Abstract 4638: Colorectal adenoma-to-carcinoma progression: The role of miR-17-92 cluster

Abstract

Abstract Background Chromosomal instability plays an important role in the progression of colorectal adenoma to carcinoma. We previously observed that specific non-random DNA copy number changes (8q, 13q, 20q gain, and 8p, 15q, 17p, 18q loss) were already present in the benign adenoma component of malignant polyps (i.e. adenomas with a focus of cancer). This indicates that these specific DNA copy number changes are associated with the progression from adenoma to cancer. DNA copy number dosage affects the expression of different loci, which may play an important functional role in the colorectal adenoma-to-carcinoma progression. We observed that overexpression of the miR-17-92 cluster (located on 13q) is associated with gain of 13q, one of the cancer associated DNA copy number changes. The aim of the present study was to investigate the biological meaning of miR-17-92 overexpression in benign adenomas and its role in adenoma-to-carcinoma progression. Methods Patient-derived colorectal adenoma organoids were used as model system. Two different background adenoma organoids were transduced with a miR-17-92 expression vector. Overexpression of members of the miR-17-92 cluster in the transduced adenoma organoids was confirmed by real-time quantitative RT-PCR for all individual miRNAs. Both miR-17-92-overexpressing organoids and their counterparts containing empty vectors (controls) were subjected to mRNA sequencing and subsequent differential gene expression analysis and subsequent establishement of a miR-17-92 gene expression signature. Enrichment of the miR-17-92 gene signature was evaluated in an independent series of 52 colorectal adenoma and carcinoma tissue samples. In vitro proliferation rates as well as invasion capacity of the transduced organoids were evaluated by measuring the size of the organoids and by using transwell invasion assays, respectively. Results We successfully overexpressed the miR-17-92 cluster in the two adenoma-derived organoids. Expression of 42 genes was significantly different (FDR<0.05, >4 fold difference) between organoids transduced with the miR-17-92 cluster and those transduced with the empty vector. In addition, in the series of 52 tumor tissue samples this gene signature could separate adenomas from carcinomas and was enriched in tumours with 13q gain. In vitro functional assays showed that proliferation capacity did not change after overexpression of the miR17-92 cluster in adenoma organoids, but capacity to invade was acquired. Conclusion We confirmed that overexpression of the miR-17-92 cluster leads to downstream gene expression alterations associated with colorectal cancer. Moreover, we showed that overexpression of this miRNA cluster promotes invasion of adenoma organoids in vitro. These results support a role of this locus in the progression from adenoma to carcinoma. Citation Format: Sanne R. Martens-de Kemp, Malgorzata A. Komor, Rosa Hegi, Marianne Tijssen, Anne S. Bolijn, Gerrit A. Meijer, Connie R. Jimenez, Remond J. Fijneman, Beatriz Carvalho. Colorectal adenoma-to-carcinoma progression: The role of miR-17-92 cluster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4638.