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Joseph F Costello

Publications and source records attributed to Joseph F Costello.

18 recordsLinked to original sources
PubMed2025

Longitudinal profiling of IDH-mutant astrocytomas reveals acquired RAS-MAPK pathway mutations associated with inferior survival.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant astrocytomas represent the most frequent primary intraparenchymal brain tumor in young adults, which typically arise as low-grade neoplasms that often progress and transform to higher grade despite current therapeutic approaches. However, the genetic alterations underlying high-grade transformation and disease progression of IDH-mutant astrocytomas remain inadequately defined. METHODS: Genomic profiling was performed on 205 IDH-mutant astrocytomas from 172 patients from both initial treatment-naive and recurrent post-treatment tumor specimens. Molecular findings were integrated with clinical outcomes and pathologic features to define the associations of novel genetic alterations in the RAS-MAPK signaling pathway. RESULTS: Likely oncogenic alterations within the RAS-MAPK mitogenic signaling pathway were identified in 13% of IDH-mutant astrocytomas, which involved the KRAS, NRAS, BRAF, NF1, SPRED1, and LZTR1 genes. These included focal amplifications and known activating mutations in oncogenic components (e.g. KRAS, BRAF), as well as deletions and truncating mutations in negative regulatory components (e.g. NF1, SPRED1). These RAS-MAPK pathway alterations were enriched in recurrent tumors and occurred nearly always in high-grade tumors, often co-occurring with CDKN2A homozygous deletion. Patients whose IDH-mutant astrocytomas harbored these oncogenic RAS-MAPK pathway alterations had inferior survival compared to those with RAS-MAPK wild-type tumors. CONCLUSIONS: These findings highlight novel genetic perturbations in the RAS-MAPK pathway as a likely mechanism contributing to the high-grade transformation and treatment resistance of IDH-mutant astrocytomas that may be a potential therapeutic target for affected patients and used for future risk stratification.

IDH1 mutation↗
PubMed2006

Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation.

Genome-wide reduction in 5-methylcytosine is an epigenetic hallmark of human tumorigenesis. Experimentally induced hypomethylation in mice promotes genomic instability and is sufficient to initiate tumorigenesis. Here, we report that global hypomethylation is common in primary human glioblastomas [glioblastoma multiforme (GBM)] and can affect up to an estimated 10 million CpG dinucleotides per haploid tumor genome. Demethylation involves satellite 2 (Sat2) pericentromeric DNA at chromosomes 1 and 16, the subtelomeric repeat sequence D4Z4 at chromosomes 4q and 10q, and interspersed Alu elements. Severe hypomethylation of Sat2 sequences is associated with copy number alterations of the adjacent euchromatin, suggesting that hypomethylation may be one factor predisposing to specific genetic alterations commonly occurring in GBMs. An additional apparent consequence of global hypomethylation is reactivation of the cancer-testis antigen MAGEA1 via promoter demethylation, but only in GBMs and GBM cell lines exhibiting a 5-methylcytosine content below a threshold of approximately 50%. Primary GBMs with significant hypomethylation tended to be heterozygous or homozygous for the low-functioning Val allele of the rate-limiting methyl group metabolism gene methylenetetrahydrofolate reductase (MTHFR), or had a deletion encompassing this gene at 1p36. Tumors with severe genomic hypomethylation also had an elevated proliferation index and deletion of the MTHFR gene. These data suggest a model whereby either excessive cell proliferation in the context of inadequate methyl donor production from MTHFR deficiency promotes genomic hypomethylation and further genomic instability, or that MTHFR deficiency-associated demethylation leads to increased proliferative activity in GBM.

5-Methylcytosine↗
PubMed2006

Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells.

Alterations in DNA methylation are important in cancer, but the acquisition of these alterations is poorly understood. Using an unbiased global screen for CpG island methylation events, we have identified a non-random pattern of DNA hypermethylation acquired in p16-repressed cells. Interestingly, this pattern included loci located upstream of a number of homeobox genes. Upon removal of p16(INK4A) activity in primary human mammary epithelial cells, polycomb repressors, EZH2 and SUZ12, are up-regulated and recruited to HOXA9, a locus expressed during normal breast development and epigenetically silenced in breast cancer. We demonstrate that at this targeted locus, the up-regulation of polycomb repressors is accompanied by the recruitment of DNA methyltransferases and the hypermethylation of DNA, an endpoint, which we show to be dependent on SUZ12 expression. These results demonstrate a causal role of p16(INK4A) disruption in modulating DNA hypermethylation, and identify a dynamic and active process whereby epigenetic modulation of gene expression is activated as an early event in breast tumor progression.

Carrier Proteins↗
PubMed2006

DNA motifs associated with aberrant CpG island methylation.

Epigenetic silencing involving the aberrant methylation of promoter region CpG islands is widely recognized as a tumor suppressor silencing mechanism in cancer. However, the molecular pathways underlying aberrant DNA methylation remain elusive. Recently we showed that, on a genome-wide level, CpG island loci differ in their intrinsic susceptibility to aberrant methylation and that this susceptibility can be predicted based on underlying sequence context. These data suggest that there are sequence/structural features that contribute to the protection from or susceptibility to aberrant methylation. Here we use motif elicitation coupled with classification techniques to identify DNA sequence motifs that selectively define methylation-prone or methylation-resistant CpG islands. Motifs common to 28 methylation-prone or 47 methylation-resistant CpG island-containing genomic fragments were determined using the MEME and MAST algorithms (). The five most discriminatory motifs derived from methylation-prone sequences were found to be associated with CpG islands in general and were nonrandomly distributed throughout the genome. In contrast, the eight most discriminatory motifs derived from the methylation-resistant CpG islands were randomly distributed throughout the genome. Interestingly, this latter group tended to associate with Alu and other repetitive sequences. Used together, the frequency of occurrence of these motifs successfully discriminated methylation-prone and methylation-resistant CpG island groups with an accuracy of 87% after 10-fold cross-validation. The motifs identified here are candidate methylation-targeting or methylation-protection DNA sequences.

Algorithms↗
PubMed2005

Meningioma transcript profiles reveal deregulated Notch signaling pathway.

Meningiomas constitute the second most common central nervous system tumor, and yet relatively little is known about the molecular events that are important for the pathogenesis and malignant progression of these tumors. We have used serial analysis of gene expression to compare the transcriptomes of nonneoplastic meninges and meningiomas of all malignancy grades. A novel finding from this screen is the induction of three components of the Notch signaling pathway: the transcription factor, hairy and enhancer of Split1 (HES1) and two members of the Groucho/transducin-like enhancer of Split family of corepressors, TLE2 and TLE3. TLE corepressors interact and modulate the activity of a wide range of transcriptional regulatory systems, one of which is HES1. We have shown that the transcript and protein levels of HES1, the Notch2 and Notch1 receptors and the Jagged1 ligand are induced in meningiomas of all grades, whereas induction of TLE2 and TLE3 occurs specifically in higher-grade meningiomas. Meningioma cell lines express components of the Notch signaling pathway and an inhibitor of this pathway suppresses meningioma cell survival. These results suggest that deregulated expression of the Notch pathway is a critical event in meningioma pathogenesis and that modulation of this and potentially other signaling pathways by TLE corepressors leads to a more malignant phenotype.

Basic Helix-Loop-Helix Proteins↗
PubMed2005

Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3.

CpG islands are present in one-half of all human and mouse genes and typically overlap with promoters or exons. We developed a method for high-resolution analysis of the methylation status of CpG islands genome-wide, using arrays of BAC clones and the methylation-sensitive restriction enzyme NotI. Here we demonstrate the accuracy and specificity of the method. By computationally mapping all NotI sites, methylation events can be defined with single-nucleotide precision throughout the genome. We also demonstrate the unique expandability of the array method using a different methylation-sensitive restriction enzyme, BssHII. We identified and validated new CpG island loci that are methylated in a tissue-specific manner in normal human tissues. The methylation status of the CpG islands is associated with gene expression for several genes, including SHANK3, which encodes a structural protein in neuronal postsynaptic densities. Defects in SHANK3 seem to underlie human 22q13 deletion syndrome. Furthermore, these patterns for SHANK3 are conserved in mice and rats.

Animals↗
PubMed2005

Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8.

Tumors arise in part from the deleterious effects of genetic and epigenetic mechanisms on gene expression. In several mouse models of human tumors, the tumorigenic phenotype is reversible, suggesting that epigenetic mechanisms also contribute significantly to tumorigenesis in mice. It is not known whether these are the same epigenetic mechanisms in human and mouse tumors or whether they affect homologous genes. Using an integrated approach for genome-wide methylation and copy number analyses, we identified SLC5A8 on chromosome 12q23.1 that was affected frequently by aberrant methylation in human astrocytomas and oligodendrogliomas. SLC5A8 encodes a sodium monocarboxylate cotransporter that was highly expressed in normal brain but was significant down-regulated in primary gliomas. Bisulfite sequencing analysis showed that the CpG island was unmethylated in normal brain but frequently localized methylated in brain tumors, consistent with the tumor-specific loss of gene expression. In glioma cell lines, SLC5A8 expression was also suppressed but could be reactivated with a methylation inhibitor. Expression of exogenous SLC5A8 in LN229 and LN443 glioma cells inhibited colony formation, suggesting that it may function as a growth suppressor in normal brain cells. Remarkably, 9 of 10 murine oligodendroglial tumors (from p53+/- or ink4a/arf+/- animals transgenic for S100beta-v-erbB) showed a similar tumor-specific down-regulation of mSLC5A8, the highly conserved mouse homologue. Taken together, these data suggest that SLC5A8 functions as a growth suppressor gene in vitro and that it is silenced frequently by epigenetic mechanisms in primary gliomas. The shared epigenetic inactivation of mSLC5A8 in mouse gliomas indicates an additional degree of commonality in the origin and/or pathway to tumorigenesis between primary human tumors and these mouse models of gliomas.

Animals↗
PubMed2003

The contribution of genetic and epigenetic mechanisms to gene silencing in oligodendrogliomas.

Very little is known of the genes and mechanisms contributing to the genesis of oligodendrogliomas, a subtype of primary brain tumors. Using an integrated genetic and epigenetic analysis of oligodendrogliomas, we show that aberrant CpG island methylation is the most prevalent alteration in these tumors, and the majority of methylated genes are independent of regions affected by deletion. In contrast, a subset of the gene-associated CpG islands are preferentially affected by converging methylation and deletion, including a putative zinc finger gene, ZNF342, located in a commonly deleted region at chromosome 19q13. ZNF342 expression is specifically decreased in primary oligodendrogliomas and up-regulated in glioma cell lines treated with a demethylating agent, whereas the expression level of the adjacent gene, Gemin7, is not consistently altered in these samples. This initial integrated approach identifies novel targets of gene silencing, and provides a more comprehensive view of the genes and mechanisms underlying oligodendrogliomas.

Brain Neoplasms↗
PubMed2003

SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer.

Lung cancer is the leading cause of cancer death in the world, but the molecular mechanisms for its development have not been well characterized. The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Eight SOCS proteins with similar structures have been identified so far. SOCS family members, however, have distinct mechanisms of inhibition of JAK/STAT signaling. Abnormalities of the JAK/STAT pathway are associated with cancer. Inhibition of signaling results in growth suppression in various cell types. Recently, the involvement of SOCS-1 in carcinogenesis has been reported. Here, we report identification of frequent hypermethylation in CpG islands of the functional SOCS-3 promoter that correlates with its transcription silencing in cell lines (lung cancer, breast cancer, and mesothelioma) and primary lung cancer tissue samples. Restoration of SOCS-3 in lung cancer cells where SOCS-3 was methylation-silenced resulted in the down-regulation of active STAT3, induction of apoptosis, and growth suppression. Our results suggest that methylation silencing of SOCS-3 is one of the important mechanisms of constitutive activation of the JAK/STAT pathway in cancer pathogenesis. The data also suggest that SOCS-3 therapy may be useful in the treatment of cancer.

Apoptosis↗
PubMed2003

DNA methylation in brain development and gliomagenesis.

The underlying basis of human tumors involves genomic alterations that activate oncogenes and inactivate tumor suppressor genes, culminating in unregulated cell growth. The existing models of tumorigenesis, the selection of subsets of genes contributing to this process and many cancer therapies are based on this genomic approach. However, epigenomic alterations such as gene silencing by aberrant methylation of promoters are also involved in tumorigenesis, but because methylation is not detected by standard genome screening many of these genes have remained undiscovered. Advances in our ability to observe the methylation status of the entire cancer cell genome have led to the unmistakable conclusion that methylation abnormalities are far more prevalent than expected, particularly in low-grade gliomas where genomic changes are less common. In addition, the aberrant methylation of particular genes can influence tumor response to therapy and is strongly associated with patient survival. Thus it is likely that our understanding of tumor genomes is far from complete, and that a significant number of prognostic indicators and therapeutic targets remain to be explored. These studies raise important questions regarding the relative contribution of genomic and epigenomic mechanisms in the genesis and malignant progression of gliomas. Here I begin with the evidence supporting a role for methylation in normal brain cell function and the consequence of its dysfunction, and conclude with an effort to integrate epigenomic views of the genesis of sporadic brain tumors with the traditional genomic model.

Animals↗
PubMed2002

Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors.

Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.

Alleles↗
PubMed2002

Restriction landmark genome scanning.

Restriction landmark genome scanning (RLGS) is a quantitative approach that is uniquely suited for simultaneously assessing the methylation status of thousands of CpG islands. RLGS separates radiolabeled NotI fragments (or other CpG-containing restriction enzyme fragments) in two dimensions and allows distinction of single-copy CpG islands from multicopy CpG-rich sequences. The methylation sensitivity of the endonuclease activity of NotI provides the basis for differential methylation analysis, and NotI sites occur primarily in CpG islands and genes. RLGS has been used to identify novel imprinted genes, novel targets of DNA amplification and methylation in human cancer, and to identify deletion, methylation, and gene amplification in a mouse model of tumorigenesis. Such massively parallel analyses are critical for pattern recognition within and between tumor types, and for estimating the overall influence of CpG island methylation on the cancer cell genome. RLGS is also a useful method for integrating methylation analyses with high-resolution gene copy number analyses.

Brain Neoplasms↗