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D Easton

Publications and source records attributed to D Easton.

At least 19 recordsLinked to original sources
PubMed2007

A physical analysis of the Y chromosome shows no additional deletions, other than Gr/Gr, associated with testicular germ cell tumour.

Testicular germ cell tumour (TGCT) is the most common malignancy in men aged 15-45 years. A small deletion on the Y chromosome known as 'gr/gr' was shown to be associated with a two-fold increased risk of TGCT, increasing to three-fold in cases with a family history of TGCT. Additional deletions of the Y chromosome, known as AZFa, AZFb and AZFc, are described in patients with infertility; however, complete deletions of these regions have not been identified in TGCT patients. We screened the Y chromosome in a series of TGCT cases to evaluate if additional deletions of Y were implicated in TGCT susceptibility. Single copy Y chromosome STS markers with an average inter-marker spacing of 128 kb were examined in constitutional DNA of 271 index TGCT patients. Three markers showed evidence of deletions, sY1291, indicative of 'gr/gr' (eight out of 271; 2.9%), Y-DAZ3 contained within 'gr/gr' (21 out of 271; 7.7%) and a single deletion of the marker G66152 was identified in one TGCT case. No other markers demonstrated deletions. While several regions of the Y chromosome are known to be deleted and associated with infertility, our study provides no evidence to suggest regions of Y deletion, other than 'gr/gr', are associated with susceptibility to TGCT in UK patients.

Chromosome Deletion↗
PubMed2006

Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs X-ray mammography of women at a high familial risk of breast cancer.

Contrast enhanced magnetic resonance imaging (CE MRI) is the most sensitive tool for screening women who are at high familial risk of breast cancer. Our aim in this study was to assess the cost-effectiveness of X-ray mammography (XRM), CE MRI or both strategies combined. In total, 649 women were enrolled in the MARIBS study and screened with both CE MRI and mammography resulting in 1881 screens and 1-7 individual annual screening events. Women aged 35-49 years at high risk of breast cancer, either because they have a strong family history of breast cancer or are tested carriers of a BRCA1, BRCA2 or TP53 mutation or are at a 50% risk of having inherited such a mutation, were recruited from 22 centres and offered annual MRI and XRM for between 2 and 7 years. Information on the number and type of further investigations was collected and specifically calculated unit costs were used to calculate the incremental cost per cancer detected. The numbers of cancer detected was 13 for mammography, 27 for CE MRI and 33 for mammography and CE MRI combined. In the subgroup of BRCA1 (BRCA2) mutation carriers or of women having a first degree relative with a mutation in BRCA1 (BRCA2) corresponding numbers were 3 (6), 12 (7) and 12 (11), respectively. For all women, the incremental cost per cancer detected with CE MRI and mammography combined was pound28 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to pound11 731 (CE MRI vs mammography) and pound15 302 (CE MRI and mammography vs mammography). Results were most sensitive to the unit cost estimate for a CE MRI screening test. Contrast-enhanced MRI might be a cost-effective screening modality for women at high risk, particularly for the BRCA1 and BRCA2 subgroups. Further work is needed to assess the impact of screening on mortality and health-related quality of life.

Adult↗
PubMed2006

A prospective study of neurofibromatosis type 1 cancer incidence in the UK.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition affecting around one in 3000 live births. The manifestations of this condition are extremely variable, even within families, and genetic counselling is consequently difficult with regard to prognosis. Individuals with NF1 are acknowledged to be at increased risk of malignancy. Several studies have previously attempted to quantify this risk, but have involved relatively small study populations. We present prospective data from 448 individuals with NF1 with a total of 5705 years of patient follow-up. These data have been collected via the UK NF1 association for patients. Demographic information on the affected individuals was cross-referenced with UK cancer registry data by the UK Office of National Statistics. The overall risk of cancer was 2.7 times higher in this cohort of NF1 patients than in the general population (95% confidence interval (CI) 1.9-3.7). The cumulative risk of a malignancy by age 50 years was 20% (95% CI 14-29%); beyond this age, the risk of cancer was not significantly elevated (P=0.27). The most frequent types of cancer were connective tissue (14% risk by age 70, 95% CI 7.8-24%) and brain tumours (7.9, 95% CI 3.9-16%). There was no statistically significant excess of cancers at other sites (P=0.22).

Adolescent↗
PubMed2004

Somatic mutations of KIT in familial testicular germ cell tumours.

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.

DNA Mutational Analysis↗
PubMed2003

Apoptosis, ageing and cancer susceptibility.

We have previously shown that peripheral blood lymphocytes (PBL) from individuals carrying a germline TP53 mutation show a dramatically reduced apoptotic response to radiation. As part of a study of this phenomenon, we also investigated apoptotic response in a series of breast cancer patients lacking TP53 mutations and in a control group of individuals without cancer. There was a significant reduction in mean apoptotic response with increasing age in all groups. These findings are consistent with a number of studies in rodents, which have demonstrated a reduction in DNA damage-induced apoptosis with increasing age. In addition, after adjusting for age, breast cancer patients showed significantly reduced apoptotic responses compared with normal controls (P=0.002). The odds ratio for breast cancer in women with an apoptotic response of <35%, compared with women with a response of >49%, was 6.42 (95% CI 1.68-24.6). The data further support the hypothesis that a reduction in apoptotic response to DNA damage with increasing age may play a significant role in the age-related increase in cancer.

Adult↗
PubMed2003

Supportive care management of brain metastases: what is known and what we need to know. Conference proceedings of the National Cancer Institute of Canada (NCIC) Workshop on Symptom Control in Radiation Oncology.

OBJECTIVES: To review the results of published randomised controlled trials in the treatment of brain metastases and, from the knowledge gained from these trials, to identify potential study questions. MATERIALS AND METHODS: The literature was searched for randomised controlled trials that dealt with the management of brain metastases. Potential research questions were identified on the basis of the results of the literature review. RESULTS: A number of research questions were identified. In the context of the NCIC Symptom Control Group, a trial of supportive care alone vs supportive care and whole-brain radiotherapy (WBRT) in a subset of patients with the diagnosis of brain metastases was deemed to be of highest priority. We discussed a number of issues relating to the feasibility of such a trial. CONCLUSIONS: The optimal management of brain metastases remains elusive. Despite the results of numerous randomised controlled trials, many questions remain unanswered. The magnitude of benefit using WBRT above supportive care alone is uncertain. A trial of supportive care alone vs supportive care and WBRT may be successful once target population, feasibility and methodological issues are thoroughly solved.

Brain Neoplasms↗
PubMed2003

Association between leptin receptor gene polymorphisms and early-onset prostate cancer.

OBJECTIVE: To report a case-control study examining the relationship between polymorphisms in the leptin receptor (OBR) gene and the development of young-onset prostate cancer, because epidemiological studies report that prostate cancer risk is associated with animal fat intake, and thus we investigated if this association occurs via this genetic mechanism. PATIENTS, SUBJECTS AND METHODS: The Lys109Arg (OBR1) and Gln223Arg (OBR2) polymorphisms in the coding region of OBR were studied in blood DNA from 271 patients with prostate cancer aged < 56 years at diagnosis and 277 geographically matched control subjects. Cases were collected through the Cancer Research UK/British Prostate Group Familial Prostate Cancer Study. Blood DNA was genotyped using the polymerase chain reaction and a restriction enzyme digest. RESULTS: There was no statistically significant association between the OBR genotype and prostate cancer risk; men homozygous for 109Arg genotype had a slightly increased risk for prostate cancer, with a relative risk (95% confidence interval) of 1.36 (0.65-2.85), and those homozygous for the 223Arg allele had some reduction in prostate cancer risk, at 0.82 (0.58-1.26), but neither was statistically significant. CONCLUSION: This case-control study showed no significant association between leptin receptor gene polymorphisms and the risk of young-onset prostate cancer, suggesting that genetic variations in OBR are unlikely to have a major role in the development of early-onset prostate cancer in the UK.

Adult↗
PubMed2002

Apolipoprotein E4 is only a weak predictor of dementia and cognitive decline in the general population.

BACKGROUND: Apolipoprotein E (APOE) polymorphisms are unequivocally associated with risk for Alzheimer's disease (AD). It is crucial to understand how this genetic factor affects dementia risk in the general population, as well as in narrowly diagnosed, selected, patient groups. METHODS: We assessed the cross sectional association between APOE genotype and dementia status in a community based sample, the MRC Cognitive Function and Ageing Study (MRC CFAS). In addition, we tested the effects of APOE genotypes on the differences in MMSE scores between the first and third assessment waves (about six years apart), an index of cognitive decline. RESULTS: The APOE epsilon4 allele conferred increased risk for dementia (OR=1.5, 95% CI=1.1 to 2.2) compared to epsilon3 in the MRC CFAS sample. Compared with APOE epsilon3/epsilon 3 subjects, those with the epsilon3/epsilon4 genotypes were not at significantly higher risk for dementia (OR=1.1, 95% CI=0.6 to 1.9), although epsilon4/epsilon4 subjects were (OR= 3.8, 95% CI=1.0 to 14.0). Risk estimates were not different between men and women. Notably, our risk estimates for dementia were significantly lower than those reported for a diagnosis of Alzheimer's disease. MMSE scores at wave 3 and the difference in MMSE between baseline and at the third assessment wave were not different across APOE genotypes. INTERPRETATION: The APOE epsilon4 allele is a weaker predictor for dementia in the general population than for AD. This may be because dementia can be caused by non-AD pathological processes and because most prevalent dementia occurs at an age when the APOE epsilon4 effect on AD risk (and therefore dementia) has started to decline.

Aged↗
PubMed2001

Alzheimer disease is not associated with polymorphisms in the angiotensinogen and renin genes.

Hypertension has been implicated as a risk factor for Alzheimer disease (AD) and dementia in epidemiological studies of humans. It is thus possible that there are common genetic determinants for hypertension and AD. Epidemiological, clinical, and experimental data suggest that the renin-angiotensin-aldosterone system is a critical regulator of blood pressure. The presence of an MboI site in an RFLP in the renin gene and the Thr at the Met/Thr polymorphism at codon 235 (M235T) of the angiotensinogen gene have been reported to be associated with hypertension. These variants were studied in autopsy-confirmed AD cases and matched controls from the U.K. While no association was detected with the renin polymorphism, a weak deleterious effect was observed in cases homozygous for the angiotensinogen Thr allele. However, this association was not observed in a French cohort of clinically diagnosed AD cases and controls, suggesting that the initial observation was a type I error. Thus, these polymorphisms are unlikely to be associated with AD risk.

Aged↗
PubMed2001

Genome-wide linkage disequilibrium mapping of late-onset Alzheimer's disease in Finland.

BACKGROUND: AD is a complex neurodegenerative disorder comprising several disease-associated chromosome loci. To find novel susceptibility genes for late-onset AD, a population-based genome-wide search using linkage disequilibrium (LD) mapping approach has been performed. METHOD: Forty-seven patients with late-onset AD and 51 age-matched control subjects were carefully chosen from the same geographic area in eastern Finland, where the population is descended mainly from a small group of original founders. These subjects were initially genotyped with 366 polymorphic microsatellite markers, and a follow-up analysis was performed with additional microsatellite markers for those chromosome loci found to be associated with AD. RESULTS: Initial genome-wide screening revealed 21 chromosomal loci significantly associated with AD in addition to the 13q12 locus described previously. Subsequent comparison of single-allele frequencies of the microsatellite markers in the AD and control groups indicated the presence both of possible risk alleles (odds ratio [OR] > 1) and of possible protective alleles (OR < 1). Screening of the LD regions with additional microsatellite markers revealed seven chromosomal loci where more than one microsatellite marker was associated with AD (1p36.12, 2p22.2, 3q28, 4p13, 10p13, 18q12.1, and 19p13.3) in addition to the 13q12 locus. CONCLUSIONS: These genome-wide LD screening data suggest that several AD-associated chromosomal loci exist, which may encompass novel susceptibility genes for late-onset AD. Therefore, extensive screening of the genes located in the vicinity of these LD regions is necessary to elucidate their role in AD.

Age of Onset↗
PubMed2001

The BACE gene: genomic structure and candidate gene study in late-onset Alzheimer's disease.

Alzheimer's disease (AD) pathology is characterized by beta-amyloid plaques and neurofibrillary tangles. Studies of autosomal dominant early-onset AD mutations suggest that beta-amyloid overproduction is sufficient to cause AD. Recently, the BACE gene, which encodes beta-secretase, the rate limiting enzyme in beta-amyloid formation, has been identified. Since this gene is a strong candidate gene for late-onset AD because of its function, we have characterized its genomic organization and identified two polymorphisms. Neither of these polymorphisms were associated with AD risk in genetic association studies comparing autopsy-confirmed late-onset AD cases and age-matched non-demented controls. Thus, we find no evidence that this locus influences risk for late-onset AD.

3' Untranslated Regions↗
PubMed2001

Sibling risks in cancer: clues to recessive or X-linked genes?

A systematic analysis of cancer risks to offspring and to siblings of cancer cases was carried out based on the nation-wide Swedish Family-Cancer Database. For all 13 cancer sites examined, risks to both offspring and siblings of cases of cancer at the same site were significantly elevated. The relative risk to siblings was approximately 2 fold more than the offspring risk for cancers of the prostate, testis, kidney and bladder, suggesting that recessive or X-linked susceptibility genes may be important for these cancers. Risks to siblings of cases where a parent was also affected were increased >20 fold over population rates for colorectal, ovarian, prostate and renal cancer, and for leukaemia, consistent with the effects of rare high-risk susceptibility alleles.

Family Health↗
PubMed2001

Variation in cancer risks, by mutation position, in BRCA2 mutation carriers.

Cancer occurrence in 164 families with breast/ovarian cancer and germline BRCA2 mutations was studied to evaluate the evidence for genotype-phenotype correlations. Mutations in a central portion of the gene (the "ovarian cancer cluster region" [OCCR]) were associated with a significantly higher ratio of cases of ovarian:breast cancer in female carriers than were mutations 5' or 3' of this region (P<.0001), extending previous observations. The optimal definition of the OCCR, as judged on the basis of deviance statistics, was bounded by nucleotides 3059-4075 and 6503-6629. The relative and absolute risks of breast and ovarian cancer associated with OCCR and non-OCCR mutations were estimated by a conditional likelihood approach, conditioning on the set of mutations observed in the families. OCCR mutations were associated both with a highly significantly lower risk of breast cancer (relative risk [RR] 0.63; 95% confidence interval (95% CI) 0.46-0.84; P=.0012) and with a significantly higher risk of ovarian cancer (RR = 1.88; 95% CI = 1.08-3.33; P=.026). No other differences in breast or ovarian cancer risk, by mutation position, were apparent. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation (RR = 0.52; 95% CI = 0.24-1.00; P=.05), but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92% (95% CI = 1.20%-38.57%). Possible mechanisms for the variation in cancer risk are suggested by the coincidence of the OCCR with the RAD51-binding domain.

Adult↗
PubMed2001

Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study.

We used data from a population based series of breast cancer patients to investigate the genetic models that can best explain familial breast cancer not due to the BRCA1 and BRCA2 genes. The data set consisted of 1,484 women diagnosed with breast cancer under age 55 registered in the East Anglia Cancer registry between 1991-1996. Blood samples taken from the patients were analysed for mutations in BRCA1 and BRCA2. The genetic models were constructed using information on breast and ovarian cancer history in first-degree relatives and on the mutation status of the index patients. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene BRCA3, and a polygenic effect. The models were assessed by likelihood comparisons and by comparison of the observed numbers of mutations and affected relatives with the predicted numbers. BRCA1 and BRCA2 could not explain all the familial clustering of breast cancer. The best-fitting single gene model for BRCA3 was a recessive model with a disease allele frequency 24% and penetrance 42% by age 70. However, a polygenic model gave a similarly good fit. The estimated population frequencies for BRCA1 and BRCA2 mutations were similar under both recessive and polygenic models, 0.024 and 0.041%, respectively. A dominant model for BRCA3 gave a somewhat worse fit, although the difference was not significant. The mixed recessive model was identical to the recessive model and the mixed dominant very similar to the polygenic model. The BRCA3 genetic models were robust to the BRCA1 and BRCA2 penetrance assumptions. The overall fit of all models was improved when the known effects of parity on breast and ovarian cancer risks were included in the model-in this case a polygenic model fits best. These findings suggest that a number of common, low-penetrance genes with additive effects may account for the residual non-BRCA1/2 familial aggregation of breast cancer, but Mendelian inheritance of an autosomal recessive allele cannot be ruled out.

Adult↗
PubMed2001

Relationship between glutathione S-transferase M1, P1 and T1 polymorphisms and early onset prostate cancer.

There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer patients and for 280 geographically matched control subjects. We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1.80 (95% FCI 1.11-2.91); Ptrend = 0.026. These results suggest that the GSTP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017).

Adult↗
PubMed2001

Genetic association of an LBP-1c/CP2/LSF gene polymorphism with late onset Alzheimer's disease.

OBJECTIVES: The only locus unequivocally associated with late onset Alzheimer's disease (AD) risk is APOE. However, this locus accounts for less than half the genetic variance. A recent study suggested that the A allele of the 3'UTR biallelic polymorphism in the LBP-1c/CP2/LSF gene was associated with reduced AD risk. Samples were diagnosed predominantly by clinical rather than pathological criteria. We have sought to replicate this finding in a series of necropsy confirmed, late onset AD cases and non-demented controls. METHODS: The 3'UTR polymorphism in the LBP-1c/CP2/LSF gene was typed in 216 necropsy confirmed AD cases and 301 non-demented controls aged >73 years. RESULTS: We found different LBP-1c/CP2/LSF allele distributions in our AD cases and controls (p=0.048); the A allele was associated with reduced AD risk. The allele and genotype frequencies observed in our cases and controls were similar to those previously reported. No significant effects emerged when the data were adjusted for age, sex, or apoE epsilon4 carrier status. CONCLUSIONS: Our data support LBP-1c/CP2/LSF as a candidate gene/risk factor for AD and provide justification for future studies to investigate the role of this gene in Alzheimer's disease.

Age of Onset↗
PubMed2001

"War stories": AIDS prevention and the street narratives of drug users.

The day-to-day discourse of illicit drug users is replete with stylized narratives of street experience. These "war stories," as they are popularly known, are shared among drug users as they hustle for money, purchase drugs, get high, and hang out in diverse street locations. Drug-user narratives, which describe complex adventures and grave suffering, are primary ethnographic sources of information about patterns of drug consumption and risk behaviors. Importantly, in the time of AIDS, street narratives provide a much-needed window on the generally hidden lives of socially marginalized street drug users. As part of an effort to put the analysis of drug-user war stories to use in HIV prevention, in this article the authors analyze a corpus of street narratives told to members of an HIV-prevention research team in Hartford, Connecticut.

Adaptation, Psychological↗