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D T Bishop

Publications and source records attributed to D T Bishop.

At least 37 records · Page 2Linked to original sources
PubMed2001

Using single nucleotide polymorphisms to investigate association between a candidate gene and disease.

A range of study designs, using unrelated or family controls, were used to investigate the pattern of association with disease of single nucleotide polymorphisms (SNPs) within candidate gene 1 (simulated data). Strong evidence of disease association at the functional locus was detected using all study designs, and in the "general" but not the "isolated" population the functional polymorphism displayed considerably higher association than surrounding SNPs. There was much variation in the strength of association of SNPs with disease, up to 70% of which was explained by SNP allele frequency and distance from the functional polymorphism. Some common polymorphisms very close to the functional locus however showed no association with disease. Analysis of short haplotypes of SNPs reduced but did not totally remove this feature.

Adult↗
PubMed2001

Susceptibility markers in colorectal cancer.

Many susceptibility factors contribute to an individual's risk of developing colorectal cancer. Family history of colorectal cancer (particularly with early age of onset), maleness and increasing age are all factors associated with increasing risk. About three quarters of colorectal cancers are thought to be due to somatic mutations, and both high- and low-penetrance predisposing genes contribute to the remaining quarter of cases. Many of the highly penetrant dominant genes are known, but others remain to be identified. Describing the contribution of individual genes is likely to be very complex, as some modify the impact of other genes and other environmental factors rather than incurring a direct, easily attributable effect. The two dominant predisposing syndromes are familial adenomatous polyposis and Lynch syndrome, the first due to a mutant tumour-suppressor gene APC, and the second due to mutations in a number of genes responsible for mismatch repair in DNA at cell division. Establishing genetic susceptibility for colorectal cancer will soon be possible, and could save lives by allowing targetting of screening and the encouragement of preventive behaviours. However, there will always be a risk of making healthy people "sick" through the identification of predisposing genes, and there are many potential ways by which a gene carrier may be stigmatized by society, insurance companies and employers.

Aged↗
PubMed2000

Association between loss of heterozygosity of BRCA1 and BRCA2 and morphological attributes of sporadic breast cancer.

Germline mutations in the breast cancer-associated genes BRCA1 and BRCA2 confer a lifetime risk of malignancy. Distinctive morphological features have been attributed to these familial tumours; however, in sporadic breast cancer, the inter-relationship between loss of heterozygosity (LOH) of these loci and tumour morphology remains to be fully elucidated. We studied a series of 120 sporadic breast carcinomas using microsatellite markers to identify LOH of BRCA1, BRCA2, p53 and PTEN. The associations between loss at each of the loci were examined and related to tumour morphology. LOH of the 4 loci did not occur independently; there were highly significant associations between LOH of BRCA1 and both BRCA2 (p < 0.001) and p53 (p < 0.001). LOH at all 4 loci was significantly associated with a high degree of nuclear pleomorphism. Tumours with LOH of BRCA1 also had high mitotic indices, few tubules and a paucity of DCIS, all of which are morphological features similar to those described for familial cases. Following Bonferroni's correction for multiple tests, we found that the tumours with LOH of BRCA1 were still significantly associated with a high mitotic index (p = 0.0006) and a high degree of nuclear pleomorphism (p = 0.001).

BRCA2 Protein↗
PubMed2000

Isolation of an essential Schizosaccharomyces pombe gene, prp31(+), that links splicing and meiosis.

We carried out a screen for mutants that arrest prior to premeiotic S phase. One of the strains we isolated contains a temperature-sensitive allele mutation in the fission yeast prp31(+) gene. The prp31-E1 mutant is defective in vegetative cell growth and in meiotic progression. It is synthetically lethal with prp6 and displays a pre-mRNA splicing defect at the restrictive temperature. We cloned the wild-type gene by complementation of the temperature-sensitive mutant phenotype. Prp31p is closely related to human and budding yeast PRP31 homologs and is likely to function as a general splicing factor in both vegetative growth and sexual differentiation.

Amino Acid Sequence↗
PubMed2000

Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours.

Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.

Adolescent↗
PubMed2000

Lack of linkage between chromosome 5q23-33 markers and IgE/bronchial hyperreactivity in 67 Scottish families.

BACKGROUND: Raised serum immunoglobulin E (IgE) and bronchial hyperreactivity (BHR) are risk factors for the expression of the asthma phenotype. Previous studies have reported evidence for linkage between these traits and markers on the 5q23-33 cytokine gene cluster. OBJECTIVE: To test for linkage between total serum IgE/BHR and microsatellite markers which map to the 5q23-33 region in an ethnically distinct cohort of families from Aberdeen, Scotland. METHODS: We performed a linkage study between five polymorphic markers (spanning the chromosome 5q23-33 region) and total serum IgE and BHR traits. A cohort of 67 families, who were recruited originally to study the natural history of wheeze, were clinically characterized and genotyped for D5S404, IL4, IRF-1, IL9, D5S436 markers. Linkage analyses were performed using the nonparametric Haseman-Elston algorithm for the quantitative trait log IgE, and the nonparametric LOD score (NPL-score) of the GENEHUNTER package for the qualitative traits serum IgE and BHR. RESULTS: The results of the nonparametric linkage analysis using either the Haseman-Elston algorithm or NPL-score were consistent and showed no evidence for linkage with IgE. There was also no evidence for linkage between the BHR traits (at cut-off values of PD20FEV1 < 8 mmol and 16 mmol) and any of the tested five microsatellite markers. CONCLUSIONS: This study presents evidence against the presence of a gene with a major effect on total serum IgE or BHR in the 5q23-33 region, in this ethnic group.

Adolescent↗
PubMed2000

Evidence for a role of HLA DRB1 alleles in the control of IgE levels, strengthened by interacting TCR A/D marker alleles.

BACKGROUND: MHC class II alleles at human chromosome 6p21.1 and alleles in the TCR A/D locus at human chromosome 14q11.2 have been implicated in susceptibility to specific allergies and the modulation of total serum IgE. It has also been hypothesized that HLA and TCR allelic interactions may have a strong influence on predisposition to allergic disease. OBJECTIVE: This study was performed to investigate the influence of HLA-DRB and DQB1 alleles and D14S50 alleles (adjacent to TCR A/D locus on 14q11.2), individually and in-combination, on total serum IgE levels, and on the development of specific allergies. METHODS: We performed an association study between HLA-DRB, HLA-DQB1 polymorphisms, D14S50 alleles, total serum IgE expression and specific allergies to house dust mite, grass pollens and cat fur. A sample of 181 individuals was drawn from a larger set of 2415 adults, sampled at random from a district in Nottingham. RESULTS: Strong association was observed between HLA-DRB1*0701 allele and high total serum IgE expression (P < 0.001). D14S50 alleles alone showed no evidence for independent association. However, there was a significant interaction between DRB1*0701 and D14S50 allele 170 such that, when both were present, there was a further increase in total serum IgE levels. CONCLUSION: This study suggests that DRB1*0701 allele is involved in the modulation of total serum IgE, and that there is an interaction between DRB1*0701 and a marker adjacent to TCR A/D in the control of IgE expression.

Adolescent↗
PubMed2000

Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations.

Patients with a family history of melanoma are at increased risk of this tumor. Those family members who also have the atypical mole syndrome are commonly targeted for screening in the belief that they are more likely to be mutant gene carriers. We have correlated the atypical mole syndrome phenotype and gene carrier status in five families with germline CDKN2A mutations and shown that family members with the atypical mole syndrome were three times more likely to be mutant gene carriers than their relatives who did not have the atypical mole syndrome (odds ratio 3.4; confidence interval 1.0-11. 1), supporting the view that CDKN2A is nevogenic. Individual characteristics which best predicted mutant gene carrier status were: nevi on the buttocks (odds ratio 4.4; confidence interval 1. 6-12.4), nevi on the feet (odds ratio 4.2; confidence interval 1. 4-12.5), total nevus number being at least 100 (nevi > or = 2 mm in diameter) (odds ratio 3.4; confidence interval 1.0-11.1) and two or more clinically atypical nevi (odds ratio 3.1; confidence interval 1. 1-9.0). Gene carriers were also significantly more likely to have noticeable freckling and possibly also Fitzpatrick skin types 1-3. The overlap between gene carriers and nongene carriers was, however, marked: the atypical mole syndrome did not clearly differentiate mutant gene carriers from those with a normal gene. This study is of significance to clinicians as the clinical practice of using the atypical mole syndrome to identify particular family members for surveillance is shown to be inappropriate. Until formal gene testing is available, all members of families with an excessive number of melanoma cases should be treated as potential mutation carriers at increased risk of melanoma.

Genes, p16↗
PubMed2000

Exon deletions and duplications in BRCA1 detected by semiquantitative PCR.

rearrangements have recently been identified in the BRCA1 gene. Inclusion of a method for identifying such rearrangements should now be a prerequisite for providing a comprehensive mutation detection strategy. We have developed a semiquantitative PCR-based fluorescent assay for the detection of previously identified deletions. This method avoids the need for long PCR or Southern blotting and is suitable for large-scale epidemiological studies. The assay was used to screen 44 high-risk families within the U.K. Yorkshire Health Region. No deletions were detected, but five cases (11%) with an apparent duplication of exon 13 in BRCA1 were identified. The presence of this mutation was confirmed by long PCR. Further developments include extending the assay to include all exons of BRCA1.

BRCA1 Protein↗
PubMed2000

Mutation screening of the CDKN2A promoter in melanoma families.

Germline mutations of CDKN2A, at 9p21, are responsible for predisposition to melanoma in some families. However, evidence of linkage to 9p21 has been demonstrated in a significant proportion of kindreds with no detectable mutations in CDKN2A. It is possible that mutations in noncoding regions may be responsible for predisposition to melanoma in these families. We have analyzed approximately 1 kb of the CDKN2A promoter upstream of the start codon in an attempt to identify causal mutations in 107 melanoma families. Four sequence variants were detected. Two of these (A-191G and A-493T) did not segregate with disease and were present in a control population at a comparable frequency, indicating that they are unlikely to predispose to melanoma. The A-493T variant appeared to be in linkage disequilibrium with the previously described CDKN2A polymorphism Ala148Thr. The variant G-735A was detected in the control population, but segregation of this variant with melanoma within families could not be discounted. The fourth variant (G-34T), located in the 5' UTR, creates an aberrant initiation codon. This variant appeared to segregate with melanoma and was not detected in a control population. G-34T has recently been identified in a subset of Canadian melanoma families and was concluded to be associated with predisposition to melanoma. The creation of an aberrant initiation site in the 5' UTR may have an important role in carcinogenesis in a small percentage of families; however, mutations in the CDKN2A promoter appear to have a limited role in predisposition to melanoma.

Adolescent↗
PubMed1999

Envoplakin, a possible candidate gene for focal NEPPK/esophageal cancer (TOC): the integration of genetic and physical maps of the TOC region on 17q25.

Focal nonepidermolytic palmoplantar keratoderma (NEPPK), or tylosis, is an autosomal, dominantly inherited disorder of the skin that manifests as focal thickening of the palmar and plantar surfaces. In three families studied, the skin disorder cosegregates with esophageal cancer and oral lesions. New haplotype analysis, presented here, places the tylosis esophageal cancer (TOC) locus between D17S1839 and D17S785. Envoplakin (EVPL) is a protein component of desmosomes and the cornified envelope that is expressed in epidermal and esophageal keratinocytes and has been localized to the TOC region. Mutation analysis of EVPL in the three affected families failed to show tylosis-specific mutations, and haplotype analysis of three intragenic sequence polymorphisms of the EVPL gene placed it proximal to D17S1839. Confirmation of the exclusion of EVPL as the TOC gene by location was obtained by integration of the genetic and physical mapping data using radiation hybrid, YAC, BAC, and PAC clones. This new physical map will allow further identification of candidate genes underlying NEPPK associated with esophageal cancer, which may also be implicated in the development of sporadic squamous cell esophageal carcinoma and Barrett's adenocarcinoma.

Base Sequence↗
PubMed1999

K-ras mutation and loss of heterozygosity of the adenomatous polyposis coli gene in patients with colorectal adenomas with in situ carcinoma.

BACKGROUND: The majority of colorectal carcinomas, if not all, arise from a benign adenoma. The DNA of the carcinomatous cells frequently has mutations in several genes. However, it is not exactly clear when during the neoplastic process each mutation develops. An adenoma with an area of in situ carcinoma provides an opportunity to evaluate genetic changes within a single neoplasia whose separate areas are comprised of both the benign adenoma as well as the malignant carcinoma. METHODS: Thirty-seven neoplasms with areas of both benign adenoma and in situ carcinoma were studied. Both portions were evaluated for loss of heterozygosity (LOH) of the adenomatous polyposis coli (APC) gene and for mutations in codons 12/13 of the K-ras oncogene using the polymerase chain reaction technique. RESULTS: Twenty-eight neoplasms showed no LOH in either portion whereas both portions of 4 neoplasms revealed a loss of heterozygosity. In three lesions the APC gene was normal in the adenomatous portion but LOH was present in the carcinomatous portion. Two neoplasms were uninformative for LOH of the APC gene. Thirteen neoplasms showed the wild-type pattern for the K-ras oncogene whereas 15 contained the identical mutation in both portions. Of the remaining nine neoplasms, six had a K-ras mutation in the adenomatous portion only and three had one pattern in the adenomatous portion and a different pattern in the in situ carcinoma portion. CONCLUSIONS: LOH of the APC gene is an early and persistent feature in the evolution of a benign colorectal adenoma into an in situ carcinoma. There is less consistency regarding K-ras mutations; one in five in situ carcinomas contains a K-ras mutation different from that observed in the adenomatous portion.

Adenomatous Polyposis Coli↗
PubMed1999

Analysis of simulated data: evidence for genetic and environmental effects.

We approached the simulation as though it were an international study with similar but not identical information being collected from different populations. In keeping with this we analyzed one replicate from each population. Initially we examined the risk of disease in relatives of cases to determine whether the disease appeared to be "more genetic" in one population than in the others and we examined the evidence for environmental risk factors in each population. Nonparametric linkage analysis and transmission/disequilibrium testing (TDT) were used to search for loci linked to the disease in each population. Using these methods we identified several candidate regions for a susceptibility gene which on examination of the answers are explicable in terms of the underlying model.

Environment↗
PubMed1999

Site specificity of colorectal neoplasms in families without an inherited syndrome.

BACKGROUND: Relatives of patients with bowel neoplasia have an increased risk of bowel neoplasia. If there were concordance in location of neoplasia between relatives, then location-specific screening could be used. Such concordance might also assist in the understanding of the etiology of neoplasia within individual families. METHODS: We have investigated the concordance in anatomic location of colonic neoplasia between first-degree relatives using a new statistical technique for paired data called alternating logistic regression. RESULTS: A total of 146 families were ascertained, none of which had clinical evidence of a hereditary predisposition to edon neoplasia. Among those with neoplasia, there was an increased risk for right-sided disease with older age (40% for less than age 60 vs. 58% for at least 70 years of age, p = 0.008). As assessed by the odds ratio, we found no significant concordance within families for location of neoplasia (odds ratio = 1.2: CI [0.7, 2.2]), although there was a suggestion that location in family members of the same generation was more strongly associated (odds ratio 1.87: CI [0.82, 4.25]). CONCLUSIONS: The lack of concordance within families for location argues against considering family-specific bowel screening protocols and indicates that the most important causes of bowel neoplasia are not sufficiently focused on one anatomic site to facilitate etiologic research.

Adenoma↗
PubMed1999

Comparison of allelic ratios from paired blood and paraffin-embedded normal tissue for use in a polymerase chain reaction to assess loss of heterozygosity.

BACKGROUND: One method to assess loss of heterozygosity (LOH) of various genes is the amplification of DNA from neoplastic tissue by using microsatellite markers. LOH can best be considered on a quantitative basis as a comparison of allelic ratios of neoplastic tissue to that of the normal control. We will illustrate through quantitative methods the importance of using the appropriate controls when determining allelic loss. METHODS AND RESULTS: DNA extracted from 28 paired blood and formalin-fixed, paraffin-embedded normal mucosal tissue was amplified using the DP1 microsatellite marker, consisting of a variable number of CA repeats. This marker is located within the D5S346 (DP1) region on chromosome 5 and is linked to the adenomatous polyposis coli gene. Allelic ratios were calculated after scanning autoradiographs on a densitometer. Ratio values approaching 1 were observed when the two alleles were close in molecular weight, whereas ratios less than 1 were detected when the two alleles had very different molecular weights. This discrepancy was more pronounced in paraffin-embedded tissue than with blood samples. CONCLUSION: For LOH amplification assays, it is best to use normal control samples that are of the same tissue source as the neoplastic sample being analyzed. When assessing LOH in neoplastic tissue, a quantitative value rather than visual assessment of the alleles should be considered. The values may be normalized by dividing the ratio of the two tumor alleles by the ratio of the two normal alleles.

Alleles↗
PubMed1999

Mutation testing in melanoma families: INK4A, CDK4 and INK4D.

The INK4A gene which codes for the cyclin-dependent kinase (CDK) inhibitor INK4A or p16 underlies susceptibility to melanoma in some families. Germline mutations in the gene that codes for the target protein of p16, CDK4, underlie susceptibility in very rare families. We report mutation screening of the INK4A and CDK4 genes in 42 UK families. A total of nine families were identified with INK4A mutations and none with CDK4 exon 2 mutations. These mutations were in 8/22 (35%) families with three or more cases of melanoma and 1/20 (5%) families with only two cases. In one of these nine families a novel single base pair substitution was identified, Gly67Arg. In an attempt to identify another melanoma susceptibility gene, a member of the INK4 family, the p19 INK4D gene has been studied. The p19 gene was sequenced in DNA from the 42 UK families and six additional US families. No mutations were identified.

Carrier Proteins↗