Malignant germ cell tumours display conserved microRNA (miRNA) profiles resulting in global changes in expression of mRNA targets


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Matthew Murray1, Harpreet Saini2, Stijn van Dongen2, Cei Abreu-Goodger2, Roger Palmer1, James Nicholson3, Anton Enright2, Nicholas Coleman1

1Medical Research Council Cancer Cell Unit, Cambridge, UK, 2EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK, 3Addenbrooke's Hospital, Cambridge, UK

Abstract

Proffered paper presentation

Background
Germ cell tumours (GCT) are malignant neoplasms thought to have a common origin from primordial germ cells. They may therefore share fundamental biological abnormalities despite their clinical and histopathological heterogeneity. We tested the hypothesis that GCTs are characterized by conserved patterns of miRNA expression that are functionally significant by affecting levels of mRNA targets.

Method
We used the miRCURY miRNA microarray (Exiqon) to quantify global miRNA expression levels in 28 GCTs and 14 non-malignant samples (eight controls and six teratomas) from paediatric subjects. For 21 of these samples (17 GCT, four non-malignant) global mRNA expression profiles had been obtained using the U133A GeneChip (Affymetrix). We compared our findings with a re-analysis of published profiling in adult GCTs of miRNAs (obtained by qRT-PCR)1 and mRNAs (obtained by U133A assessment of testicular GCTs)2. All data were analysed using R and Bioconductor. We used the novel bioinformatic algorithm Sylamer3 to investigate enrichment and depletion of miRNA seed complimentary regions (SCRs) in 3UTRs of mRNAs ranked according to expression levels in GCTs.

Results
miR-302 and miR-371~373 clusters are universally over-expressed in GCTs regardless of patient age or tumour histological type or site. Sylamer demonstrated that the most significantly over-represented SCR in the 3UTRs of down-regulated mRNAs was GCACTT, corresponding to the AAGUGC seed conserved in both miR-302 and miR-371~373 clusters. Gene ontology analysis showed that the down-regulated mRNAs containing this conserved SCR in paediatric GCTs were members of major cancer-associated cellular pathways.

Conclusion
Our data suggests a fundamental role for miR-302 and miR-371~373 clusters in GCT biology.

References
1 Gillis et al. J Pathol 2007, 213:319-328.
2Korkola et al. Cancer Res 2006, 66:820-827.
3 van Dongen et al. Nat Methods 2008, 5:1023-1025.