Characterization of 19 novel and six recurring APC mutations in Italian adenomatous polyposis patients, using two different mutation detection techniques.
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Adenomatous Polyposis Coli↗
Biomedical subjects
L Varesco
Publications and source records attributed to L Varesco.
Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis.
BACKGROUND & AIMS: Hereditary nonpolyposis colorectal cancer is characterized by early-onset colorectal cancer and the occurrence of various other cancers. The recent isolation of four mismatch repair genes responsible for hereditary nonpolyposis colorectal cancer allows for the identification of carriers within affected families. The purpose of this study was to assess the age-specific cancer risk in a large series of gene carriers. METHODS: Thirty-four families were studied by mutation analysis. In 19 of these families, pathogenic mutations were found at hMSH2 or hMLH1. Of 382 relatives, 124 had a mutation in hMLH1 and 86 in hMSH2. RESULTS: The lifetime risk of colorectal cancer was the same in both groups of gene carriers (80%). The risk of endometrial cancer was greater in hMSH2 gene carriers compared with hMLH1 gene carriers (61% vs. 42%), but the difference was not statistically significant. A very high relative risk of cancer of the small bowel (relative risk of >100) was observed in carriers of either gene. Only the carriers of hMSH2 mutations had a significantly increased relative risk of cancer of the urinary tract (kidney and ureter) (relative risk of 75.3), stomach (relative risk of 19.3), and ovaries (relative risk of 8.0). CONCLUSIONS: This study provides estimates of cancer risk that may contribute to the appropriate management of gene carriers within families with hereditary nonpolyposis colorectal cancer.
Adolescent↗
Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% of the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for > 20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services.
Adaptor Proteins, Signal Transducing↗
Familial adenomatous polyposis and inflammatory bowel disease associated in two kindreds.
We describe two families in which some members are affected by familial polyposis syndrome: in one family a case of ulcerative colitis and in the other a case of Crohn's disease were found. This is the first report about this family association, but in our opinion the fact that two cases have been found in one series suggests that this association could be more frequent than reported so far. The research for a genetic pattern of inflammatory bowel disease could be addressed towards chromosome 5.
Adenomatous Polyposis Coli↗
Mutation in a splice-donor site of the APC gene in a family with polyposis and late age of colonic cancer death.
Adenomatous polyposis coli (APC) is an autosomal dominant disease characterized by the development of hundreds of colorectal adenomatous polyps during the first decades of life. The expression of the disease varies, as the age of onset of colonic cancer and the severity of extracolonic manifestations often differ between affected families. An attenuated form of APC has also been described in which a small number of polyps and a later age of onset of colonic cancer is observed. Cloning of the APC gene has allowed disease-causing mutations in APC families to be identified. Here, we report a novel splice site mutation (a G to T transversion at position +5 of the splice donor site in intron 9) in the APC gene of affected individuals in an Italian family. Characterization of the transcription products from this mutant APC allele revealed that normal splicing was disrupted: a shorter mRNA was expressed in which exon 8 was connected directly to exon 10. This created a shift in the reading frame and the introduction of a stop codon at position 1358. In addition, some normal APC transcript was produced from the mutant allele in lymphoblastoid cells. A comparison of the clinical features of affected members of this family with four unrelated Italian APC kindreds, in which the same AAAAG deletion at position 3926 has been found, showed a significant difference in the onset of disease symptoms and in the age of death attributable to colorectal cancer. Inefficient exon skipping may be, at least in part, responsible for the delay in the development of the disease in the reported family.
Adenomatous Polyposis Coli↗
Granulomatous slack skin: cytogenetic and molecular analyses.
Granulomatous slack skin (GSS) is a rare disorder which is considered a slowly evolving T-cell lymphoma associated with granulomatous inflammation that mediates clastolysis. A combined cytogenetic, molecular, and cellular analysis was conducted on a clinically and histologically defined case of GSS. Cell cultures obtained from the skin biopsy showed trisomy of chromosome 8, and the DNA sample extracted from the skin biopsy showed a T-cell receptor beta-chain rearrangement.
Abdomen↗
A low NM23.H1 gene expression identifying high malignancy human melanomas.
The NM23 gene has been proposed as a metastasis-suppressor gene, and its use has been suggested as prognostic factor. NM23 was identified in a system of murine melanoma cell lines, in which an inverse relationship was found between NM23 expression and metastatic ability. In a human malignant melanoma study NM23 expression was found to be significantly lower in metastases that developed less than 24 months after diagnosis of the primary tumours. The present paper studies the expression of the NM23.H1 gene in cell lines which derive from primary or metastatic human malignant melanomas in relation to staging, infiltration degree, lymphocytic infiltration, cell morphology, cell pigmentation, karyotype, and disease-free survival. The level of mRNA expression of the NM23 gene is significantly lower in cell lines that derive from more infiltrating primary melanomas than in cell lines obtained from less infiltrating tumours. Moreover, cell lines derived from tumours of patients with a disease-free survival of more than 24 months (24-58 months) express the NM23 gene at higher levels than cell lines obtained from melanomas of patients with a disease-free survival of less than 24 months (6-15 months).
Cell Line↗
Age of onset in familial adenomatous polyposis: heterogeneity within families and among APC mutations.
Heterogeneity among and within FAP pedigrees for the age of symptom onset and the age at death from colorectal cancer was studied in a sample of 583 patients of the Italian Polyposis Registry. The among pedigree variation was largely explained by clustering of families in two groups, 'early FAP' (most colorectal cancer deaths below 45 years of age) and 'late FAP' families (most deaths above age 45). The within-family variation was explained by a marked phenomenon of anticipation (15 years per generation, on the average), possibly not due to ascertainment bias. We then considered the pedigrees with identified mutation in the APC gene. Six families shared a common deletion at codon 1309 and showed the early FAP phenotype. Two families shared a mutation at codon 1061 and revealed the late FAP phenotype. Another two families (codons 453 and 302) clustered with the late FAP group, whereas a family with mutation at codon 835 clustered with the early FAP group. We suggest that there are at least two classes of mutations in the APC gene with different consequences at the phenotypic level. It seems that there are several critical points within the APC protein sequence at which truncation causes a more aggressive disease than truncation at other points.
Adenomatous Polyposis Coli↗
A rapid screening method to detect nonsense and frameshift mutations: identification of disease-causing APC alleles.
A functional screen for nonsense and frameshift mutations has been devised that allows genes of interest to be scanned in segments. This assay is based on the cloning of these segments in-frame with a colorimetric marker gene (lacZ) followed by screening for the level of functional activity from the marker polypeptide (beta-galactosidase). Individuals at risk for any one of a number of genetic diseases, in particular familial adenomatous polyposis coli (APC), can be quickly screened for chain-terminating mutations introduced by stops and frameshifts. At present, scanning of the APC gene for mutation requires significant effort because it is a large gene and most APC mutations are unique. Therefore, this assay offers a powerful option for the diagnosis of this and other genetic diseases, as well as great potential for the development of a similar rapid screen to detect APC mutations in colorectal adenomas and carcinomas.
Alleles↗
Identification of APC gene mutations in Italian adenomatous polyposis coli patients by PCR-SSCP analysis.
The APC gene is a putative human tumor-suppressor gene responsible for adenomatous polyposis coli (APC), an inherited, autosomal dominant predisposition to colon cancer. It is also implicated in the development of sporadic colorectal tumors. The characterization of APC gene mutations in APC patients is clinically important because DNA-based tests can be applied for presymptomatic diagnosis once a specific mutation has been identified in a family. Moreover, the identification of the spectrum of APC gene mutations in patients is of great interest in the study of the biological properties of the APC gene product. We analyzed the entire coding region of the APC gene by the PCR-single-strand conformation polymorphism method in 42 unrelated Italian APC patients. Mutations were found in 12 cases. These consist of small (5-14 bp) base-pair deletions leading to frameshifts; all are localized within exon 15. Two of these deletions, a 5-bp deletion at position 3183-3187 and a 5-bp deletion at position 3926-3930, are present in 3/42 and 7/42 cases of our series, respectively, indicating the presence of mutational hot spots at these two sites.
Adenomatous Polyposis Coli↗
APC gene mutations in Italian familial polyposis coli patients.
Adenomatous polyposis coli is an autosomal dominant disease characterized by the development of hundreds of colorectal adenomas in young adults. If prophylactic colectomy is not performed, colorectal cancer develops in virtually all affected individuals by the fifth decade of life. All at-risk relatives older than 10 years of age need to be screened regularly by endoscopy. Recently, the gene responsible for the disease, the APC gene, was cloned. The finding of inactivating mutations of the APC gene in Italian APC patients allowed us to offer DNA-based diagnostic tests to these families.
Adenomatous Polyposis Coli↗
The NM23 gene maps to human chromosome band 17q22 and shows a restriction fragment length polymorphism with BglII.
The NM23-Hl gene is a putative tumor suppressor gene that may be important in the metastasic process. Recent genetic and immunological data indicate that the NM23-Hl gene encodes a protein with nucleoside diphosphate (NDP) kinase activity. The mapping of NM23-Hl by panels of rodent-human somatic cell hybrids and in situ hybridization showed that the gene is located in human chromosome band 17q22. A two-allele polymorphism with BglII was demonstrated.
Alleles↗
Fine mapping of probes in the adenomatous polyposis coli region of chromosome 5 by in situ hybridization.
The gene for adenomatous polyposis coli has been localized to 5q21-22. We have mapped six probes from this region using isotopic or nonisotopic in situ hybridization. Using tritium-labeled probes we localized II227 (D5S37) to 5q14-15 and ECB27 (D5S98) to 5q21. Following hybridization with biotin-labeled probes, the positions of signals along the chromosomes were measured as fractional length relative to the length of the chromosome arm from centromere to qter (FLcen-qter). Ninety-five percent confidence limits, compared with standard karyotypes, provided the corresponding band localization. By this method we localized Cllpll (D5S71) to FLcen-qter 0.407-0.452 (5q21.1-21.3), ECB27 to FLcen-qter 0.426-0.473 (5q21.3), YN5.48 (D5S81) to FLcen-qter 0.459-0.496 (5q21.3-22.2), and ECB134 (D5S97) to FLcen-qter 0.509-0.533 (5q22.3-23.1). ECB220 had three sites of hybridization, a major site at FLcen-qter 0.460-0.492 (5q21.3-22.1) and minor sites at FLcen-qter 0.299-0.339 (5q14.3-15) and FLcen-qter 0.629-0.691 (5q23.3-31.2). We have shown that the chromosome 5 breakpoint in a t(5;15) translocation from a patient with Gardner's syndrome (GM03314) is between Cllpll and ECB27. Linkage data are presented suggesting that ECB27 is located on the same side of the APC locus as II227. These and published results including data on several constitutional deletions (M, SD, and brothers PW and ND) give a probable order of [cen] - [II227, proximal SD breakpoint] - [Cllpll] - [proximal PW/ND, M breakpoint(s), GM03314 breakpoint] - [ECB27] - [APC] - [YN5.48] - [distal PW/ND breakpoint] - [ECB134] - [distal M breakpoint] - [qter]. The major site of ECB220 appears to be between ECB27 and the distal PW/ND breakpoint; the distal SD breakpoint is distal to YN5.48.
Adenomatous Polyposis Coli↗
A BstXI polymorphism at the D5S116 locus.
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Chromosomes, Human, Pair 5↗
CpG island clones from a deletion encompassing the gene for adenomatous polyposis coli.
Adenomatous polyposis coli (APC), a dominantly inherited disorder, has been mapped to chromosome 5q15-q21 by family linkage studies. Cells from patients with deletions in this region, in one case associated with polyposis in a family, have been used to construct human hamster hybrid cell lines that retain either the normal or deleted chromosome 5. These lines have been used to identify markers from the region of the polyposis gene obtained by cloning the ends of 0.5- to 2-megabase BssHII fragments purified by pulsed-field gel electrophoresis. Three markers are described that map within the deletions and must therefore be close to the APC gene.
Adenoma↗
Genetic analysis of colorectal cancer.
Adenomatous polyposis, mainly of the colon, (APC) is a rare dominantly inherited susceptibility to colon cancer in which individuals develop hundreds of polyps mainly in their large bowel. The APC gene has been localised to chromosome 5q21 by following up a case report of an individual with an interstitial deletion on chromosome 5q who had multiple developmental abnormalities together with adenomatous polyposis. A DNA marker (D5S71) was found to be closely linked to APC in family studies and localised to 5q21 by in situ annealing. Material from further patients with deletions in this region of chromosome 5 has been used, by a combination of somatic cell hybrid and long-range DNA analysis, to identify new DNA markers close to the APC gene. These and other markers now provide the basis for genetic counselling of nearly all families with APC. These studies are being extended, together with other approaches for analysing DNA clones around the APC gene, in the search for the gene itself. Allele loss in tumour as compared to normal tissue from sporadic cases of colorectal carcinomas has clearly implicated the APC gene in at least 25 to 40% of all cases of colorectal carcinomas. Similar studies by Vogelstein and others as well as ourselves have further implicated recessive changes on chromosomes 17 and 18 in the development of colorectal carcinomas. Following the demonstration by Vogelstein of the role of p53 mutations in connection with the chromosome 17 changes, we have now shown, using monoclonal antibodies to the mutant p53 products and by other approaches, that changes in the p53 gene may occur in up to 50% or more of colorectal carcinomas. Frequent mutations of the K-ras dominant oncogene, as well as changes in the expression of human leucocyte antigen (HLA)-A, B, C determinants, are further genetic changes that appear commonly to be involved in the progression of colorectal carcinomas. The latter have important implications for T cell immune response to tumours and its manipulation for treatment and even prevention of colorectal cancer. We may soon be approaching a situation when it will become possible to identify all the genetic steps and their sequence during tumour progression, as well as their functional significance largely through the induction of inappropriate growth and the suppression of differentiation.
Adenomatous Polyposis Coli↗
Chronic idiopathic hyperphosphatasia and fibrous dysplasia in the same child.
A generalized skeletal dysplasia with features of chronic idiopathic hyperphosphatasia and fibrous dysplasia of the mandible were observed in a 6-year-old child. The abnormal development of the bones resulted from enhanced remodeling and the failure of mature bone to form. The occurrence of the two lesions in the same child and a review of the literature support the hypothesis that pathogenesis of fibrous dysplasia and idiopathic hyperphosphatasia reflect an underlying common defect in the control of bone cell activity.
Diagnosis, Differential↗
Molecular genetics of hereditary non-polyposis colorectal cancer (HNPCC).
The story of the molecular genetics of HNPCC is one of astonishingly rapid achievements. In just 16 months, from May 1993 to September 1994, four different genes, namely hMSH2, hMLH1, hPMS1 and hPMS2 have been identified and demonstrated to be associated with the disease. Their cloning was facilitated by the finding that tumor cells in HNPCC patients display a hypermutability of DNA short tandem repeats (microsatellite instability). In fact, HNPCC associated genes are the human counterparts of genetic elements known to control the fidelity of DNA replication in lower organisms. So far, more than 50 germline mutations of hMSH2 and hMLH1 genes have been reported in HNPCC kindreds. In addition, somatic mutations have been documented in hereditary as well as sporadic cancers. Unfortunately, the molecular diagnosis of HNPCC is hampered by the lack of mutational "hot spots" and of clearly defined genotype-phenotype correlations and different screening methods are to be employed for the analysis of affected and at-risk individuals.
Colorectal Neoplasms, Hereditary Nonpolyposis↗