Biomedical subjects
D Easton
Publications and source records attributed to D Easton.
The extent of linkage disequilibrium in four populations with distinct demographic histories.
The design and feasibility of whole-genome-association studies are critically dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empirical data exist. The authors have determined the extent of LD among 38 biallelic markers with minor allele frequencies >.1, since these are most comparable to the common disease-susceptibility polymorphisms that association studies aim to detect. The markers come from three chromosomal regions-1,335 kb on chromosome 13q12-13, 380 kb on chromosome 19q13.2, and 120 kb on chromosome 22q13.3-which have been extensively mapped. These markers were examined in approximately 1,600 individuals from four populations, all of European origin but with different demographic histories; Afrikaners, Ashkenazim, Finns, and East Anglian British. There are few differences, either in allele frequencies or in LD, among the populations studied. A similar inverse relationship was found between LD and distance in each genomic region and in each population. Mean D' is.68 for marker pairs <5 kb apart and is.24 for pairs separated by 10-20 kb, and the level of LD is not different from that seen in unlinked marker pairs separated by >500 kb. However, only 50% of marker pairs at distances <5 kb display sufficient LD (delta>.3) to be useful in association studies. Results of the present study, if representative of the whole genome, suggest that a whole-genome scan searching for common disease-susceptibility alleles would require markers spaced < or = 5 kb apart.
Familial cancer risks to offspring from mothers with 2 primary breast cancers: leads to cancer syndromes.
The nationwide Swedish Family-Cancer Database was used to analyse the risk of cancer among the offspring of bilateral breast cancer patients. We studied 4,734 such mothers who had 9,391 offspring, of whom 328 presented with a primary cancer in the years 1958-1996. Standardised incidence ratios (SIRs) were increased for breast [SIR 3.05, 95% confidence interval (CI) 2.57-3.59], ovarian (SIR 1.84, 95% CI 1.03-3.05) and anogenital (SIR 1.75, 95% CI 1.11-2.63) cancers and childhood sarcomas (SIR 9.39, 95% CI 1.93-29.13). Additionally, squamous-cell skin cancer was increased among sons and all childhood cancers among daughters. When analysed by histological type, adenocarcinomas of the breast and ovary, all squamous-cell carcinomas and tumours at glandular epithelium (seminomas and intestinal carcinoids) were increased. Mothers with bilateral breast cancer had an excess of 2 or more children with cancer. The increased risk of ovarian cancer is consistent with germline mutations in the BRCA1 and BRCA2 genes, while the risk of soft tissue and bone sarcomas may reflect the association of these tumours with Li-Fraumeni syndrome. The increases in squamous-cell carcinomas at many sites may reflect a new susceptibility syndrome.
Re: "Presenting statistical uncertainty in trends and dose-response relations".
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Bone marrow staging of patients with non-Hodgkin lymphoma by flow cytometry: correlation with morphology.
BACKGROUND: Immunophenotypic analysis is an established tool in the diagnosis and classification of many hematolymphoid disorders; however, the role of flow cytometry (FC) in detecting bone marrow involvement during the staging of non-Hodgkin lymphoma (NHL) has yet to be defined. METHODS: The authors retrospectively analyzed 157 staging and 70 restaging bone marrow biopsies on which morphologic and FC analyses were performed; these biopsies were taken from 195 consecutive patients. Bone marrow biopsies were blindly and independently reviewed and determined to be positive, negative, or suspicious for morphologic involvement by NHL, with disagreements settled by a third reviewer. A selected panel of monoclonal antibodies was used to determine whether bone marrow involvement was immunophenotypically positive (>5%), minimal (<5%), negative, or nondiagnostic. RESULTS: FC and morphology agreed in 78% of cases (178 of 227: 129 both negative, 49 both positive) and were discrepant in 22% (49 of 227). Seven percent (16 of 227) were morphologically positive but showed no evidence of disease on FC, whereas 12% (27 of 227) were positive by FC but had no morphologic involvement. Of the 162 morphologically negative or suspicious bone marrows, 27 were shown to be involved by FC, resulting in a false-negative detection rate of 17%. Most of these (22 of 27, 81%) had minimal detectable disease. Seven percent of Stage I and 26% of Stage II NHL cases with negative staging bone marrow morphologically were found to be involved by FC. CONCLUSIONS: Neither morphologic examination of bone marrow biopsy specimens nor FC alone is adequate to detect all cases of NHL with bone marrow involvement. FC is most sensitive for detecting minimal bone marrow lymphoma, whereas morphology will detect most cases in which involvement is >5%. Cases of early stage NHL with morphologically negative bone marrow could potentially be restaged as Stage IV on the basis of FC results. The clinical importance of minimal bone marrow involvement by NHL needs further evaluation.
Breast cancer--not just whether but when?
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High risk genes predisposing to prostate cancer development-do they exist?
There is evidence for genetic predisposition to prostate cancer. However, prostate cancer genes have been more difficult to find than genes for some of the other common cancers, such as breast and colon cancer. The reasons for this are discussed in this article and it is now becoming clear that prostate cancer is probably due to multiple genes, many of which are moderate or low penetrance. The advances in the Human Genome Project and technology, especially that of robotics, will help to overcome these problems. Prostate Cancer and Prostatic Diseases (2000) 3, 241-247
Structural barriers and facilitators in HIV prevention: a review of international research.
OBJECTIVES: This article provides an overview of a growing body of international research focusing on the structural and environmental factors that shape the spread of the HIV/AIDS epidemic, and create barriers and facilitators in relation to HIV-prevention programs. OVERVIEW OF STRUCTURAL-FACTORS LITERATURE: Most of the research on structural and environmental factors can be grouped into a small number of analytically distinct but interconnected categories: economic (under)development and poverty; mobility, including migration, seasonal work, and social disruption due to war and political instability; and gender inequalities. An additional focus in research on structural and environmental factors has been on the effects of particular governmental and intergovernmental policies in increasing or diminishing HIV vulnerability and transmission. INTERVENTIONS: A smaller subset of the research on structural factors describes and/or evaluates specific interventions in detail. Approaches that have received significant attention include targeted interventions developed for heterosexual women, female commercial sex workers, male truck drivers, and men who have sex with men. CONCLUSIONS: The structural and environmental factors literature offers important insights and reveals a number of productive intervention strategies that might be explored in both resource-rich and -poor settings. However, new methodologies are required to document and evaluate the effects of the structural interventions, which by their very nature involve large-scale elements that cannot be easily controlled by experimental or quasi-experimental research designs. Innovative, interdisciplinary approaches are needed that can move beyond the limited successes of traditional behavioral interventions and explicitly attempt to achieve broader social and structural change.
Suggestive evidence for a site specific prostate cancer gene on chromosome 1p36. The CRC/BPG UK Familial Prostate Cancer Study Coordinators and Collaborators. The EU Biomed Collaborators.
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The ACE gene and Alzheimer's disease susceptibility.
A recent study suggested that the insertion (I) allele in intron 16 of the angiotensin converting enzyme gene (ACE) is associated with Alzheimer's disease (AD) risk. In our series of 239 necropsy confirmed late onset AD cases and 342 elderly non-demented controls aged >73 years, we found significantly different ACE genotype distributions in the case and control groups (p=0.007). Homozygotes for both the I and D alleles were associated with a higher risk compared to DI heterozygotes. While the APOE epsilon4 allele was strongly associated with AD risk in our series, we found no evidence for an interaction between the APOE and ACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A meta-analysis of all published reports (12 case-control series in total) suggested that both the II and ID ACE genotypes are associated with increased AD risk (odds ratio (OR) for II v DD 1.36, 95% confidence interval (CI)=1.13-1.63, OR for DI v DD 1.33, 95% CI=1.14-1.53, p=0.0002).
The chaperoning activity of hsp110. Identification of functional domains by use of targeted deletions.
hsp110 is one of major heat shock proteins of eukaryotic cells and is a diverged relative of the hsp70 family. It has been previously shown that hsp110 maintains heat-denatured luciferase in a soluble, folding competent state and also confers cellular heat resistance in vivo. In the present study the functional domains of hsp110 that are responsible for its chaperoning activity are identified by targeted deletion mutagenesis using the DnaK structure as the model. The chaperoning activity of mutants is assessed based on their ability to solubilize heat-denatured luciferase as well as to refold luciferase in the presence of rabbit reticulocyte lysate. It is shown that these functions require only an internal region of hsp110 that includes the predicted peptide binding domain and two immediately adjacent C-terminal domains. It is also shown that although hsp110 binds ATP, binding can be blocked by its C-terminal region.
Familial risks of cancer.
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Linkage analysis of 56 multiplex families excludes the Cowden disease gene PTEN as a major contributor to familial breast cancer.
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Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial.
BACKGROUND: Tamoxifen, a drug with antioestrogenic effects, is predicted to prevent the occurrence of breast cancer. We have undertaken a trial of tamoxifen in healthy women who are at increased risk of breast cancer because of family history. We report a planned interim analysis. METHODS: Between October, 1986, and April, 1996, we accrued 2494 healthy women aged between 30 and 70 with a family history of breast cancer. They have been randomised (double blind) to receive tamoxifen 20 mg per day orally or placebo for up to 8 years. Follow-up included clinical assessment, annual mammography, and assessment of toxicity and compliance. The primary endpoint was the occurrence of breast cancer, which was analysed on an intention-to-treat basis with a survival curve. FINDINGS: With a median follow-up of 70 months, 2471 women (tamoxifen 1238, placebo 1233) were suitable for analysis. The groups were evenly matched at baseline, and compliance was good. The overall frequency of breast cancer is the same for women on tamoxifen or placebo (tamoxifen 34, placebo 36, relative risk 1.06 [95% CI 0.7-1.7], p=0.8). Participants who were already on hormone-replacement therapy when they entered the study had an increased risk of breast cancer compared with non-users. Those participants who started such therapy while on trial had a significantly reduced risk. The safety profile of tamoxifen was as expected. INTERPRETATION: We have been unable to show any effect of tamoxifen on breast-cancer incidence in healthy women, contrary to the report from the NSABP-P1 study showing a 45% reduction in healthy women given tamoxifen versus placebo. Differences in the study populations for the two trials may underlie these conflicting findings: eligibility in our trial was based predominantly on a strong family history of breast cancer whereas in the NSABP trial was mostly based on non-genetic risk factors. The importance of oestrogen promotion may vary between such populations.
Linkage analysis of chromosome 1q markers in 136 prostate cancer families. The Cancer Research Campaign/British Prostate Group U.K. Familial Prostate Cancer Study Collaborators.
Prostate cancer shows evidence of familial aggregation, particularly at young ages at diagnosis, but the inherited basis of familial prostate cancer is poorly understood. Smith et al. recently found evidence of linkage to markers on 1q, at a locus designated "HPC1," in 91 families with multiple cases of early-onset prostate cancer. Using both parametric and nonparametric methods, we attempted to confirm this finding, in 60 affected related pairs and in 76 families with three or more cases of prostate cancer, but we found no significant evidence of linkage. The estimated proportion of linked families, under a standard autosomal dominant model, was 4%, with an upper 95% confidence limit of 31%. We conclude that the HPC1 locus is responsible for only a minority of familial prostate cancer cases and that it is likely to be most important in families with at least four cases of the disease.
Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study.
Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P<.001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P=.0005).
A systematic review and meta-analysis of family history and risk of ovarian cancer.
OBJECTIVE: To estimate the relative risk and lifetime risk of ovarian cancer in women with various categories of family history. DESIGN: A meta-analysis of all published case-control and cohort studies. METHODS: Pooled relative risk estimates were calculated for the case control studies, using the Mantel-Haenzel method. These estimates were combined with the relative risks from the cohort studies. The pooled estimates of relative risk were used to estimate lifetime risks of ovarian cancer from age 15 up to age 75, for various categories of family history. MAIN OUTCOME MEASURES: Relative risks and lifetime risks of developing ovarian cancer were calculated for the categories of women with 1. an affected first degree relative; 2. an affected mother; 3. an affected sister; and 4. women with more than one affected relative. RESULTS: The relative risk to first degree relatives is 3.1 (95% CI 2.6-3.7). There is some evidence that this relative risk declines with age. The relative risk to mothers of cases 1.1 (95% CI 0.8-1.6) was lower than the relative risks to sisters: 3.8 (95% CI 2.9-5.1), and daughters: 6.0 (95% CI 3.0-11.9); the explanation of this difference is unclear. CONCLUSIONS: Women with a family history of ovarian cancer have a substantially higher risk of developing ovarian cancer compared with women without such a history. However the risk is small for most categories of family history, except for the small number of individuals who have more than one affected relative.
Creutzfeldt-Jakob disease (CJD) after blood product transfusion from a donor with CJD.
We report a second case of an association between an albumin transfusion and Creutzfeldt-Jakob disease. On balance, we believe our case represents a chance and not a causal relation.