which can also be applied to other disease causing genetic alterations which commonly lead to truncations such in HNPCC, von Hippel-Lindau, osteogenesis imperfecta, retinoblastoma, BCRAI, beta-thalassemia, hemophilia B, Duchenene and Becker muscular dystrophy.
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PMID:Direct analysis for familial adenomatous polyposis mutations. 1187 75

The genomic alterations in preneoplastic lesions are summarized in this review. 3p and 9p in the lung, 9p in the bladder, 8p in the prostata, 19q and 1p in oligodendroglioma, and 22q in meningioma were reported to be deleted. Somatic mutation of p53 was found in preneoplastic lesions of the esophagus, stomach, colon, thyroid, and astrocytoma. Adenoma-carcinoma sequence (Apc, ras, p53 gene alterations) in colon, LKB1 gene in Peutz-Jeghers syndrome, Smad4 in juvenile polyposis, hMSH2, hMLH1, PMS1, PMS2 genes in HNPCC, VHL gene in kidney, WT1 in Wilms tumor, RB gene in retinoblastoma, and ret gene in MEN were reportedly altered in preneoplastic lesions involved in hereditary tumors. Cervical dysplasia and papilloma of the head and neck infected by human papilloma virus and liver infected by B-type hepatitis virus are also precancerous. Genomic instability, APC gene alteration, point mutation of K-ras in preneoplastic lesions of stomach and K-ras and p16 alterations in metaplasia of pancreas were also found. Advances in research on genomic alterations in preneoplastic lesions will contribute to prevention and early detection of cancer.
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PMID:[Genomic alterations in preneoplastic lesions]. 1250 66

The observed increased incidence of colorectal cancer in Ashkenazi Jews compared to other populations is unexplained but likely has a genetic component. The I1307K APC polymorphism/mutation is carried by 6-8% of Ashkenazim and increases the risk of colorectal cancer 1.5-2 fold. There are few differences between the phenotype of colorectal cancer in I1307K carriers and sporadic cases. It is estimated that the mutation accounts for 6% of cases of colorectal cancer in Jews of Eastern European heritage. It should not be the subject of mass screening in Ashkenazi Jews, although it may be important in cases of familial colorectal cancer. Even rarer is the 1906G-->C MSH2 mutation carried by less than 1% of Ashkenazim, but as with other HNPCC mutations likely associated with a high risk of malignancy. Mutations at 15q13-14 are associated with the colorectal adenoma and carcinoma syndrome (CRAC) described in Ashkenazi families. The prevalence of the mutation is not known, nor its significance as a cause of colorectal cancer. Despite the paucity of genetic explanations for the high risk of colorectal cancer in Ashkenazim, that risk warrants aggressive colorectal cancer screening and particular attention to family history of malignancy in all Jews of Ashkenazi descent.
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PMID:Genetic factors and colorectal cancer in Ashkenazi Jews. 1551 44

Heterozygous germline DNA mismatch repair gene mutations are typically associated with HNPCC. Here we report the case of a proband whose father was known for familial adenomatous polyposis. The number of polyps (less than ten) was not typical of polyposis; therefore, the diagnosis of HNPCC was entertained. Microsatellite instability analyses were performed on peripheral blood and biopsy of a right-sided dysplastic adenoma. The tumour tissue showed high-grade instability, and subsequently, immunohistochemistry showed that neither MSH2 nor MSH6 proteins were expressed in tumour cells. Prophylactic colectomy was performed, and an adenocarcinoma developing within the adenoma was diagnosed (pT1N0). Genomic DNA analysis revealed a novel mutation in MSH2 as a frameshift mutation in exon 7 (c.1,191_1,192dupG). Both parents of the proband were analyzed for MSH2 and APC mutations, and in the father, a truncating mutation in exon 15 of APC was identified as del3471-3473GAGA. This mutation was found to be present in the proband. His mother was found to bear the MSH2 exon 7 mutation. At follow-up, the proband was diagnosed with fundic, antral and duodenal adenomas (one fundic adenoma showed low-grade dysplasia). Several tubular rectal adenomas with low-grade dysplasia were excised. The patient later developed an intra-abdominal desmoid tumour.
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PMID:Double frameshift mutations in APC and MSH2 in the same individual. 1667 98

HNPCC and FAP are inherited diseases with a lifetime risk of colorectal cancer (CRC) of 80-100% in gene carriers. Disease-causing mutations have been identified in the APC gene at FAP and in MMR genes at HNPCC. In FAP-patients, screening has reduced the prevalence of CRC by 55%, and the survival rate has improved considerably. For HNPCC-patients, 77% of CRCs found by screening were Duke' A or B, and survival after CRC has improved significantly since 1990. Continuous central registration in the HNPCC and Polyposis registers is recommended to ensure identification of high-risk families and evaluate the effect of screening.
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PMID:[Hereditary colorectal cancer]. 1626 67

Hereditary non-polyposis colorectal cancer and familial adenomatus polyposis are autosomal dominant diseases accounting for 5-7% of all colorectal cancer cases. Inheritance of mutations associated with both syndromes in the same individual has, so far, only been observed in a few cases. This report outlines the findings in a proband of a HNPCC family, who presented with colorectal cancer and with multiple adenomas at the age of 18. He was shown to be compound heterozygous for MSH6 mutations: a nonsense mutation in exon 4 (c.1836 C>A, p.S612X); and a missense mutation in exon 5 (c.3226 C>T, p.R1076C). In addition, an APC missense mutation was revealed (c.7504 G>A, p.G2502S). Immunohisto-chemical analysis showed lack of expression of MSH6 in tumour tissue, as well as accumulation of betacatenin in the nuclei of the tumour cells. We suggest that the presence of mutations in both alleles of one gene and mutations in different genes, may influence the phenotype in hereditary colorectal cancer. Biallelic and/or polygenic mutations should be suspected when facing unusual severe variants of "classic monogenic phenotypes", such as HNPCC.
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PMID:Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait. 1652 81

Heterozygous germline DNA mismatch repair gene mutations are typically associated with HNPCC. Here we report the case of a proband whose father was known for familial adenomatous polyposis. The number of polyps (less than ten) was not typical of polyposis; therefore, the diagnosis of HNPCC was entertained. Microsatellite instability analyses were performed on peripheral blood and biopsy of a right-sided dysplastic adenoma. The tumor tissue showed high-grade instability, and a subsequent, immunohistochemistry showed that neither MSH2 nor MSH6 proteins were expressed in tumor cells. Prophylactic colectomy was performed, and an adenocarcinoma developing within the adenoma was diagnosed (pT1N0). Genomic DNA analysis revealed a novel mutation in MSH2 as a frameshift mutation in exon 7 (c.1191_1192dupG). Both parents of the proband were analysed for MSH2 and APC mutations, and in the father, a truncating mutation in exon 15 of APC was identified as del3471-3473GAGA. This mutation was found to be present in the proband. His mother was found to bear the MSH2 exon 7 mutation. At the follow-up, the proband was diagnosed with fundic, antral and duodenal adenomas (one fundic adenoma showed low-grade dysplasia). Several tubular rectal adenomas with low-grade dysplasia were excised. The patient later developed an intra-abdominal desmoid tumor.
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PMID:Double frameshift mutations in APC and MSH2 in the same individual. 1583 12

Colorectal cancer is rare in childhood. The 2 best characterized familial syndromes, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) and familial adenomatous polyposis (FAP), are autosomal dominant inherited disorders. HNPCC is relevant to pediatric gastroenterology practice because children and adolescents with underlying colorectal cancer can have germ-line mutations of mismatch repair genes. Recent attention has focused on characterizing genetic predisposition to attenuated FAP in individuals who do not have germ-line mutations in the APC gene. The identification of a second mechanistic explanation called MYH-associated polyposis (MAP), which is an autosomal-recessive condition, has important implications for both screening and management strategies. Hereditary colorectal cancer including HNPCC, FAP, attenuated FAP and MYH-associated polyposis in children are the subject of this review.
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PMID:Genetic predisposition to colorectal cancer: new pieces in the pediatric puzzle. 1681 71


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