Search PubMed⌕ Search

Biomedical subjects

D G Evans

Publications and source records attributed to D G Evans.

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

High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CGH methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.

Adolescent↗
PubMed2001

High detection rate for BRCA2 mutations in male breast cancer families from North West England.

33 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA2 mutations. 12 pathogenic BRCA2 mutations were identified (36%) in samples from an affected family member. All mutations segregated with disease where it was possible to check. Of the 14 families fulfilling BCLC criteria, 9 (64%) had mutations whilst only 3/16 (19%) of male breast cancer patients with less significant female breast cancer family history having a mutation. All 3 families with ovarian cancer and 3 families with multiple male breast cancer cases had BRCA2 mutations. These data are a further guide to how to prioritise samples for BRCA2 mutation analysis.

Adult↗
PubMed2001

Screening of patients at high risk of colorectal cancer.

OBJECTIVE: To determine the present state of colonoscopic screening practice for patients at a high risk of developing colorectal cancer. METHODS: We assessed colonoscopic screening practice in nine colorectal surgery or gastroenterology units referring patients to the regional genetics centre in the North-west of England. The validity of the pedigree was confirmed by inspection of Hospital records, use of cancer registries and records of general practitioners across the United Kingdom. The screening activity at the participating centres was investigated by means of a questionnaire, site visit and study of case notes. RESULTS: One hundred and eight high risk families were identified. Outside the genetics unit, family history was not taken in a structured manner and family pedigree was not confirmed. In four units screening was offered directly by the consultant surgeon. Differing protocols for screening were in place in six units, but were frequently not adhered to. Colonoscopy completion rates were known in only four units (range 83-97%). Frequency of screening varied from 2 to 5 years. Recording of information was minimal outside the patients' records and there were no dedicated databases. Facilities for families to be screened together existed in three units and the psychological effect of screening was not determined outside the genetics centre. CONCLUSIONS: Screening practice should be standardized and specific criteria met before regular screening is initiated. A dedicated database should be established to record information from units screening patients at high risk of colorectal cancer.

Journal Article↗
PubMed2001

Helicobacter pylori CagA: analysis of sequence diversity in relation to phosphorylation motifs and implications for the role of CagA as a virulence factor.

CagA is transported into host target cells and subsequently phosphorylated. Clearly this is a mechanism by which Helicobacter pylori could take control of one or more host cell signal transduction pathways. Presumably the end result of this interaction favors survival of H. pylori, irrespective of eventual damage to the host cell. CagA is noted for its amino acid (AA) sequence diversity, both within and outside the variable region of the molecule. The primary purpose of this review is to examine how variation in the type and number of CagA phosphorylation sites might determine the outcome of infection by different strains of H. pylori. The answer to this question could help to explain the widely disparate results obtained when H. pylori CagA status has been compared to type and severity of disease outcome in different populations, that is in different countries. Analysis of all available CagA sequences revealed that CagA contains both tyrosine phosphorylation motifs (TPMs) and cyclic-AMP-dependent phosphorylation motifs (CPMs). There are two potential CPMs near the N-terminus of CagA and at least two in the repeat region; these are not all equally well conserved. We also defined a 48-residue AA sequence, which includes the N-terminal TPM at tyrosine (Y)-122, which distinguishes between Eastern (Hong Kong-Taiwan-Japan-Thailand) H. pylori isolates and those from the West (Europe-Africa-the Americas-Australia). All 28 of the Eastern type CagA proteins have a functional N-terminal TPM whereas 11 of 47 (23.4%) of the Western type contain an inactive motif, with threonine (T) replacing the critical aspartic acid (D) residue. Only 13 of 24 (54%) known CagA sequences have an active TPM in the repeat region and only one has two TPMs in this region. The potential TPM near the C-terminus of CagA is not likely to be important since only 3 of 24 (12.5%) sequences were found to be intact. Protein database searches revealed that the AA sequence immediately following the TPM at Y-122 in CagA is homologous with a pair of PDZ domains which are common in signal transducing proteins, particularly tyrosine phosphatases. This provides a theoretical link between CagA and many of the observed responses of host cells to H. pylori. In summary, not all CagA proteins are equal in their potential for initiating host cell responses via signal transduction pathways. The degree of functional diversity of this protein depends upon which phosphorylation motifs are critical to the biological activity of CagA.

Amino Acid Motifs↗
PubMed2001

There may never be a final cure for breast cancer.

This paper challenges the perception that the success of the human genome project has brought us to the threshold of a cure for many common cancers. Paradoxically, the message emerging from the genetics of breast cancer may be that the genetic damage associated with malignant transformation, and the mutations predisposing to the disease in our gene pool, may prove impossible to eliminate.

Breast Neoplasms↗
PubMed2000

Associations of clinical features in neurofibromatosis 1 (NF1).

Neurofibromatosis 1 (NF1), an autosomal dominant disease, exhibits extreme clinical variability. This variability greatly increases the burden for affected families and impairs our ability to understand the pathogenesis of NF1. Recognition of heterogeneity within a disease may provide important pathogenic insights, therefore we tested clinical data from three large sets of NF1 patients for evidence that certain common features are more likely to occur in some NF1 patients than in others. Clinical information on 4,402 patients with NF1 was obtained from three independent databases. We examined associations between pairs of clinical features in individual affected probands. We also examined associations between the occurrence of individual features in affected relatives. Associations were summarized as odds ratios with 95% confidence intervals. We found associations between several pairs of features in affected probands: intertriginous freckling and Lisch nodules, discrete neurofibromas and plexiform neurofibromas, discrete neurofibromas and Lisch nodules, plexiform neurofibromas and scoliosis, learning disability or mental retardation and seizures. We also found associations between the occurrence of Lisch nodules, macrocephaly, short stature, and learning disability or mental retardation as individual features in parents and children with NF1. Our observations suggest that, contrary to established belief, some NF1 patients are more likely than others to develop particular manifestations of the disease. Genetic factors appear to determine the development of particular phenotypic features.

Adult↗
PubMed2000

Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12-q13.

Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.

Carcinoma, Adenoid Cystic↗
PubMed2000

Magnetic resonance imaging screening in women at genetic risk of breast cancer: imaging and analysis protocol for the UK multicentre study. UK MRI Breast Screening Study Advisory Group.

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.

Adult↗
PubMed2000

Identification of the familial cylindromatosis tumour-suppressor gene.

Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).

Amino Acid Sequence↗
PubMed2000

Helicobacter pylori adhesins: review and perspectives.

It is highly unlikely that chronic infection with H. pylori could occur in the absence of adhesin-host cell interactions. Also, there is no evidence that any of the serious outcomes of H. pylori infection such as gastric and duodenal ulcers, gastric cancer or mucosa-associated lymphoid tissue (MALT) lymphoma could occur without prior colonization of the gastric epithelium mediated by H. pylori adhesins. H. pylori is highly adaptable, as evidenced by the fact that it can occupy a single host for decades. An important facet of this adaptability is its ability to physically interact with various types of host cells and also with host mucins and extracellular matrix proteins using a number of different adhesins displaying a variety of unique receptor specificities. Thus it is highly unlikely that any one particular H. pylori adhesin will ever be proven responsible for a particular outcome such as duodenal ulcer, MALT lymphoma, or adenocarcinoma. Also, while the search for additional H. pylori adhesins should and certainly will continue, we suggest that the scope of this effort should be expanded to include investigations into the patterns of expression and interaction between individual outer membrane proteins. Which of the numerous H. pylori outer membrane proteins (OMPs) actually function as adhesins (i.e., have receptor-binding sites) and which OMPs are simply necessary for optimal display of the adhesive OMPs? There are many other important questions about H. pylori adhesins waiting to be answered. For example, which adhesins are responsible for loose adherence to host cells and which adhesins are responsible for intimate, or membrane-to-membrane, adherence, and do these adhesins normally work in concert or in a sequential fashion? Also, is a specific type of adhesin necessary for type IV protein translocation into host cells and, if so, is adhesin expression coregulated with the effector protein export?

Adhesins, Bacterial↗
PubMed2000

A protocol for preventative mastectomy in women with an increased lifetime risk of breast cancer.

This paper describes a protocol for women at high risk of breast cancer wishing to undergo preventative mastectomy. The protocol described is a holistic approach to each woman involving the use of a multidisciplinary team. The protocol takes a number of months from initiation to surgery. A time delay is deliberate to allow women to fully address the issues involved with a decision for surgery. Early evidence suggests that this prepares the women emotionally and physically for their surgery.

Adult↗
PubMed2000

Rationale for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer.

In 1994, the UK National Health Service identified as a research priority that magnetic resonance imaging (MRI) should be assessed as a screening tool for young, pre-menopausal women who are at a high genetic risk of developing breast cancer. In 1997 a national multicentre study was established to compare MRI with X-ray mammography as a method for screening for breast cancer in this group of women. This paper reviews the relevant literature and describes the rationale that led to the setting up of this study.

Journal Article↗
PubMed2000

Protocol for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer.

The protocol of the national multicentre study of Magnetic Resonance Imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The sensitivity and specificity of contrast-enhanced MRI will be compared with two-view X-ray mammography in a comparative trial. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for 3 years, with annual MRI and X-ray examination continuing for up to 5 years. A symptomatic cohort will be measured in the initial phase of the study to ensure consistent reporting between centres. The MRI examination will comprise an initial high-sensitivity screening measurement, followed by a high-specificity measurement in equivocal cases. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. The psychological impact of screening in this high-risk group will be ascertained.

Journal Article↗