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J M Maris

Publications and source records attributed to J M Maris.

At least 37 records · Page 2Linked to original sources
PubMed1999

Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.

Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

Amino Acid Sequence↗
PubMed1999

Molecular biology of neuroblastoma.

UNLABELLED: PURPOSE AND RESULTS: Neuroblastoma, the most common solid extracranial neoplasm in children, is remarkable for its clinical heterogeneity. Complex patterns of genetic abnormalities interact to determine the clinical phenotype. The molecular biology of neuroblastoma is characterized by somatically acquired genetic events that lead to gene overexpression (oncogenes), gene inactivation (tumor suppressor genes), or alterations in gene expression. Amplification of the MYCN proto-oncogene occurs in 20% to 25% of neuroblastomas and is a reliable marker of aggressive clinical behavior. No other oncogene has been shown to be consistently mutated or overexpressed in neuroblastoma, although unbalanced translocations resulting in gain of genetic material from chromosome bands 17q23-qter have been identified in more than 50% of primary tumors. Some children have an inherited predisposition to develop neuroblastoma, but a familial neuroblastoma susceptibility gene has not yet been localized. Consistent areas of chromosomal loss, including chromosome band 1p36 in 30% to 35% of primary tumors, 11q23 in 44%, and 14q23-qter in 22%, may identify the location of neuroblastoma suppressor genes. Alterations in the expression of the neurotrophins and their receptors correlate with clinical behavior and may reflect the degree of neuroblastic differentiation before malignant transformation. Alterations in the expression of genes that regulate apoptosis also correlate with neuroblastoma behavior and may help to explain the phenomenon of spontaneous regression observed in a well-defined subset of patients. CONCLUSION: The molecular biology of neuroblastoma has led to a combined clinical and biologic risk stratification. Future advances may lead to more specific treatment strategies for children with neuroblastoma.

Child↗
PubMed1998

Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity.

Meningioma is a common tumor of the central nervous system. Deletions of the short arm of chromosome 1 (1p) are the second most commonly observed chromosomal abnormality in these tumors. Here, we analyzed tumor and normal DNAs from 157 meningioma patients using PCR-based polymorphic loci. Loss of heterozygosity (LOH) for at least one informative marker on 1p was observed in 54 cases (34%), whereas LOH on 1q occurred in only 9 cases (8%). High-resolution deletion mapping defined a consensus region of deletion flanked distally by D1S2713 and proximally by D1S2134, which spans 1.5 cM within 1p32. LOH in this region has also been observed in several other malignancies, suggesting the presence of a tumor suppressor gene or genes that are important for several types of cancer. Statistical analysis revealed that 1p LOH was associated with chromosome 22 deletions and with abnormalities of the NF2 gene in meningioma. In addition, unlike other clinical and molecular characteristics, only 1p LOH was shown to be significantly associated with recurrence-free survival.

Alleles↗
PubMed1998

Physical mapping of the CA6, ENO1, and SLC2A5 (GLUT5) genes and reassignment of SLC2A5 to 1p36.2.

Several human malignancies frequently exhibit deletions or rearrangements of the distal short arm of chromosome 1 (1p36), and a number of genetic diseases also map to this region. The carbonic anhydrase (CA6) and alpha-enolase (ENO1) genes, previously mapped to 1p36, were physically linked in yeast- and P1-artificial chromosome (YAC and PAC) contigs. PACs from the contig were mapped to 1p36.2 by fluorescence in situ hybridization. The ESTs D1S2068, D1S274E, D1S3275, and stSG4370 were also placed in the same contig. The physical map was integrated with the genetic map of chromosome 1 by assignment of genetic markers D1S160, D1S1615, and D1S503 to the contig. Sequencing of the EST clone representing D1S274E indicated that it was derived from the same transcript as D1S2068E and corresponded to the SLC2A5 (GLUT5) gene, previously assigned to 1p31. Reassignment of SLC2A5 to 1p36.2 was confirmed by somatic cell and radiation hybrid mapping panels and was consistent with previous EST mapping data. Sequencing of the EST clone for D1S274E revealed the presence of intronic sequences, suggesting that the clone was derived from an unprocessed message. The presence of unprocessed and/or alternatively spliced EST clones has potential ramifications for EST-based genomic projects. This information should facilitate the mapping of tumor suppressor and genetic disease loci that have been localized to this region.

Carbonic Anhydrases↗
PubMed1997

An integrated transcript map of human chromosome 1p35-p36.

The distal short arm of human chromosome 1 (1p) is rearranged in a variety of malignancies, and several genetic diseases also map to this region. We have constructed an integrated transcript map to precisely define the positions of genes and expressed sequence tags (ESTs) previously mapped to 1p35-p36, a region spanning approximately 40 Mb. To anchor the integrated map, a framework genetic map was constructed with 24 genetic markers and a marker order of 1000:1 odds, yielding an average resolution of 2.8 cM. An additional 106 genetic markers were localized relative to the framework genetic map. To place markers more precisely within 1p35-p36, a chromosome 1-specific, radiation-reduced hybrid (RH) panel was created. Individual DNA fragments of the RH panel were identified and ordered by PCR with the framework genetic map. A total of 250 markers, including 142 genes and ESTs, were mapped by PCR against the RH panel. The map has an observed resolution of 800 kb, and the results closely match and more precisely define previous mapping information for most markers. This map will help to identify candidate genes for genetic diseases mapping to distal 1p and is fully integrated with existing genetic and RH maps of the human genome.

Animals↗
PubMed1997

Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1.

BACKGROUND: Children with neurofibromatosis type 1 (NF1) are at increased risk of developing benign and malignant solid tumors as well as hematologic malignancies, including de novo juvenile chronic myelogenous leukemia, monosomy 7 syndrome, and acute myelogenous leukemia. The normal NF1 allele is frequently deleted in the bone marrow cells from NF1 patients with hematologic malignancies, suggesting a pathogenic role in primary leukemogenesis. The authors report monosomy 7 myelodysplastic syndrome (MDS) as a second malignant neoplasm (SMN) in five children with sporadic NF1, the results of molecular analysis for NF1 and ras alterations in their bone marrow, and summarize their experience with SMNs in pediatric patients with NF1. METHODS: Monosomy 7 MDS was diagnosed as an SMN in five children with NF1 by morphologic and cytogenetic studies of bone marrow specimens. DNA extracted from these malignant bone marrows was analyzed for allelic loss at the NF1 locus and for the presence of ras mutations. The Children's Hospital of Philadelphia (CHOP) Tumor Registry was also reviewed to estimate the incidence of SMNs in pediatric NF1 patients. RESULTS: Bone marrow specimens from four patients retained constitutional heterozygosity at the NF1 locus; one specimen was uninformative. There was no evidence of activating ras mutations. The risk of an SMN was approximately 11% among the 64 NF1 registrants with primary malignancies in the CHOP registry, but was 75% (6 of 8) among patients treated for a pediatric embryonal cancer. CONCLUSIONS: Children with NF1 are susceptible to the development of malignant myeloid disorders both as a primary event and as an SMN. Additional molecular genetic analysis is necessary to determine if the NF1 gene is inactivated by somatic mutation in these secondary leukemias.

Blotting, Southern↗
PubMed1997

Familial neuroblastoma: a three-generation pedigree and a further association with Hirschsprung disease.

Like the other embryonal cancers of childhood, neuroblastoma occasionally occurs within families. We now provide an update on a nuclear family in which seven individuals are affected with neuroblastoma, inherited in an autosomal dominant fashion over three generations. In addition, two of these individuals are also affected with Hirschsprung disease. This family may lend insight into the molecular pathogenesis of familial neuroblastoma.

Child↗
PubMed1997

Novel regions of chromosomal loss in familial neuroblastoma by comparative genomic hybridization.

Childhood neuroblastoma, an embryonal neoplasm of sympathetic nervous system progenitors, occurs in a familial form with an autosomal dominant mode of inheritance. Genetic susceptibility to this disorder is thought to arise via a germline mutation affecting a tumor suppressor gene, in accord with the two-hit model established for familial and sporadic retinoblastoma. Surprisingly, the familial neuroblastoma predisposition locus does not map to chromosome band 1p36, a genomic region likely to contain one or more neuroblastoma suppressor genes. We reasoned that inherited point mutations affecting one allele would be unmasked in many cases by somatically acquired deletions of the second allele that included the target gene in the tumor cells from these patients. Thus, to identify chromosomal regions that might contain suppressor genes important in hereditary neuroblastoma, we analyzed six familial tumors by comparative genomic hybridization. Recurrent losses of genetic material were detected on chromosome arms 3p (consensus region, 3p24-pter), 10p (consensus, 10p12-p13), 10q (consensus, 10q25-qter), 16q (consensus, 16q12-q22), and 20q (consensus, 20q13.3-qter), in addition to the regions commonly deleted in sporadic neuroblastomas (1p36 and 11q). These chromosomal sites may harbor novel tumor suppressor genes that could aid in our understanding of the predisposition to and pathogenesis of familial neuroblastoma and potentially sporadic tumors as well.

Child, Preschool↗
PubMed1997

Molecular genetic analysis of familial neuroblastoma.

Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes.

Adult↗
PubMed1997

Human Krüppel-related 3 (HKR3): a candidate for the 1p36 neuroblastoma tumour suppressor gene?

Human Krüppel-related 3 (HKR3) is a zinc finger gene that maps within chromosome subbands 1p36.2-.3, a region postulated to contain a tumour suppressor gene associated with advanced neuroblastomas. Genomic clones of HKR3 were isolated from a P1 library and physically mapped to within 40 kb of D1S214 at 1p36.3. The gene is ubiquitously expressed in human tissues, but especially high levels are present in human fetal and adult nervous tissues. Hemizygous deletion of HKR3 in a lymphoblastoid cell line derived from a neuroblastoma patient with a constitutional 1p36 interstitial deletion and in the neuroblastoma cell line SK-N-AS, which also has a small interstitial 1p36 deletion, has been observed. Allelic loss at D1S214 in 15/15 informative primary neuroblastoma specimens with 1p36 deletions has also been observed. In a panel of 16 neuroblastoma cell lines, no gross genomic DNA rearrangements were noted, the gene was always expressed (albeit at variable levels) and there was no evidence for truncating mutations. Furthermore, there were no mutations detected in the zinc finger coding region in four neuroblastoma cell lines with 1p deletions analysed by direct sequence analysis. We conclude that HKR3 is a novel zinc finger gene that maps to a region of the genome commonly rearranged or deleted in neuroblastoma and other human cancers.

Adult↗
PubMed1997

Molecular analysis of the region of distal 1p commonly deleted in neuroblastoma.

Cellular, cytogenetic, and molecular evidence indicates that chromosome band 1p36 is often deleted in neuroblastoma cell lines and tumours, suggesting the presence of one or more tumour suppressor genes in this region. We used a multifaceted approach to analyse the commonly deleted region, 28 distal 1p-specific polymorphic loci were used to detect loss of heterozygosity (LOH) in a panel of primary neuroblastoma tumours. Thirty-two of 122 tumours (26%) demonstrated LOH at three or more loci. In addition, a patient with a constitutional deletion of 1p36.2-.3 and two neuroblastoma cell lines with 1p36 abnormalities were characterised by FISH. When combined with the LOH data, a single consensus region of deletion was defined proximally by PLOD and distally by D1S80, a region spanning approximately five megabases. Several proposed candidate tumour suppressor genes, including ID3, CDC2L1, DAN, PAX7, E2F2, TNFR2 and TCEB3, map outside of this region; however, the transcription factor HKR3 cannot be excluded. LOH for 1p is correlated with adverse clinical and biological features and a poor prognosis, but 1p LOH is not an independent predictor of overall survival. To identify additional candidate genes, an integrated physical map of 1p35-36 is being constructed. The current map includes 445 polymerase chain reaction (PCR)-formatted markers and 608 YACs. This map will help identify region-specific transcripts by direct selection and sequencing.

Chromosome Deletion↗
PubMed1996

Familial predisposition to neuroblastoma does not map to chromosome band 1p36.

Familial predisposition to neuroblastoma, a common embryonal cancer of childhood, segregates as an autosomal dominant trait with high penetrance. It is therefore likely that neuroblastoma susceptibility is due to germ line mutations in a tumor suppressor gene. Cytogenetic, functional, and molecular studies have implicated chromosome band 1p36 as the most likely region to contain a suppressor gene involved in sporadic neuroblastoma tumorigenesis. We now demonstrate that neuroblastoma predisposition does not map to any of eight polymorphic markers spanning 1p36 by linkage analysis in three families. In addition, there is no loss of heterozygosity at any of these markers in tumors from affected members of these kindreds. Furthermore, there is strong evidence against linkage to two Hirschsprung disease (a condition that can cosegregate with neuroblastoma) susceptibility genes, RET and EDNRB. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 tumor suppressor and the currently identified Hirschsprung disease susceptibility genes.

Adolescent↗
PubMed1996

Cloning, chromosomal localization, physical mapping, and genomic characterization of HKR3.

The Krüppel-type zinc finger proteins are members of a conserved family of transcription factors that are important in developmental regulation. Altered expression of several of these proteins has been implicated in human diseases, including cancer. We report the cloning, mapping, and characterization of the zinc finger gene Human Krüppel-Related 3 (HKR3). Genomic clones of HKR3 were isolated from a P1 library and localized to human chromosome subband 1p36.3 by human-rodent somatic cell hybrid mapping and fluorescence in situ hybridization. The gene was physically mapped to within 40 kb of D1S214 by YAC content and long-range restriction mapping. HKR3 spans 9.5 kb of genomic DNA and is contained in 11 exons. Sequencing defined each of the exon/intron splice site junctions and identified a CpG island in the 5' region of the gene. HKR3 is ubiquitously expressed in human tissues as at least two major transcripts, the shorter of which excludes a conserved finger-associated box and a putative acidic activation domain contained in the full-length transcript. HKR3 is a novel zinc finger gene that maps to a region of the genome commonly rearranged or deleted in human cancers.

Adult↗
PubMed1996

Physical mapping and genomic structure of the human TNFR2 gene.

The tumor necrosis factor receptor 2 (TNFR2) gene localizes to 1p36. 2, a genomic region characteristically deleted in neuroblastomas and other malignancies. In addition, TNFR2 is the principal mediator of the effects of TNF on cellular immunity, and it may cooperate with TNFR1 in the killing of nonlymphoid cells. Therefore, we undertook an analysis of the genomic structure and precise physical mapping of this gene. The TNFR2 gene is contained on 10 exons that span 26 kb. Most of the functional domains of TNFR2 are encoded by separate exons, and each of the repeats of the extracellular cysteine-rich domain is interrupted by an intron. The genomic structure reveals a close relationship to TNFR1, another member of the TNFR superfamily. Based on electrophoretic analysis of yeast artificial chromosomes, TNFR2 maps within 400 kb of the genetic marker D1S434. In addition, we have identified a new polymorphic dinucleotide repeat within intron 4 of TNFR2. The genetic sequence information and exon-intron boundaries we have determined will facilitate mutational analysis of this gene to determine its potential role in neuroblastoma, as well as in other cancers with characteristic deletions or rearrangements of 1p36.

Amino Acid Sequence↗
PubMed1996

Chemoreduction in the initial management of intraocular retinoblastoma.

BACKGROUND: Chemoreduction is a method of reducing tumor volume to allow for more focused, less damaging therapeutic measures. OBJECTIVE: To determine whether chemoreduction could be used to decrease the size of retinoblastoma so that enucleation or external beam radiotherapy could be avoided and more conservative modalities employed. METHODS: A prospective pilot study was performed to assess the effectiveness of a 2-month chemoreduction regimen of vincristine sulfate, etoposide, and carboplatin in patients with retinoblastoma. The study included 20 patients with 54 tumors in 31 eyes. RESULTS: At the initial examination, the mean tumor base was 12 mm and the thickness, 7 mm. Vitreous seeds were present in 14 eyes (45%). A secondary retinal detachment was present in 24 eyes (77%) and, when present, involved a mean of 71% of the retina. In 11 eyes (36%) the retina was totally detached with serous subretinal fluid. After 2 months of chemoreduction, all 54 tumors showed regression in size, and 48 (89%) showed evidence of calcification. The mean tumor base was 8 mm and the thickness, 4 mm. Overall, there was a mean 35% decrease in base and 49% decrease in thickness of the tumor at the end of the treatment period. A complete response was found in 25 tumors (46%) and a partial response in 29 (54%). The subretinal fluid had resolved completely in 50% of the cases (12/24 eyes), and, in the 11 eyes with total retinal detachment, the subretinal fluid had completely resolved, leaving flat retina, in 6 eyes (54%). The vitreous seeds demonstrated some degree of regression in all cases, and in 5 eyes there was 90% to 100% calcification of the seeds. Short-term systemic toxic effects were mild (transient bone marrow suppression). Enucleation was avoided in all cases; external beam radiotherapy was necessary in 9 eyes because of diffuse vitreous seeds. The remaining 22 eyes were treated with local methods after chemoreduction. CONCLUSION: Tumor shrinkage with chemoreduction may allow treatment with less invasive measures, such as cryotherapy, laser photocoagulation, thermotherapy, or plaque radiotherapy, thereby avoiding enucleation and external beam radiotherapy.

Antineoplastic Agents, Phytogenic↗
PubMed1995

Significance of chromosome 1p loss of heterozygosity in neuroblastoma.

We analyzed 156 primary neuroblastoma tumor samples for loss of heterozygosity at the distal short arm of chromosome 1 (1p LOH). We also compared 1p LOH with known clinical and genetic prognostic variables as well as patient outcome. 1p LOH was detected in 30 of 156 tumors (19%) and was strongly associated with adverse clinical and biological features. 1p LOH was also strongly predictive of a poor outcome in univariate analyses (estimated 4-year survival, 32 +/- 10% SE versus 76 +/- 5% SE; P < 0.001). However, the prognostic value of 1p LOH was equivocal when stratified for amplification of the MYCN oncogene (P = 0.16). We conclude that 1p LOH is an important component of a pattern of genetic abnormalities in neuroblastoma associated with an aggressive clinical course.

Adrenal Gland Neoplasms↗