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B Leggett

Publications and source records attributed to B Leggett.

27 records · Page 2Linked to original sources
PubMed1995

An Alu VpA marker on chromosome I demonstrates that replication errors manifest at the adenoma-carcinoma transition in sporadic colorectal tumors.

Widespread mutations in simple tandemly repeated (STR) DNA sequences are frequently found in colorectal tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC) and less frequently in sporadic colorectal cancers. This aims of this study were to determine the type of DNA sequence most commonly affected by such mutations and to examine the point in the natural history of the tumor where replication errors (RERs) appear. An unselected series of colorectal tumors (49 adenomas and 108 carcinomas) was examined with 4 different STR markers: one Alu VpA polymorphism (MYCLI), one tetranucleotide repeat (D17S846), one dinucleotide repeat (D3S1029), and one polyA repeat (AP delta 3 delta). All 3 positive adenomas and 18 of 20 positive carcinomas showed replication errors in the Alu VpA sequence at the MYCLI locus, making this marker more than twice as sensitive as the best of the other 3 markers. Importantly, all positive adenomas showed small foci of carcinoma in situ. This suggests that replication errors manifest at the adenoma/carcinoma transition in sporadic colorectal tumors.

Adenoma↗
PubMed1995

Colorectal carcinomas show frequent allelic loss on the long arm of chromosome 17 with evidence for a specific target region.

Allelic loss is a common mechanism of inactivation of tumour-suppressor genes in colorectal carcinomas. A number of known or putative tumour-suppressor genes including NF1, BRCA1, NME1, NME2 and prohibitin are present on the long arm of chromosome 17, and this region has not been extensively analysed in colorectal tumours. In this study 72 colorectal carcinomas were examined for allelic loss at eight loci on chromosome 17. Allelic loss was frequent both at the p53 locus, which is known to be important in colorectal carcinoma, and also telomeric to p53 on 17p. Allelic loss continued to be present in more than 50% of cases in the pericentromeric region and on proximal 17q to the marker LEW101 (D17S40) at 17q22-23. The most telomeric markers on 17q showed lower rates of allelic loss. Analysis of cases with partial deletions which did not include the p53 locus showed a common region of overlap of the deletions centred on D17S40. This suggests the target of allelic loss on 17q is a tumour-suppressor gene in this region.

Alleles↗
PubMed1994

Loss of heterozygosity on the long arm of chromosome 11 in colorectal tumours.

We have examined a series of human colorectal adenomas, carcinomas and cell lines derived from human colorectal cancer for loss of heterozygosity (LOH) on chromosome 11q22-23 by polymerase chain reaction (PCR) amplification of a microsatellite polymorphism of the dopamine D2 receptor (DRD2) locus. LOH was demonstrated in 5/30 (16.7%) adenomas and 23/68 (33.8%) carcinomas. Only 2/20 (10%) cell lines showed homozygosity which could potentially be as a consequence of LOH. This moderate level of loss in the tumour samples was probably not an underestimation as a result of excessive stromal contamination because high rates (68-77%) have been detected in the same samples on chromosomes 17 and 18. In contrast to a previous report, LOH in carcinomas at 11q22-23 occurred at a lower frequency and was not associated with Dukes' stage, degree of differentiation, mucin production or the location of the cancer. However, a significant association was found between LOH on chromosome 11 and chromosome 14. Thus, inactivation of any putative tumour-suppressor gene at 11q22-23 by LOH is not a very common event in the development of colorectal tumours, but may be biologically significant if accompanied by chromosome 14 deletions.

Adenoma↗
PubMed1994

Association of the SS genotype of the L-myc gene and loss of 18q sequences with a worse clinical prognosis in colorectal cancers.

L-myc is a nuclear oncogene which is sometimes activated late in tumourigenesis. Digestion of DNA with EcoRI reveals a simple restriction fragment length polymorphism (RFLP) located in the second intron of L-myc, with allele sizes 10 kb (L-allele) and 6.6 kb (S-allele). Some studies have suggested that the presence of the S-allele in the constitutional DNA of a patient with cancer is associated with a higher risk of metastasis in lung, breast and renal cell carcinomas. The aims of this study were to determine if the S-allele was significantly associated with metastasis and also with inactivation of tumour suppressor genes in colorectal cancer. One hundred and twenty-four Caucasian colorectal cancer patients were studied for L-myc genotype, and a subgroup of these (108) had their tumours examined for allele loss at multiple loci on nine chromosomal arms (1p, 1q, 5q, 8p, 14q, 17p, 17q, 18q, 22q) and for mutations in the 12th codon of K-ras. The percentage of individuals with the SS genotype was 19% (4/21) Dukes Stage A, 19% (10/54) Dukes B, 25% (8/32) Dukes C and 40% (8/20) Dukes D. The trend observed here is significant (P < 0.05, Wilcoxon Rank Sum Test). Also, the SS genotype was significantly more common in individuals whose tumours showed allelic loss on 18q (P < 0.01, Fishers Exact Test). This work suggests that the S-allele of L-myc, or a gene in linkage disequilibrium with it, may modify the development of colorectal cancer.

Adult↗
PubMed1993

Genomic instability occurs in colorectal carcinomas but not in adenomas.

Genomic instability, as demonstrated by the presence of additional alleles at short tandemly repeated (STR) loci, has recently been observed in colorectal tumours from individuals with hereditary nonpolyposis colorectal cancer (HNPCC), and in some sporadic tumours. These neoplasms have been called replication error positive (RER+). In this study, we confirm the presence of genomic instability in a proportion of unselected colorectal carcinomas but find no evidence of instability in adenomas. We further report replication errors in a tetranucleotide sequence, and in STRs within two tumour suppressor genes. 108 colorectal adenocarcinomas and 46 adenomas were analysed for the presence of variant bands at 4-15 microsatellite markers. Seven (6.5%) of carcinomas were RER+, four of which originated from the proximal colon. Analysis of the adenomas and of matched adenoma-carcinoma and carcinoma-metastatic samples from four patients suggests that the replication errors may occur during the development of carcinomas but are rare in adenomas.

Adenocarcinoma↗
PubMed1993

Frequent loss of heterozygosity on chromosome 14 occurs in advanced colorectal carcinomas.

The current model for colorectal tumorigenesis defines four specific mutations (activation of a ras proto-oncogene and inactivation of the APC, p53 and DCC tumor-suppressor genes) that accumulate in a colonic epithelial cell as it progresses towards a carcinoma. However, further mutations must be needed for progression to malignancy because advanced adenomas have been observed with all four of these mutations. Loss of heterozygosity (LOH) for 11 loci spanning the distal portion of the long arm of chromosome 14 was studied in 89 sporadic colorectal adenocarcinomas and 25 adenomas. The overall rate of LOH in carcinomas was 53% (46/86 informative carcinomas). The smallest region of overlap (SRO) of deletions includes the markers D14S19 to D14S20. No LOH was seen in the 18 informative adenomas examined. There was a significant trend towards higher levels of LOH within the SRO in advanced Dukes' stages (P = 0.016). Since frequent loss of heterozygosity in a specific region of a chromosome may reflect the inactivation of a tumor-suppressor gene located there, these data suggest that a gene involved in the progression of colonic neoplasia may reside on the distal portion of the long arm of chromosome 14, and that its inactivation may be a critical event in this process.

Adenocarcinoma↗
PubMedDate not supplied

CAH or SLE?

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Fluorescent Antibody Technique↗