75 research outputs found
The novel <i>RASSF6</i> and <i>RASSF10</i> candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias
No full textBackground: The Ras-assocation family (RASSF) of tumour suppressor genes (TSGs) contains 10 members that encode proteins containing Ras-assocation (RA) domains. Several members of the RASSF family are frequently epigenetically inactivated in cancer, however, their role in leukaemia has remained largely uninvestigated. Also, RASSF10 is a predicted gene yet to be experimentally verified. Here we cloned, characterised and demonstrated expression of RASSF10 in normal human bone marrow. We also determined the methylation status of CpG islands associated with RASSF1-10 in a series of childhood acute lymphocytic leukaemias (ALL) and normal blood and bone marrow samples. Results: COBRA and bisulphite sequencing revealed RASSF6 and RASSF10 were the only RASSF members with a high frequency of leukaemia-specific methylation. RASSF6 was methylated in 94% (48/51) B-ALL and 41% (12/29) T-ALL, whilst RASSF10 was methylated in 16% (8/51) B-ALL and 88% (23/26) T-ALL. RASSF6 and RASSF10 expression inversely correlated with methylation which was restored by treatment with 5-aza-2'deoxycytidine (5azaDC). Conclusion: This study shows the hypermethylation profile of RASSF genes in leukaemias is distinct from that of solid tumours and represents the first report of inactivation of RASSF6 or RASSF10 in cancer. These data show epigenetic inactivation of the candidate TSGs RASSF6 and RASSF10 is an extremely frequent event in the pathogenesis of childhood leukaemia. This study also warrants further investigation of the newly identified RASSF member RASSF10 and its potential role in leukaemia
Epigenetic analysis of childhood acute lymphoblastic leukemia
No full textWe used a chromosome 3 wide NotI microarray for identification of epigenetically inactivated genes in childhood acute lymphoblastic leukemia (ALL). Three novel genes demonstrated frequent methylation in childhood ALL. PPP2R3A (protein phosphatase 2, regulatory subunit B'', a) was frequently methylated in T (69%) and B (82%)-ALL. Whilst FBLN2 (fibulin 2) and THRB (thyroid hormone receptor, beta) showed frequent methylation in B-ALL (58%; 56% respectively), but were less frequently methylated in T-ALL (17% for both genes). Recently it was demonstrated that BNC1 (Basonuclin 1) and MSX1 (msh homeobox 1) were frequently methylated across common epithelial cancers. In our series of childhood ALL BNC1 was frequently methylated in both T (77%) and B-ALL (79%), whilst MSX1 showed T-ALL (25%) specific methylation. The methylation of the above five genes was cancer specific and expression of the genes could be restored in methylated leukemia cell lines treated with 5-aza-2'-deoxycytidine. This is the first report demonstrating frequent epigenetic inactivation of PPP2R3A, FBLN2, THRB, BNC1 and MSX1 in leukemia. The identification of frequently methylated genes showing cancer specific methylation will be useful in developing early cancer detection screens and for targeted epigenetic therapies
Discrimination of Pseudogene and Parental Gene DNA Methylation Using Allelic Bisulfite Sequencing
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Epigenetic markers in human gliomas: prospects for therapeutic intervention
No full textGliomas represent the most common CNS cancers in adults. Prognosis for patients harboring malignant gliomas is particularly dismal and, despite current treatment strategies comprising surgery, radiotherapy and chemotherapy, the median survival time after diagnosis is still in the range of just 12 months. In recent years, there has been an increased effort to identify tumor biomarkers that can be used as diagnostic tools, or markers for predicting therapeutic response and prognosis. Investigation of genetic changes has identified several such markers that have shown some success in predicting the most effective therapy. In recent years, however, it has become apparent that the biology of many cancers of the CNS is determined not only by their genetic profile but also their epigenetic profile. Epigenetic biomarkers show great potential in effectively predicting patient prognosis and response to therapy. The eventual application of epigenetic profiling of tumors may help to indicate the most effective tailored therapy for individual patients
A correlation of the endoscopic characteristics of colonic laterally spreading tumours (LSTS) with genetic mutations
No full textDefining the criteria for identifying constitutional epimutations
No full textIn the January 2016 issue of Clinical Epigenetics, Qui�onez-Silva et al. (Clin Epigenetics 8:1, 2016) described a possible constitutional epimutation of the RB1 gene as a cause of hereditary predisposition to retinoblastoma. The term constitutional epimutation describes an epigenetic aberration in normal tissues that predisposes to disease. The data presented by Qui�onez-Silva et al. are interesting, but further analysis is required to demonstrate a constitutional epimutation in this family. Here, we define the criteria and describe the experimental approach necessary to identify an epigenetic aberration as a constitutional epimutation
Abstract 2000: Investigation of the molecular events associated with gene resilencing following withdrawal of epigenetic therapies
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