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Biomedical subjects

N K Spurr

Publications and source records attributed to N K Spurr.

At least 19 recordsLinked to original sources
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

Rearrangement of the long arm of chromosome 10 in the prostate adenocarcinoma cell line LNCaP.

Rearrangement of distal 10q is a common feature of many tumor types and tumor-derived cell lines. More specifically, loss of 10q23-25 has been demonstrated in a large proportion of prostate tumors, indicative of the presence of a tumor suppressor gene at this location. Using whole-chromosome paints and human genomic YAC clones as FISH probes, we have performed a detailed cytogenetic analysis of distal 10q rearrangements in the prostate adenocarcinoma cell line LNCaP. Our data reveal nonreciprocal translocation of 10q24.1-qter material to two sites on chromosome 5q, giving der(5)t(5;10) (q14-23;q24.1)t(5;10)(q35;q24.2) loss of 10q material at the 10q24.1 breakpoint. Deleted chromatin at the distal breakpoint includes the cytochrome P450IIC (CYP2C) gene cluster, thought to be involved in steroid hormone metabolism and therefore of possible significance to the growth rate of this androgen-dependent cell line. Deleted material at the proximal breakpoint overlaps with a region of deletion at the 10q23-24 boundary recently identified in a high proportion of prostate tumors, adding to the evidence for a tumor suppressor gene in this interval.

Adenocarcinoma↗
PubMed1998

Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN.

The chromosomal region 10q23-24 is frequently deleted in a number of tumour types, including prostate adenocarcinoma and glioma. A candidate tumour-suppressor gene at 10q23.3, designated PTENor MMAC1, with putative actin-binding and tyrosine phosphatase domains has recently been described. Mutations in PTEN have been identified in cell lines derived from gliomas, melanomas and prostate tumours and from a number of tumour specimens derived from glial, breast, endometrial and kidney tissue. Germline mutations in PTEN appear to be responsible for Cowden disease. We identified five PTEN mutations in 37 primary prostatic tumours analysed and found that 70% of tumours showed loss or alteration of at least one PTEN allele, supporting the evidence for PTEN involvement in prostate tumour progression. We raised antisera to a peptide from PTEN and showed that reactivity occurs in numerous small cytoplasmic organelles and that the protein is commonly expressed in a variety of cell types. Northern blot analysis revealed multiple RNA species; some arise as a result of alternative polyadenylation sites, but others may be due to alternative splicing.

Amino Acid Sequence↗
PubMed1997

Detailed physical analysis of a 1.5-megabase YAC contig containing the MXI1 and ADRA2A genes.

The distal long arm of chromosome 10 harbors genes of biomedical interest such as MXI1, a putative tumor suppressor gene, and those encoding the adrenergic receptors alpha2A (ADRA2A) and beta1 (ADRB1). As part of a physical and genetic study of this genomic region, we constructed a 1.5-Mb YAC contig mapping to 10q25 that contains MXI1 and ADRA2A as well as a number of STSs. Rare cutting restriction site analysis of overlapping YACs allowed fine mapping of these genes and markers along the contig and revealed the presence of four CpG islands. MXI1 and ADRA2A appear to be about 600 kb apart, whereas ADRB1 is separated from ADRA2A by a distance larger than previously reported.

Basic Helix-Loop-Helix Proteins↗
PubMed1997

An integrated physical and genetic map spanning chromosome band 10q24.

Chromosome band 10q24 is rich in genes involved in development, tumorigenesis, neurological disorders, hormone metabolism, and environmentally induced disease susceptibility. We have constructed an STS-based integrated physical and genetic map of 10q24 derived from the CEPH-Généthon mega-YAC contig data for this region. This map consists of 42 fluorescence in situ hybridization-mapped overlapping CEPH mega-YACs spanning approximately 15 Mb to which 49 STS markers have been assigned, including 24 Généthon CA repeat genetic markers, 10 known gene loci from the 10q24 region (IFI56, IDE, PDE6C, RBP4, CYP2C, CD39, DNTT, GOT1, WNT8B, and PAX2) and 11 additional expressed sequences of unknown function.

Chromosome Banding↗
PubMed1997

Human 5-HT5A receptor gene: systematic screening for DNA sequence variation and linkage mapping on chromosome 7q34-q36 using a polymorphism in the 5' untranslated region.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of sensory, motor, and cortical functions by activating multiple 5-HT receptor subtypes. In the present study we performed a systematic mutation scan of the complete coding region of the 5-HT5A receptor to explore its variability in the general population. Investigating 46 unrelated healthy subjects by single-strand conformation analysis no sequence changes of likely functional relevance were observed. The detection of a frequent G-->C substitution at position -19 was used for fine scale linkage mapping of the 5-HT5A gene. Employing a polymerase-chain-reaction based assay we genotyped 7 CEPH families (Centre d'Etude du Polymorphisme Humaine) and mapped the receptor to genetic markers on chromosome 7q34-q36.

Chromosome Mapping↗
PubMed1997

Chromosomal assignment of 311 sequences transcribed in human adult testis.

A total of 311 expressed sequence tags (ESTs) derived from human adult testis have been assigned to human chromosomes by Southern analysis of a monochromosome somatic cell hybrid panel. Over 70% of the ESTs show conservation to hamster and mouse DNA, and the overall distribution of transcripts correlates well with physical chromosome size and to a greater extent with male meiotic chromosome length. The notable exception is the X chromosome, for which the number of testis-derived ESTs is greatly underrepresented. This finding may reflect inactivation of the X chromosome during the meiotic phase of spermatogenesis and a consequent selection against large numbers of X-linked germ cell transcripts. Further analysis of the distribution of testis ESTs showed that the EST density remains significantly correlated with the recombination density of each autosome. Analysis of a comparable number (320) of brain EST autosome assignments showed no similar correlation. These data suggest a specific association between transcription in testis tissue and male meiotic recombination.

Adult↗
PubMed1997

Mapping of the human adenosine A2a receptor gene: relationship to potential schizophrenia loci on chromosome 22q and exclusion from the CATCH 22 region.

Chromosome 22 contains two potential schizophrenia loci on chromosomal regions 22q11.2 and 22q12-13. In the present study we report results from linkage mapping of the gene coding for the human A2a adenosine receptor (AR), which is one of two receptors mediating central nervous system effects of adenosine. From seven CEPH (Centre d'Etude du Polymorphisme Humain) families, 120 individuals were typed utilizing an intragenic restriction fragment length polymorphism. Significant linkage was found with many markers on chromosome 22. A 10-cM 1000:1 support interval between markers D22S301 and D22S300 is defined on the CHLC (Cooperative Human Linkage Center) framework map of chromosome 22. Localization of the A2aAR gene outside the CATCH 22 syndrome region on 22q11.2 is demonstrated by the observation of heterozygous individuals with defined 2-Mb deletions from this region. Thus, the A2aAR gene is not the schizophrenia susceptibility gene suspected in the CATCH 22 syndrome region on 22q11.2, but remains a candidate for a schizophrenia susceptibility gene on 22q12-13.

Abnormalities, Multiple↗
PubMed1997

Germline BRCA2 mutations in men with breast cancer.

Breast cancer in men is rare and is clearly due in some cases to an inherited predisposition. A total of 28 male breast cancer patients were tested for BRCA2 mutations; two frameshifts and one putative missense mutation were identified. One of the frameshifts was detected in the same position as a mutation estimated to be responsible for 40% of all male breast cancer cases in Iceland.

BRCA2 Protein↗
PubMed1997

Report on the Fifth International Workshop on Chromosome 9 held at Eynsham, Oxfordshire, UK, September 4-6, 1996.

The Fifth International workshop on chromosome 9 comprised a gathering of 36 scientists from seven countries and included a fairly even distribution of interests along chromosome 9 as well as a strong input from more global activities and from comparative mapping. At least eight groups had participated in the goal set at the previous workshop which was to improve the fine genetic mapping in different regions of chromosome 9 by meiotic breakpoint mapping in allocated regions and this has resulted in some greatly improved order information. Excellent computing facilities were available and all contributed maps were entered not only into SIGMA (and thence submitted to GDB) but also into a dedicated version of ACEDB which can be accessed on the Web in the form of one of 28 slices into which the chromosome has been arbitrarily divided. It was generally agreed that the amount of data is now overwhelming and that the integration and validation of all data is not only unrealistic in a short meeting but probably impossible until the whole chromosome has been sequenced and fully annotated. Sequence-ready contigs presented at the meeting totalled about 3 MB which is about one fiftieth of the estimated length. The single biggest barrier to integration of maps is the problem of non-standard nomenclature of loci. In the past 2 workshops efforts have been made to compare traditional 'consensus' maps made by human insight (still probably best for small specific regions) with those generated with some computer assistance (such as SIGMA) and those generated objectively by defined computer algorithms such as ldb. Since no single form of map or representation is entirely satisfactory for all purposes the maps reproduced in the published version of the report are confined to one of the genetic maps, in which Genethon and older markers have been incorporated, a Sigma map of the genes as symbols together with a listing of known 'disease' genes on chromosome 9, and a revised assessment of the mouse map together with a list of mouse loci predicted to be on human chromosome 9. One of the 28 ACEDB slices is also shown to illustrate strengths and weaknesses of this approach. Workshop files include not only all maps available at the time but also details of loci and details of the meiotic breakpoints in the CEPH families (http:/(/)www.gene.ucl.ac.uk/scw9db.shtml) .

Animals↗
PubMed1997

Germline mutations of the CDKN2 gene in UK melanoma families.

Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin D kinase inhibitor p16, and more rarely, mutations in the gene coding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and analysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in CDKN2 were found in six families. Three of the mutations (Met53Ile, Arg24Pro and 23ins24) have been reported previously. We have identified two novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CDKN2 protein. In binding assays the protein expressed from the previously described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Thr appeared to be functional in this assay. Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon. The penetrance of these mutant CDKN2 genes is not yet established, nor is the risk of non-melanoma cancer to gene carriers.

Adult↗
PubMed1997

A first-generation whole genome-radiation hybrid map spanning the mouse genome.

We have assembled a first-generation anchor map of the mouse genome using a panel of 94 whole-genome-radiation hybrids (WG-RHs) and 271 sequence-tagged sites (STSs). This is the first genome-wide RH anchor map of a model organism. All of the STSs have been previously localized on the genetic map and are located 8.8 Mb apart on average. This mouse WG-RH panel, known as T31, has an average retention frequency of 27.6% and an estimated potential resolution of 145 kb, making it a powerful resource for efficient large-scale expressed sequence tag mapping. [All of the mapping data for the maps presented here have been deposited at the Research Genetics, Inc., web site and can be freely accessed and downloaded at http://www.resgen.com/.]

Animals↗
PubMed1997

Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families.

BRCA1 is a tumour suppressor gene located on chromosome band 17q21. It is estimated that mutations in the BRCA1 gene account for approximately 45% of the breast cancer families and almost all of the breast/ovarian cancer families. We have used single strand conformation polymorphism analysis, direct sequencing, allele specific oligonucleotide hybridisation, and reverse transcription polymerase chain reaction (RT-PCR) to look for mutations in the BRCA1 gene in 49 breast or breast/ovarian cancer families. Five distinct mutations, three novel and two previously observed, were detected in seven families. Each novel mutation was identified in one family: 3896delT in exon 11, a splicing mutation in the intron 9-exon 10 junction, and an inferred regulatory mutation. The 185delAG in exon 2 was found in three families sharing the same haplotype, but this haplotype is different from that shared by the Ashkenazi Jewish families, suggesting that the 185delAG in our families may have arisen independently. Another previously reported mutation, the 3875del4 in exon 11, was identified in one family. Of the 49 families examined, linkage analyses for both the BRCA1 and the BRCA2 regions were performed on 33 families, and mutations in the BRCA1 gene were identified in all but one family that have a lod score above 0.8 for BRCA1. All of the mutations cause either a truncated BRCA1, or loss of a BRCA1 transcript, thus are likely to be functionally disruptive. In addition, we found that alternative splicing is a common phenomenon in the processing of the BRCA1 gene. Seven variant BRCA1 transcripts were identified by RT-PCR; all but one maintained the BRCA1 open reading frame. We believe that alternative splicing may play a significant role in modulating the physiological function of BRCA1.

Alternative Splicing↗
PubMed1996

Construction of a radiation hybrid map of chromosome 9p.

A radiation hybrid panel has been constructed for chromosome 9 using the somatic cell hybrid GM10611 as the donor cell line fused to the hamster cell line A23. The hybrid GM10611 was characterized by fluorescence in situ hybridization and reverse painting onto spreads of normal human metaphase chromosomes; it contains human chromosome 9 as the only cytogenetically detectable human material. GM10611 was irradiated with 6000 rads of X rays prior to fusion, a total of 93 independent clones were selected, and frozen stocks and DNA were prepared from each clone. These clones were screened by PCR amplification with oligonucleotide primers for sequence-tagged sites specific for 50 single-copy loci mapping to the short arm of chromosome 9. The average retention frequency of these hybrids was approximately 23%. The markers were ordered into a framework map by analyzing coretention patterns, minimizing the number of obligatory chromosome breaks, and finally confirming the order by maximum likelihood methods. A framework map ordering 27 markers with odds greater than 1000:1 was constructed. A further 16 markers that could not be uniquely placed on the map with the required support were positioned within a range of adjacent intervals.

Animals↗