Abstract 3424: Malignant germ cell tumors display common microRNA profiles resulting in global changes in expression of mRNA targets

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background As malignant germ cell tumors (MGCTs) are thought to have a common origin from primordial germ cells, they may share fundamental biological abnormalities despite their clinical and histopathological heterogeneity. We tested the hypothesis that MGCTs are characterized by common patterns of microRNA (miRNA) expression that are functionally significant by affecting levels of mRNA targets. We further investigated relationships between miRNA profiles and transcription factor expression, in order to identify potential regulators of miRNA transcription in MGCTs. Methods We used the miRCURY microarray (Exiqon) to quantify global microRNA expression levels in 28 gonadal and extragonadal GCTs and 14 non-malignant samples (eight controls, six teratomas) from pediatric subjects. For 21 of these samples (17 MGCT, 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 qRT-PCR miRNA and U133A GeneChip mRNA profiling in adult gonadal MGCTs. Data were analysed using R and Bioconductor. We used the novel bioinformatic algorithm Sylamer to investigate enrichment and depletion of miRNA seed complementary regions (SCRs) in 3’UTRs of mRNAs ranked according to expression levels in MGCTs. For the pediatric MGCT samples we compared miRNA profiles with transcription factor expression using linear regression plots. Results miR-302 and miR-371∼373 clusters were universally over-expressed in MGCTs regardless of patient age (pediatric or adult), tumor histological type [yolk sac tumors (YSTs), seminomas or embryonal carcinomas] or anatomical site (gonadal or extragonadal). Sylamer demonstrated that the most significantly over-represented SCR in the 3’UTRs of down-regulated mRNAs was GCACTT, corresponding to the AAGUGC seed common to the six members of the miR-302a∼d and miR-372∼373 family. Gene Ontology (GO) analysis revealed that the down-regulated mRNAs containing this common SCR in pediatric MGCTs were members of major cancer-associated cellular pathways. The transcription factor SOX17 was highly significantly over-expressed in pediatric and adult MGCTs (adjusted p-value=3.0×10−4 and 1.4×10−11, respectively), and showed a strong positive correlation in matched pediatric samples with combined median expression values for miR-302a∼d and miR-372∼3 (p-value=4.9×10−4). Conclusion Our data suggests a fundamental role for miR-302 and miR-371∼373 clusters in the biology of MGCTs and identifies SOX17 as a candidate regulator of these clusters. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3424.