Biomedical subjects

T Melot

Publications and source records attributed to T Melot.

28 records · Page 2Linked to original sources

PubMed1993

Regional fine mapping of the beta crystallin genes on chromosome 22 excludes these genes as physically linked markers for neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disease, characterized by the development of bilateral vestibular schwannomas. The NF2 gene has been assigned to chromosome 22. Cataract and other eye abnormalities are frequently seen in NF2 patients. The specific association of eye abnormalities and NF2 might be caused by a genetic change on chromosome 22 that affects both the NF2 gene and a physically linked crystallin gene. In order to test this hypothesis, we regionally localized the known crystallin genes (i.e. CRYBB2, CRYBB2P1, CRYBB3, and CRYBA4) on chromosome 22. Crystallin gene-specific probes were hybridized to an extended panel of human x rodent somatic cell hybrids containing various portions of chromosome 22. It was found that all crystallin genes map to a very small region on chromosome 22 that is physically separate from the NF2 gene region by at least 160 kb of DNA. In addition, we found that the beta B crystallin genes (CRYBB2, CRYBB2P1, and CRYBB3) are clustered on a 300 kb SacII fragment and that the beta A4 crystallin gene (CRYBA4) is not part of this cluster. We conclude that the ocular manifestations in many NF2 patients are probably not the primary consequence of rearrangements on chromosome 22 that involve both the NF2 gene and a nearby beta crystallin gene.

Animals↗

PubMed1993

Combinatorial generation of variable fusion proteins in the Ewing family of tumours.

Balanced translocations involving band q12 of human chromosome 22 are the most frequent recurrent translocations observed in human solid tumours. It has been shown recently that this region encodes EWS, a protein with an RNA binding homologous domain. In Ewing's sarcoma and malignant melanoma of soft parts, translocations of band 22q12 to chromosome 11 and 12 result in the fusion of EWS with the transcription factors FLI-1 and ATF1, respectively. The present analysis of 89 Ewing's sarcomas and related tumours show that in addition to the expected EWS-FLI-1 fusion, the EWS gene can be fused to ERG, a transcription factor closely related to FLI-1 but located on chromosome 21. The position of the chromosome translocation breakpoints are shown to be restricted to introns 7-10 of the EWS gene and widely dispersed within introns 3-9 of the Ets-related genes. This heterogeneity generates a variety of chimeric proteins that can be detected by immuno-precipitation. On rare occasions, they may be associated with a truncated EWS protein arising from alternate splicing. All 13 different fusion proteins that were evidenced contained the N-terminal domain of EWS and the Ets domain of FLI-1 or ERG suggesting that oncogenic conversion is achieved by the linking of the two domains with no marked constraint on the connecting peptide.

Amino Acid Sequence↗

PubMed1992

Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.

Ewing's sarcoma and related subtypes of primitive neuroectodermal tumours share a recurrent and specific t(11;22) (q24;q12) chromosome translocation, the breakpoints of which have recently been cloned. Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation. Here we use these fragments to screen human complementary DNA libraries to show that the translocation alters the open reading frame of an expressed gene on chromosome 22 gene by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the human homologue of murine Fli-1.

Amino Acid Sequence↗

PubMed1992

Cloning and characterization of the Ewing's sarcoma and peripheral neuroepithelioma t(11;22) translocation breakpoints.

Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are related tumors, possibly of neural crest origin, which are cytogenetically characterized by the specific translocation t(11;22)(q24;q12). The cos5 locus, previously identified in the vicinity of the chromosome 22 breakpoint of this translocation, was shown by in situ hybridization on interphase nuclei to lie between VIIIF2 and LIF, two loci located on either side of the breakpoint and at a distance of less than 2,000 kb. The progressive expansion of this locus by chromosome walking led to the construction of a 300 kb contig, which finally crossed the breakpoint. The subsequent cloning of the two translocation junction fragments of a PN, followed by the molecular characterization of the translocation breakpoints of 20 ES and PN, showed that most chromosome 22 breakpoints are clustered within a small, 2 kb region. In contrast, the chromosome 11 breakpoints are scattered over a region of at least 40 kb. The translocation leads to the synthesis of chimeric transcript that links sequences from chromosomes 22 and 11. Finally, no evidence was found of any specific difference in the position of ES and PN translocation breakpoints.

Bone Neoplasms↗

PubMed1992

[Familial adenomatous polyposis: early diagnosis by genetic mapping].

The use of probes detecting polymorphic loci within the human population has enabled accurate localization of the genetic defect responsible for familial adenomatous polyposis on chromosome 5. This was used to screen two families for the presymptomatic diagnosis in children of an affected parent. In both cases, the use of 8 polymorphic probes located on either side of the gene provided information which could be used in the management of children born from the patients at risk. The set of probes used in this work should be informative in most of the affected adenomatous polyposis families.

Adenomatous Polyposis Coli↗

PubMed1992

Survival and acquired genetic alterations in colorectal cancer.

To set the basis for a precise assessment of new therapeutic approaches, the prognosis of patients with colorectal cancer should be evaluated with the highest precision. The recent discovery, in tumor cells, of somatically acquired genetic alterations believed to be instrumental in tumor behavior may provide new independent prognostic factors. In the present study, the usual prognostic factors and a set of genetic alterations, i.e., Ki-ras mutations, DNA content, and allelic losses on chromosome 17p, 18q, 5q, and 1p, were investigated in 109 colorectal carcinomas. Univariate analysis for correlation with 5-year survival showed the following significant associations: histological staging (P less than 0.00001), preoperative serum carcinoembryonic antigen concentration (P less than 0.002), DNA content (P less than 0.009), and allelic loss on the short arm of chromosome 17 (P less than 0.002) and 1 (P less than 0.03). In multivariate analysis, only histological staging and allelic loss on the short arm of chromosome 17 were found to be independently associated with shorter survival (P less than 0.0001 and P less than 0.004, respectively). Loss of 17p alleles in colorectal carcinoma thus appears to be a marker of tumor aggressiveness. Its monitoring may lead to an improved classification of patients when adjuvant chemotherapy is considered.

Aged↗

PubMed1991

Association of Ki-ras mutation with differentiation and tumor-formation pathways in colorectal carcinoma.

The occurrence of a point mutation on the 12th and 13th codons of the Ki-ras oncogene has been investigated in 99 colorectal carcinomas in relation to 3 histological parameters: extent of differentiation, occurrence of a mucinous component within the tumor, and presence of peripheral adenomatous polyp remnants. The mutation frequency increased with each parameter: from 13% (2/15) to 44% (37/84) with differentiation, from 33% (26/79) to 65% (13/20) with mucinous character, and from 27% (15/56) to 56% (24/43) with the presence of polyp remnants. The frequency was highest in well-differentiated mucinous tumors with adenomatous remnants 83% (5/6). We suggest that Ki-ras mutation is preferentially involved in carcinomas that have developed from adenoma and that the mutation preserves differentiation and mucin secretion in these cancer cells.

Adenocarcinoma, Mucinous↗

PubMed1991

Genetic characterization of the APC locus involved in familial adenomatous polyposis.

Familial adenomatous polyposis is a rare disease inherited in a Mendelian dominant fashion. It is characterized by the occurrence of more than 100 adenomatous polyps in the large bowels of affected individuals. The genetic defect responsible for adenomatous polyposis resides at a locus called APC which has been localized to the long arm of human chromosome 5. In this study, the APC locus was mapped with respect to 11 markers known to map to this chromosomal segment. Linkage of APC to four of these markers had been previously reported. Three additional markers are shown here to be linked to APC. By multipoint analysis, the APC locus maps to an interval bounded by D5S49 and D5S58. The refined map of the APC locus and the new markers described here improve the informativeness and accuracy of the presymptomatic diagnosis of familial adenomatous polyposis.

Adenomatous Polyposis Coli↗

PubMed1990

[A joint study of mutation of the Ki-ras oncogene and overexpression of the Tp53 oncogene in colorectal cancer].

Twenty-five colorectal tumors (rectum 6, left colon 13, right colon 6) were studied with respect to the overexpression of p53 and the activation by point mutation of the Ki-ras oncogene. Single point mutations on codon 12 and codon 13 were analyzed after PCR amplivication, dotblotting and sequential hybridization with 12 different oligonucleotides. The intranuclear concentration of p53 protein was measured by flow cytometry after immunofluorescence staining with monoclonal antibody Pab 421. Twelve tumors were found to significantly overexpress p53 and 6 of them had an activated Ki-ras (5 on codon 12, 1 on codon 13). Of 13 tumors which failed to demonstrate over expression of p53, 8 had an activated Ki-ras (5 on codon 12, 3 on codon 13). In our series, p53 overexpression and ki-ras activation appeared to be independent.

Adenocarcinoma↗

PubMed1989

Multiple genetic alterations in distal and proximal colorectal cancer.

Multiple genetic alterations were investigated in colorectal cancer, including changes in DNA content, mutations in ras oncogenes, and deletions involving chromosomes 5, 17, and 18. A non-random association of deletions and mitotic abnormalities by site was seen, with both types of alterations occurring significantly more frequently in distal tumours. In contrast, the frequency of c-Ki-ras mutations did not differ between proximal and distal cancers. In addition, deletions were significantly associated with each other and with change in DNA content. The data provide strong support for the hypothesis that proximal and distal colon carcinoma might differ in the genetic mechanisms in their initiation and/or progression.

Adenocarcinoma↗