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MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours.

ABSTRACT: Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour.

SUBMITTER: Perlman EJ

PROVIDER: S-EPMC4686660 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours.

Perlman Elizabeth J EJ Gadd Samantha S Arold Stefan T ST Radhakrishnan Anand A Gerhard Daniela S DS Jennings Lawrence L Huff Vicki V Guidry Auvil Jaime M JM Davidsen Tanja M TM Dome Jeffrey S JS Meerzaman Daoud D Hsu Chih Hao CH Nguyen Cu C Anderson James J Ma Yussanne Y Mungall Andrew J AJ Moore Richard A RA Marra Marco A MA Mullighan Charles G CG Ma Jing J Wheeler David A DA Hampton Oliver A OA Gastier-Foster Julie M JM Ross Nicole N Smith Malcolm A MA

Nature communications 20151204

Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mut ...[more]

PMID: 26635203

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Project description:Overexpression of carbonic anhydrase (CA IX) is associated with poor survival in several adult-type cancers but its expression is undocumented in Wilms tumour (WT), the most common tumour of the paediatric kidney.CA9 expression was measured using polymerase chain reaction (PCR) in 13 WTs and matched-paired non-neoplastic kidneys (NKs). CA IX and hypoxia-inducible factor-1 ?-subunit (HIF-1?) protein were quantified in 15 matched-paired WTs and NKs using enzyme-linked immunosorbent assays. CA IX and HIF-1? were localised by immunostaining tissue sections of 70 WTs (untreated WTs, n = 22; chemotherapy-treated WTs, n = 40; relapsed/metastatic WTs, n = 8). CA IX-positive untreated WTs (n = 14) were immunostained for vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT1) and CD31. Double staining for CA IX and CD31 was performed in WTs (n = 14).CA9 full length (FL) was significantly up-regulated in WTs compared to NKs (p = 0.009) by real-time PCR. Conventional PCR showed expression of alternative splice variant in all NKs and WTs but FL in WTs only. WTs showed a 2-fold increase in CA IX protein over NKs (p = 0.01). HIF-1? levels were up-regulated in WTs compared to NKs, although the difference was not statistically significant (p = 0.09). CA IX and HIF-1? immunolocalisation were observed in 63% and 93% of WTs, respectively. The median fraction of cells staining positively for CA IX and HIF-1? was 5% and 22%, respectively. There was no significant association between the expression of either CA IX or HIF-1? and clinicopathological variables in WTs resected following chemotherapy. VEGF and GLUT1 immunoreactivity was seen in 94% and 100% with the median fraction of 10% and 60% respectively. Co-expression and co-localisation of all four hypoxia markers was seen in 7/14 and 6/14 cases respectively. CA IX was seen in well vascularised areas as well as in the peri-necrotic areas.Carbonic anhydrase 9 (mRNA and protein), and HIF-1? protein are overexpressed in a significant portion of WTs. No significant association was detected between the expression of either CA IX or HIF-1? and clinicopathological variables in WTs resected following chemotherapy. Cellular localisation studies in untreated WTs suggest that CA IX and HIF-1? are regulated by hypoxia and non-hypoxia mechanisms.

Dataset Information

MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours.

Publications

MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours.

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