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The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias.

ABSTRACT: The Ras-association family (RASSF) of tumour suppressor genes (TSGs) contains 10 members that encode proteins containing Ras-association (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.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).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.

SUBMITTER: Hesson LB

PROVIDER: S-EPMC2711046 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias.

Hesson Luke B LB Dunwell Thomas L TL Cooper Wendy N WN Catchpoole Daniel D Brini Anna T AT Chiaramonte Raffaella R Griffiths Mike M Chalmers Andrew D AD Maher Eamonn R ER Latif Farida F

Molecular cancer 20090701

<h4>Background</h4>The Ras-association family (RASSF) of tumour suppressor genes (TSGs) contains 10 members that encode proteins containing Ras-association (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 a ...[more]

PMID: 19570220

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Project description:Tumor suppressor genes (TSGs) are sometimes inactivated by transcriptional silencing through promoter hypermethylation. To identify novel methylated TSGs in melanoma, we carried out global mRNA expression proﬁling on a panel of 12 melanoma cell lines treated with a combination of 5-Aza-2-deoxycytidine (5AzadC) and an inhibitor of histone deacetylase, Trichostatin A. Reactivation of gene expression after drug treatment was assessed using Illumina whole-genome microarrays. After qRT-PCR conﬁrmation, we followed up 8 genes (AKAP12, ARHGEF16, ARHGAP27, ENC1, PPP1R3C, PPP1R14C, RARRES1, and TP53INP1) by quantitative DNA methylation analysis using mass spectrometry of base-speciﬁc cleaved ampliﬁcation products in panels of melanoma cell lines and fresh tumors. PPP1R3C, ENC1, RARRES1, and TP53INP1, showed reduced mRNA expression in 35–59% of the melanoma cell lines compared to melanocytes and which was correlated with a high proportion of promoter methylation (>40–60%). The same genes also showed extensive promoter methylation in 6–25% of the tumor samples, thus conﬁrming them as novel candidate TSGs in melanoma. We sought to identify melanoma TSGs silenced by promoter methylation by carrying out an array-based analysis in a well-annotated panel of 12 cell lines after combined treatment with 5AzadC and an inhibitor of histone deacetylase, Trichostatin A (TSA). Expression profiles were generated for each cell line before and after drug treatment using Illumina Sentrix Human-6 Expression version 2 BeadChips. Genes reactivated in all 12 cell lines were removed from further analysis since they are likely responding to drug treatment as part of the ‘‘cellular stress response,’’ or due to promoter demethylation of genes normally silenced in the melanocytic lineage. Genes were further ﬁltered to identify those with an average of >4-fold increased expression in at least four samples in the panel of 12 lines and >10-fold increase in at least one of the cell lines.

Dataset Information

The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias.

Publications

The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias.

Similar Datasets

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