RESUMO
Epigenetic dysregulation is a hallmark of cancer executed by a number of complex processes the most important of which converge on DNA methylation and histone protein modifications. Epigenetic marks are potentially reversible and thus promising drug targets. In the setting of acute lymphoblastic leukemia (ALL) they have been associated with clinicopathological features including risk of relapse or molecular subgroups of the disease. Here, using immunocytochemistry of bone marrow smears from diagnosis, we studied global histone H4 acetylation, whose loss was previously linked to treatment failure in adults with ALL, in pediatric patients. We demonstrate that preserved global histone H4 acetylation is significantly associated with favorable outcome (RFS, EFS, OS) in children with B cell progenitor (BCP) ALL, recapitulating the findings from adult populations. Further, for the first time we demonstrate differential histone H4 acetylation in molecular subclasses of BCP-ALL including cases with ETV6-RUNX1 fusion gene or PAX5 deletion or deletions in genes linked to B cell development. We conclude global histone H4 acetylation is a prognostic marker and a potential therapeutic target in ALL.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Epigênese Genética , Histonas/metabolismo , Proteínas de Fusão Oncogênica/fisiologia , Fator de Transcrição PAX5/deficiência , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Acetilação , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Cromossomos Humanos Par 12/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase Multiplex , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Processamento de Proteína Pós-Traducional , Indução de Remissão , Translocação Genética , Resultado do TratamentoRESUMO
WWOX is a candidate tumour suppressor gene that exhibits LOH or homozygous deletion in several tumour types. As well as the predominant full-length transcript (variant 1) there also exist alternatively spliced transcripts found previously only in malignant tissue. It has been suggested that proteins encoded by these variants may interfere with normal WWOX function in a dominant negative fashion. The most prevalent alternate transcript demonstrated in ovarian cancer is variant 4, which lacks exons 6-8. Here, we report the first comparison of the mRNA expression of WWOX variants 1 and 4 in human ovarian tumours and normal ovaries, and correlate expression with clinical data. We demonstrate significantly lower WWOX variant 1 expression in tumours than in normal ovaries. This reduction was not associated with any specific clinical subgroup. Variant 4 was expressed at low levels, and significantly associated with high grade and advanced stage ovarian cancer. Furthermore, tumours co-expressing variant 4 and relatively high levels of variant 1 showed significantly worse survival than tumours expressing variant 1 alone. However, variant 4 was also frequently identified in non-malignant ovarian tissue. These results support the role of WWOX variant 1 as a suppressor of ovarian tumourigenesis, but the role of variant 4 remains speculative.
Assuntos
Perfilação da Expressão Gênica , Genes Supressores de Tumor , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Oxirredutases/genética , RNA Mensageiro/análise , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras de Tumor , Oxidorredutase com Domínios WWRESUMO
Knudson's two-hit model of tumour suppressor genes supposes that two mutations are required to cause a tumour, one occurring in each of the two alleles of the gene. Many such cancer genes exhibiting biallelic disruption and truncating point mutations have been identified, revealing the success of the model. Despite changes in our concept of cancer genes, two inactivating point mutations are still considered the hallmark of tumour suppressor genes. Recently, however, more and more reports describe candidate tumour suppressors that do not conform to this standard definition, including haploinsufficient genes requiring inactivation of only one allele, and genes inactivated not by mutation but rather epigenetic hypermethylation. This review describes some of these exceptions and proposes a revised tumour suppressor gene definition to facilitate the identification of this new generation of tumour suppressor loci.