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D T Bishop

Publications and source records attributed to D T Bishop.

At least 55 records · Page 3Linked to original sources
PubMed1999

The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study.

We conducted a population-based study to determine the contribution of germline mutations in known candidate genes to ovarian cancer diagnosed at age <30 years. Women with epithelial ovarian cancer were identified through cancer registries. DNA samples were analyzed for mutations in BRCA1, the "ovarian cancer-cluster region" (nucleotides 3139-7069) of BRCA2, and the mismatch-repair genes hMSH2 and hMLH1. Probable germline mutations in hMLH1 were identified in 2 (2%; 95% confidence interval 1%-8%) of 101 women with invasive ovarian cancer diagnosed at age <30 years. No germline mutations were identified in any of the other genes analyzed. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or hereditary nonpolyposis colorectal cancer (HNPCC). There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk [RR] = 1.6, P=.01) but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had increased risks of ovarian cancer (RR = 4.8, P=.03), myeloma (RR = 10, P=.01), and non-Hodgkin lymphoma (RR = 7, P=.004). Germline mutations in BRCA1, BRCA2, msh2, and mlh1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Our data suggest that early-onset ovarian cancer is not associated with a greatly increased risk of cancer in close relatives.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Suggestive evidence for genetic linkage between IgE phenotypes and chromosome 14q markers.

Chromosome 14q was screened for loci modulating immunoglobulin E (IgE) phenotypes in 15 extended and 45 nuclear asthmatic families using a panel of 14 microsatellite markers. We examined the reported linkage between the TCR A/D locus on 14q11.2 and specific (cognate) allergic responses and observed supportive evidence for linkage between a general skin prick test reactivity trait (but not with total serum IgE) and TCRA microsatellite (in the total sample of informative sib-pairs p = 0.039, in selected sample of one or zero affected parent p = 0.017). We also show suggestive evidence for a novel linkage between markers D14S75 and D14S63 on 14q13-23 and log total serum IgE (p = 0.034 and p = 0.0029). The evidence for linkage with marker D14S63 on 14q23 is strengthened by the finding of association of allele 165 to log IgE (p = 0.0029). We conclude that chromosome 14q may contain a locus close to TCR A/D at 14q11.2 linked to skin prick reactivity and a locus at 14q13- 23 linked to total serum IgE.

Adolescent↗
PubMed1999

A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer.

The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated. The mutation (A-->T at nt943+3) disrupts the 3' splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported. Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed. In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland. To investigate the origin of this mutation in colorectal cancer families from England (n=4), Newfoundland (n=10), and the United States (n=3), haplotype analysis using microsatellite markers linked to MSH2 was performed. Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families. In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families. These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families. We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943+3 A-->T MSH2 mutation carriers (n=76) for all patients and for men and women separately. For both sexes combined, the penetrances at age 60 years for all cancers and for colorectal cancer were 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (p<0.01) in males than females (0.63 v 0.30 and 0.84 v 0.44 at ages 50 and 60 years, respectively). For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers.

Age Factors↗
PubMed1999

N-acetyltransferase (NAT2) genotype and susceptibility of sporadic Alzheimer's disease.

The importance of environmental aggression and individual susceptibility to develop Alzheimer's Disease (AD) has been suggested by epidemiological studies on both typical familial and sporadic AD cases. In order to elucidate functions that can influence the susceptibility to AD pathogenesis, we genotyped a group of 53 sporadic late-onset AD patients, matched control individuals and a larger randomly selected non-demented population for the N-acetyltransferase (NAT2). We determined the relative frequencies of individual allele combinations that define a broad range of acetylator phenotypes. Inter-individual variability in the cytotoxic and genotoxic responses to a wide diversity of environmental chemicals is known to result from the polymorphism of NAT2 as well as other drug-metabolizing-enzyme genes. The results presented are the first to demonstrate a significant difference in the NAT2 genotype profiles of sporadic AD patients compared with the healthy population. A lower frequency of the recessive alleles NAT2*6 (chi-squared 1 d.f. = 12.56, P < 0.0004) and NAT2*5B (chi-squared 1 d.f. = 6.72, P < 0.01) was found among the AD population compared with control individuals, which was concomitant with a significantly higher number of NAT2*4 fully active allele homozygotes and heterozygotes (chi-squared 1 d.f. = 5.69, P = 0.017). The most notable observation was the absence of NAT2*5B/NAT2*6 heterozygotes among cases while being present in 22.5% of control individuals (chi-squared 1 d.f. = 13.08, P = 0.0003). These observations indicate that NAT2 is a potential low-penetrance gene in AD pathogenesis, determining an individual susceptibility trait predisposing to this degenerative disease.

Alzheimer Disease↗
PubMed1999

BRCA1 and BRCA2 and breast cancer incidence: a review.

BACKGROUND: Epidemiological studies have repeatedly shown that having a family history is a risk factor for female (and male) breast cancer. Some rare families have many (4 or more) cases of early onset breast cancer (some of which also include women with ovarian cancer) which are most clearly explained by an autosomal dominant gene with high penetrance. DESIGN: Families with multiple cases of early onset breast (and/or ovarian cancer) have been studied using linkage analysis with the intention of finding the chromosomal region containing such genes. RESULTS: Two predisposition genes, BRCA1 and BRCA2, have been mapped and cloned. Mutations in these genes confer increased risk of cancer, although the precise level of the increased risk is still unclear. The majority of families with four or more cases of breast cancer diagnosed under the age of 60 years are due to mutations in BRCA1 or BRCA2. CONCLUSIONS: The importance of these two genes to familial breast cancer and to breast cancer incidence overall is becoming clearer; the current information is reviewed. The findings can be immediately translated into clinical practice for these multiple case families. The identification of such families raises a number of other important clinical questions concerning patient management.

BRCA2 Protein↗
PubMed1998

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

Adult↗
PubMed1998

Incidence of DNA replication errors in patients with multiple primary cancers.

PURPOSE: Multiple primary cancers are a feature of hereditary nonpolyposis colorectal cancer in which defects in DNA repair mechanisms result in accumulation of replication errors within tumor DNA. We assessed replication error incidence in multiple primary cancer patients who may have similar genetic defects. METHODS: DNA was obtained from 69 patients from the Yorkshire region who had developed colorectal cancer and one other primary tumor from the hereditary nonpolyposis colorectal cancer tumor spectrum (28 colorectal, 12 stomach, 15 ovary, and 14 uterus). DNA was also obtained from 86 sporadic, single primary cancer patients attending a colorectal cancer clinic. Replication error status was assessed at five microsatellite loci using fluorescent polymerase chain reaction and computer-assisted analysis. RESULTS: The replication error phenotype was observed in 7 of 86 (8 percent) of the sporadic single primary patients. This compared with 23 of 69 (33 percent) of the multiple primary group (P < 0.001). Replication error was also observed more frequently in each subgroup. Even excluding patients from families meeting the Amsterdam criteria (likely to be hereditary nonpolyposis colorectal cancer and have the replication error phenotype), this increased frequency remained in both the multiple primary group (P < 0.005) and multiple colorectal and colorectal/uterine subgroups (P < 0.001). CONCLUSIONS: Results suggest that genetic instability plays an important role in development of multiple primary cancers, particularly from certain cancer subsets. Testing for replication errors may be an appropriate way of identifying individuals at risk of multiple primary cancers.

Aged↗
PubMed1998

Association study of asthma and atopy traits and chromosome 5q cytokine cluster markers.

BACKGROUND: Linkage studies have provided evidence for the presence of gene(s) in the 5q cytokine cluster region which control total serum immunoglobulin E (IgE) concentration, and bronchial hyperreactivity (BHR). However, the identification of the gene(s) involved has been confounded by the lack of power of the published linkage studies and the presence of multiple candidate genes mapped to the region. OBJECTIVE: To define the important loci on 5q31-33 which are implicated in the control of total serum IgE and BHR through a case/control study of association. METHODS: We performed an association study between 11 polymorphic markers (spanning the region 5q31.1-33.1) and total serum IgE and BHR traits. A case/control sample of 181 individuals was drawn from a larger set of 2415 adults, sampled at random from a district in Nottingham, UK. Half of the subjects in this case/control sample were hyperreactive to methacholine and asthmatic (cases), while the other half were non-reactive and non-asthmatic (controls). Association analysis was performed using the non-parametric chi-squared and Mann-Whitney U-tests. RESULTS: We observed no evidence of strong allelic association between any of the above markers and the studied traits. Markers D5S404, interferon regulatory factor 1 (IRF-1) and D5S210 showed evidence of borderline association with BHR (P = 0.04, 0.03 and 0.04 respectively), and D5S404 showed borderline significance with IgE levels (P = 0.029). CONCLUSIONS: This study presents evidence against the presence of a strong association between markers mapped to 5q31-33 and either BHR or total serum IgE. The significance of the weaker associations observed with markers D4S404, IRF-1 and D5S210 is not clear. Whether this represents a type I error secondary to multiple hypothesis testing or a true association is uncertain.

Adolescent↗
PubMed1998

The genetics of melanoma: the UK experience.

Most cancers have rare familial forms and cutaneous melanoma is no exception. The studies carried out on the genetics of these rare types are of great importance because the knowledge gained from them is essential in the counselling of patients. Also of great importance is the information it provides regarding the basic aetiology of melanoma.

Female↗
PubMed1998

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

Adult↗
PubMed1998

Frequency of replication errors in colorectal cancer and their association with family history.

BACKGROUND: Replication errors (RERs) characterise tumours of hereditary non-polyposis colorectal cancer (HNPCC). RER status may therefore improve identification of such families previously diagnosed by family history alone. AIMS: To assess RER and HNPCC frequency within a population of colorectal cancer patients and a regional population of family history defined (Amsterdam criteria) HNPCC families. METHODS: Family history was assessed by personal interview in a population of 479 patients with colorectal cancer attending one follow up clinic. Seven fluorescently labelled microsatellites were used to investigate RER frequency in colorectal cancers from 89 patients of this population with varying degrees of family history and 20 Amsterdam criteria positive families (four with a known germline mutation, 16 with unknown mutation status) from the regional population. RESULTS: Only four of the follow up population (0.8%) came from families meeting the Amsterdam criteria with only one showing RERs. The frequency of RERs was similar in the early onset cancer group (less than 50 years of age), those with a family history, and those with no family history of colorectal cancer. From the regional population, RERs were identified in 4/4 families with a mutation but only 8/16 families with unknown mutation status. CONCLUSIONS: No correlation was seen between RER status and strength of family history except in HNPCC families. Results also indicate that half of the Amsterdam criteria defined families do not exhibit RERs, perhaps suggesting a different mechanism of tumorigenesis.

Adult↗
PubMed1998

Are relatives of patients with multiple HNPCC spectrum tumours at increased risk of cancer?

BACKGROUND: Relatives of patients with early onset colorectal cancer, a feature of hereditary non-polyposis colorectal cancer (HNPCC), are at increased risk of colorectal cancer. AIMS: To investigate risk in relatives of patients with multiple primary cancers, another feature of HNPCC. METHODS: Details were obtained on patients from one region who had developed colorectal cancer and a separate primary from the HNPCC tumour spectrum (colorectal, stomach, urinary, ovary, endometrial). Overall, 157 patients had second primaries occurring between 1990 and 1995 and 128 completed family histories were obtained by structured interview (study group). A comparison group of 444 patients with a single colorectal cancer were similarly interviewed. RESULTS: Fifteen families (13%) from the study group were suggestive of HNPCC compared with three (0.7%, p<0.0001) from the comparison group. Overall risk of colorectal cancer in close relatives of the study group was 3.4 times the general population rate compared with 1.8 times for the comparison group. Bowel cancer risk was even higher for relatives of bowel/ovary and bowel/endometrial subgroups, but was similar to the comparison group for the bowel/bowel subgroup. Finally, extracolonic HNPCC associated cancers were seen twice as frequently as expected in the general population in relatives of the study group. CONCLUSION: This study highlights the importance of taking a family history in patients with multiple primary cancers and indicates the risk of malignancy in their relatives.

Adult↗
PubMed1997

Family studies and the evidence for genetic susceptibility to prostate cancer.

Family studies of prostate cancer, in keeping with studies of many other common cancers, have shown an increased risk to relatives of cases over and above the general population. Male relatives of early onset prostate cancer cases are also at increased risk over relatives of later onset cases. These observations, together with a few families with four or more cases of prostate cancer, suggest that there is a high penetrance, inherited form of this cancer. Further evidence comes from the increased risk of prostate cancer in BRCA1 mutation carriers but more particularly from the recent report of the mapping of a prostate cancer susceptibility gene to chromosome 1.

Genetic Linkage↗
PubMed1997

Identification of a modifier gene locus on chromosome 1p35-36 in familial adenomatous polyposis.

Phenotypic variability based on nonallelic heterogeneity is a characteristic feature of the dominantly inherited disease, familial adenomatous polyposis (FAP). A modifying locus, called Mom-1, which strongly influences disease expression has been mapped in the mouse model of FAP to the region of murine chromosome 4, which has synteny to human chromosome 1p35-36. In the present study, this chromosomal region was investigated by using 14 microsatellite markers within a large FAP kindred in which patients harbor the same germ-line mutation but show markedly different disease characteristics. The linkage program MLINK was used to determine whether any correlation exists between these markers and the development of extracolonic symptoms in polyposis coli patients. Depending on the mode of inheritance of the affected locus, a maximum lod score was observed for markers D1S211 and D1S197, reaching 2.08 and 1.77, respectively. The observed values obtained within one large FAP family are supportive of a phenotype-modifying locus within this chromosomal region.

Adenomatous Polyposis Coli↗
PubMed1997

A segregation analysis of testicular cancer based on Norwegian and Swedish families.

Clustering of testicular cancer cases in families is well known, although the aetiology is not. We present the results of a segregation analysis performed with the algorithm Pointer on familial data on 978 Scandinavian patients with testicular cancer. The segregation analysis favoured the involvement of major gene effects over models incorporating solely polygenic effects in testicular cancer aetiology. Overall, a recessive model best fits the family observations with an estimated gene frequency of 3.8% and a lifetime risk for homozygous men of developing the disease of 43%. This implies that 7.6% of men in the general population will be carriers of the mutant allele and that 0.1% would be homozygote and are, therefore, at high risk of developing the cancer. The testicular cancer incidence has changed greatly during the last generation. Also, the lethality of the disease has changed because of the introduction of new therapy. As failure to take account of such time trends might lead to inappropriate evidence for a recessive model, the analyses were repeated under different assumptions. The analyses favoured a recessive model of inheritance under all assumptions tested. However, the assumptions underlying the analyses are complex and, as this is the first segregation analysis of testicular cancer, the results must be interpreted cautiously.

Adolescent↗
PubMed1997

A case-control study of diet and prostate cancer.

We interviewed 328 men diagnosed with prostate cancer before the age of 75 years and 328 age-matched population controls. The principal hypotheses were that risk would increase with a high intake of total or saturated fat and would decrease with a high intake of carotene (beta-carotene equivalents) or lycopene. We also examined the associations of other nutrients and foods with risk. There was no evidence for an association between fat intake and risk, although the average fat intake was high and the range of fat intakes was narrow (medians of lower and upper thirds of percentage of energy from fat among controls were 34.3% and 42.9% respectively). Risk was lower in subjects with higher carotene intake: odds ratios 0.65 (95% CI 0.45-0.94) and 0.76 (0.53-1.10) in the middle and upper thirds of carotene intake respectively (P for trend = 0.150). Lycopene was not associated with risk. Among 13 other nutrients examined, the odds ratios in the top third of intake were below 0.8 for: potassium, 0.74 (0.51-1.09; P for trend = 0.054); zinc, 0.73 (0.49-1.08; P for trend = 0.126); iodine, 0.75 (0.51-1.11; P for trend = 0.077); vitamin B6 food only, 0.77 (0.53-1.12; P for trend = 0.077); and vitamin B6 including supplements, 0.70 (0.48-1.03; P for trend = 0.029). Among 18 foods examined, statistically significant associations were observed for: garlic as food, > or = 2/week vs never, 0.56 (0.33-0.93); garlic including supplements, > or = 2/week vs never, 0.60 (0.37-0.96); baked beans, > or = 2/week vs < 1/month, 0.57 (0.34-0.95); and garden peas, > or = 5/week vs < or = 3/month, 0.35 (0.13-0.91). This study does not support the hypothesis that fat increases risk and is equivocal in relation to carotene. The possible relationships of vitamin B6, garlic, beans and peas with risk for prostate cancer should be further investigated.

Adult↗