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V P Collins

Publications and source records attributed to V P Collins.

At least 19 recordsLinked to original sources
PubMed2005

Mutations in Rb1 pathway-related genes are associated with poor prognosis in anaplastic astrocytomas.

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14(ARF)and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P=0.009). This association was consistent in multivariate analysis, including adjustment for age (P=0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy.

Adolescent↗
PubMed2005

A PDGFRA promoter polymorphism, which disrupts the binding of ZNF148, is associated with primitive neuroectodermal tumours and ependymomas.

BACKGROUND: Platelet derived growth factor receptor alpha (PDGFRalpha) expression is typical for a variety of brain tumours, while in normal adult brain PDGFRalpha expression is limited to a small number of neural progenitor cells. The molecular mechanisms responsible for the PDGFRalpha expression in tumours are not known, but in the absence of amplification, changes in transcriptional regulation might be an important factor in this process. METHODS AND RESULTS: We have investigated the link between single nucleotide polymorphisms (SNPs) within the PDGFRalpha gene promoter and the occurrence of brain tumours (medulloblastomas, supratentorial primitive neuroectodermal tumours (PNETs), ependymal tumours, astrocytomas, oligodendrogliomas, and mixed gliomas). These SNPs give rise to five different promoter haplotypes named H1 and H2alpha-delta. It is apparent from the haplotype frequency distribution that both PNET (10-fold) and ependymoma (6.5-fold) patient groups display a significant over-representation of the H2delta haplotype. The precise functional role in PDGFRalpha gene transcription for the H2delta haplotype is not known yet, but we can show that the H2delta haplotype specifically disrupts binding of the transcription factor ZNF148 as compared to the other promoter haplotypes. CONCLUSIONS: The specific over-representation of the H2delta haplotype in both patients with PNETs and ependymomas suggests a functional role for the ZNF148/PDGFRalpha pathway in the pathogenesis of these tumours.

Base Sequence↗
PubMed2003

Global amplification of mRNA by template-switching PCR: linearity and application to microarray analysis.

Conventional approaches to target labelling for expression microarray analysis typically require relatively large amounts of total RNA, a serious limitation when the sample available is small. Here we explore the cycle-dependent amplification characteristics of Template-Switching PCR and validate its use for microarray target labelling. TS-PCR identifies up to 80% of the differentially expressed genes identified by direct labelling using 30-fold less input RNA for the amplification, with the equivalent of 1000-fold less starting material being used for each hybridisation. Moreover, the sensitivity of microarray experiments is increased considerably, allowing the identification of differentially expressed transcripts below the level of detection using targets prepared by direct labelling. We have also validated the fidelity of amplification and show that the amplified material faithfully represents the starting mRNA population. This method outperforms conventional labelling strategies, not only in terms of sensitivity and the identification of differentially expressed genes, but it is also faster and less labour intensive than other amplification protocols.

DNA, Complementary↗
PubMed2003

Treatment of graft-versus-host disease after liver transplantation with basiliximab followed by bowel resection.

Graft-versus-host disease (GVHD) after orthotopic liver transplantation (OLT) is a serious complication with mortality rates over 80%. Two patients with established GVHD after OLT were treated with Basiliximab, a chimeric murine human monoclonal antibody which binds to the alpha-chain of interleukin-2 receptor (IL-2R). Two males, aged 45 and 56 years, presented after OLT with a clinical picture consistent with GVHD. Quantitative measurements of recipient peripheral blood donor lymphocyte chimerism were carried out by flow cytometric analysis, and showed peak chimerism levels of 5% and 8%, respectively. Treatment comprised 3 doses of 1 g methyl prednisolone followed by 2 doses of 20 mg of Basiliximab. In both, treatment resulted in complete disappearance of macro-chimerism in blood. There was resolution of skin rash by day 7; however, diarrhea persisted. White cell scan showed increased uptake in the terminal ileum and small-bowel resection was performed in both patients. One patient is alive and well 36 months after OLT. The other patient had resolution of GVHD, but died of recurrent hepatitis C 1 year after OLT. The combination of immunological and surgical treatment for GVHD following solid organ transplantation has not previously been described.

Antibodies, Monoclonal↗
PubMed2002

Tuberous sclerosis presenting in late adult life.

A 59 year old woman presented with a three year history of left sided weakness. Magnetic resonance imaging of the brain showed a large high signal lesion occupying most of the right temporal lobe with mass effect. A probable diagnosis of low grade glioma led to temporal lobectomy. Histology revealed dysplastic cortical morphology typical of tuberous sclerosis. There were no clinical signs or family history of the disease. Ultrasound showed multiple bilateral renal angiomyolipomas, confirming the diagnosis of tuberous sclerosis. Molecular genetic analysis of peripheral white blood cells identified a novel mis-sense mutation R1409W in exon 33 of the TSC2 gene.

Brain↗
PubMed2001

Cloning and chromosomal localization of human WIG-1/PAG608 and demonstration of amplification with increased expression in primary squamous cell carcinoma of the lung.

In this report, we describe the cloning of the coding region of human WIG-1 cDNA. The human 8 and 6 kb WIG-1 transcripts are both upregulated following ionizing irradiation of the human colon cancer cell lines HCT116 and LoVo which have wild type TP53 but not in DLD1 cells that lack wild type TP53. Basal levels of both WIG-1 transcripts were detected in human adult brain, kidney, and testis, but not in fetal brain, heart, pancreas, adrenal gland, fetal liver, and small intestine. FISH analysis mapped the human WIG-1 gene to 3q26.3. Investigation of squamous cell carcinomas of the lung by Southern blot and semiquantitative RT-PCR analysis showed amplification in combination with increased expression of WIG-1 in 1/7 tumors and increased expression in a further two cases.

Amino Acid Sequence↗
PubMed2001

Analysis of human meningiomas for aberrations of the MADH2, MADH4, APM-1 and DCC tumor suppressor genes on the long arm of chromosome 18.

We have previously reported that losses of genomic material from the long arm of chromosome 18 are frequent in atypical and anaplastic meningiomas but rare in benign meningiomas. In the present study, we have investigated a series of 37 meningiomas for mutation and expression of 4 tumor suppressor genes (MADH2, MADH4, APM-1 and DCC) located at 18q21. Comparative genomic hybridization or loss of heterozygosity analysis showed losses on chromosome 18 that included sequences from 18q21 in 15 of 37 tumors. Mutation analysis of APM-1 revealed a missense mutation (c. 1819G>A: G607S) in 1 atypical meningioma. None of the tumors showed mutations of MADH2 and MADH4 or loss of detectable transcripts from MADH2, MADH4, APM-1 and DCC. In contrast to human brain tissue, normal leptomeninges and meningiomas showed preferential expression of a DCC splice variant lacking 60 base pairs from exon 17. Taken together, our data do not support a significant role for MADH2, MADH4, APM-1 and DCC alterations in the pathogenesis of meningiomas. The targeted gene that is inactivated in most meningiomas with 18q losses remains to be identified.

Adiponectin↗
PubMed2001

Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas.

We investigated 67 meningothelial tumors (20 benign meningiomas, 34 atypical meningiomas, and 13 anaplastic meningiomas) for losses of genetic information from chromosome arms 1p and 9p, as well as for deletion, mutation, and expression of the tumor suppressor genes CDKN2A (p16(INKa)/MTS1), p14(ARF), CDKN2B (p15(INK4b)/MTS2) (all located at 9p21) and CDKN2C (1p32). Comparative genomic hybridization and microsatellite analysis showed losses on 1p in 11 anaplastic meningiomas (85%), 23 atypical meningiomas (68%), and 5 benign meningiomas (25%). One atypical meningioma with loss of heterozygosity on 1p carried a somatic CDKN2C mutation (c.202C>T: R68X). Losses on 9p were found in five anaplastic meningiomas (38%), six atypical meningiomas (18%), and one benign meningioma (5%). Six anaplastic meningiomas (46%) and one atypical meningioma (3%) showed homozygous deletions of the CDKN2A, p14(ARF), and CDKN2B genes. Two anaplastic meningiomas carried somatic point mutations in CDKN2A (c.262G>T: E88X and c.262G>A: E88K) and p14(ARF) (c.305G>T: G102V and c.305G>A: G102E). One anaplastic meningioma, three atypical meningiomas, and one benign meningioma without a demonstrated homozygous deletion or mutation of CDKN2A, p14(ARF), or CDKN2B lacked detectable transcripts from at least one of these genes. Hypermethylation of CDKN2A, p14(ARF), and CDKN2B could be demonstrated in one of these cases. Taken together, our results indicate that CDKN2C is rarely altered in meningiomas. However, the majority of anaplastic meningiomas either show homozygous deletions of CDKN2A, p14(ARF), and CDKN2B, mutations in CDKN2A and p14(ARF), or lack of expression of one or more of these genes. Thus, inactivation of the G(1)/S-phase cell-cycle checkpoint is an important aberration in anaplastic meningiomas.

Adult↗
PubMed2001

Parental cancer as a risk factor for brain tumors (Sweden).

OBJECTIVE: We used the nationwide Swedish Family-Cancer Database to analyze the risk for adult (15-61 years) brain tumors in offspring through parental cancer probands. Additionally, cancer risks were assessed among siblings of brain tumor probands. METHODS: In offspring and parents, respectively, 5,425 and 20,938 cases of brain tumors were diagnosed between the years 1958 and 1996. Groups of offspring were compared by calculating standardized incidence ratios (SIRs) for brain tumors. RESULTS: Of brain tumor patients, 2.1% had a parent with nervous system cancer; SIRs were 1.7, 2.4, and 2.5 for all brain tumors, astrocytomas, and meningiomas, respectively. Parental endometrial cancer and melanoma were associated with offspring astrocytoma, and parental breast and thyroid cancers with offspring ependymoma and neurinoma, respectively. SIR for sibling nervous system tumors from brain tumor probands was not increased overall but was 2.5 in those diagnosed at ages 15-34 years. CONCLUSION: These data show a familial risk for brain tumors among adults.

Adolescent↗
PubMed2001

Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes.

We investigated 34 oligodendroglial tumors (7 oligodendrogliomas, 11 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas) for deletion, mutation, hypermethylation, and expression of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes at 9p21. One anaplastic oligoastrocytoma carried a homozygous deletion including all 3 genes. None of the tumors demonstrated point mutations in any of the genes. Methylation-specific polymerase chain reaction (MSP) analysis and sequencing of bisulfite-modified DNA, however, revealed frequent hypermethylation of the 5'-CpG islands in CDKN2A, p14ARF, and CDKN2B. Partial or complete methylation of the majority of CpG sites analyzed from each gene was detected in 32% of the tumors at the CDKN2A gene and at a similar percentage (41%) of the tumors at the p14ARF gene and the CDKN2B gene. Most tumors with CDKN2A, p14ARF, and/or CDKN2B hypermethylation either lacked detectable transcripts from these genes or had lower mRNA levels than those determined for non-neoplastic brain tissue. There was a significant correlation between hypermethylation of these genes and the presence of allelic losses on chromosomal arms 1p and 19q. In addition, p14ARF hypermethylation was predominantly found in tumors without a demonstrated TP53 mutation. Taken together, our results indicate that hypermethylation of CDKN2A, p14ARF, and CDKN2B is an important epigenetic mechanism by which oligodendroglial tumors may escape from p53- and pRb-dependent growth control.

Adolescent↗
PubMed2001

A population-based study of familial central nervous system hemangioblastomas.

We used the nationwide Swedish Family-Cancer Database to analyze the risk for central nervous system hemangioblastoma (HB) in offspring (0-61 years) of parents with cancer. Eighty-three offspring were identified, and the age at onset showed a bimodal distribution. The early-onset component peaked at 25-29 years, was associated with von Hippel-Lindau (VHL) disease and presented with HBs, renal cell carcinomas, pheochromocytomas and insulomas in the proband or other family members. Standardized incidence ratios (SIRs) were 600 for offspring HB by parental HB, and they were even high for the other VHL-related tumors. Second tumors were common in this early-onset group, and the types were as expected in VHL. The late-onset component peaked at 40-44 years, and it was twice as prevalent as the early-onset component. Because there was no evidence of familial risks, this is suggested to be a sporadic form of HB.

Adolescent↗
PubMed2001

Molecular characterization of DDX26, a human DEAD-box RNA helicase, located on chromosome 7p12.

DEAD-box proteins comprise a family of ATP-dependent RNA helicases involved in several aspects of RNA metabolism. Here we report the characterization of the human DEAD-box RNA helicase DDX26. The gene is composed of 14 exons distributed over an extension of 8,123 bp of genomic sequence and encodes a transcript of 1.8 kb that is expressed in all tissues evaluated. The predicted amino acid sequence shows a high similarity to a yeast DEAD-box RNA helicase (Dbp9b) involved in ribosome biogenesis. The new helicase maps to 7p12, a region of frequent chromosome amplifications in glioblastomas involving the epidermal growth factor receptor (EGFR) gene. Nevertheless, co-amplification of DDX26 with EGFR was not detected in nine tumors analyzed.

Amino Acid Sequence↗
PubMed2000

The origin of alveolar macrophages in the transplanted lung: a longitudinal microsatellite-based study of donor and recipient DNA.

Transplanted lungs are initially populated by donor pulmonary alveolar macrophages (PAMs). These will form major antigen presenters for the recipient's suppressed immune system. They may be expected to be replaced by recipient major histocompatibility complex-compatible cells, with time. We have isolated CD14+ PAMs from bronchoalveolar lavage specimens for 6 months after transplantation and identified their origin by using microsatellite analysis. This DNA-based technology permits the reliable identification of the origin of cells from different individuals. We show that replacement of donor PAMs occurs with individual dynamics in each case. Recipient PAMs usually appeared within 2 weeks, whereas donor cells could be retained for as long as 6 months. In this limited series, there was no obvious correlation between the dynamics of this process and the occurrence of rejection episodes or infections.

Adult↗
PubMed2000

Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities.

Deregulation of G1-S transition control in cell cycle is one of the important mechanisms in the development of human tumors including astrocytic gliomas. We have previously reported that approximately two-thirds of glioblastomas (GBs) had abnormalities of G1-S transition control either by mutation/homozygous deletion of RB1 or CDKN2A p16INK4A), or amplification of CDK4 (K. Ichimura et al., Oncogene, 13: 1065-1072, 1996). However, abnormalities of G1-S transition control genes may induce p53-dependent apoptosis in cells. Recent investigations suggest that p14ARF is induced in response to abnormal cell cycle entry and results in p53 accumulation by inhibiting MDM2-mediated transactivational silencing and degradation of p53. To investigate the roles of the G1-S transition control system and the p14ARF/MDM2/p53 pathway in the development of astrocytic gliomas, we examined abnormalities of genes involved in these regulatory pathways in a total of 190 primary human astrocytic gliomas of different malignancy grades [136 GBs, 39 anaplastic astrocytomas (AAs) and 15 astrocytomas (As)]. Sixty-seven percent of GBs (91/136) and 21% of AAs (8/39) had abnormalities of the G1-S control system either by mutation/homozygous deletion of RB1, CDKN2A or CDKN2B, or amplification of CDK4. Seventy-six percent of GBs (103 of 136), 72% of AAs (28 of 39), and 67% of As (10 of 15) had deregulated p53 pathway either by mutation of TP53, amplification of MDM2, or homozygous deletion/mutation of p14ARF. When all of the data were combined and compared, 96% of GBs (87 of 91) and 88% of AAs (7 of 8) with abnormal G1-S transition control also had deregulated p53 pathway. Thus, we demonstrate that deregulation of the G1-S transition control system was almost always accompanied by inactivation of the p53 pathway, clearly illustrating the cooperative roles of these two systems in the development/progression of primary human astrocytic gliomas.

Astrocytoma↗
PubMed2000

Cryopreservation of viable human glioblastoma xenografts.

Human tumour xenografts maintained in nude mice are a valuable research tool. The passaging and maintenance of human tumour xenografts in immune-deficient animals are expensive and labour-intensive. This study presents a protocol that permits long-term cryopreservation of viable glioblastoma xenograft tissue pieces in liquid nitrogen. Twenty different human glioblastoma xenografts that have been successfully transplanted and repeatedly passaged in nude mice were cryopreserved to validate the method. Different passages were cryopreserved for up to 40 months. On retransplantation of the tumours, all cases except one grew successfully. In order to ensure that the individual tumours did grow (not induced mouse tumours) restriction fragment length polymorphism analysis with variable number of tandem repeats (VNTR) probes was carried out. The method permits the long-term storage of viable, retransplantable glioblastoma xenografts. It minimizes animal use for the maintenance of xenografts and permits cryo-back-up of valuable tumours, thus markedly reducing the cost and increasing the accessibility of human tumour xenografts as a research tool in biology and genetics.

Animals↗
PubMed2000

Multiple deleted regions on the long arm of chromosome 6 in astrocytic tumours.

Chromosome 6 deletions are common in human neoplasms including gliomas. In order to study the frequency and identify commonly deleted regions of chromosome 6 in astrocytomas, 159 tumours (106 glioblastomas, 39 anaplastic astrocytomas and 14 astrocytomas malignancy grade II) were analysed using 31 microsatellite markers that span the chromosome. Ninety-five per cent of cases with allelic losses had losses affecting 6q. Allelic losses were infrequent in astrocytomas malignancy grade II (14%) but more usual in anaplastic astrocytomas (38%) and glioblastomas (37%). Evidence for clonal heterogeneity in the astrocytomas and anaplastic astrocytomas was frequently observed (i.e. co-existence of subpopulations with and without chromosome 6 deletions). Clonal heterogeneity was less common in glioblastomas. Five commonly deleted regions were identified on 6q. These observations suggest that a number of tumour suppressor genes are located on 6q and that these genes may be involved in the progression of astrocytic tumours.

Astrocytoma↗
PubMed2000

Analysis of pilocytic astrocytoma by comparative genomic hybridization.

Very little is known about genetic abnormalities involved in the development of pilocytic astrocytoma, the most frequently occurring brain tumour of childhood. We have analysed 48 pilocytic astrocytoma specimens using comparative genomic hybridization. Only five of 41 tumours from children showed abnormalities detectable by comparative genomic hybridization, and in each case this represented gain of a single chromosome. Interestingly, two of seven tumours from adults showed abnormalities, which were multiple and relatively complex. Six of the seven tumours showing abnormalities were from female patients (two adults and four children). The most frequently detectable abnormality was gain of 9q34.1-qter, which was present in three cases (two adult and one paediatric).

Adolescent↗