Osteosarcoma (OS) is the common histological form of primary bone cancer and one of the leading aggressive cancers in children under age fifteen. Although several genetic predisposing conditions have been associated with OS the understanding of its molecular etiology is limited. Here, we show that microRNAs (miRNAs) at the chr.14q32 locus are significantly downregulated in osteosarcoma compared to normal bone tissues. Bioinformatic predictions identified that a subset of 14q32 miRNAs (miR-382, miR-369-3p, miR-544 and miR-134) could potentially target cMYC transcript. The physical interaction between these 14q32 miRNAs and cMYC was validated using reporter assays. Further, restoring expression of these four 14q32 miRNAs decreased cMYC levels and induced apoptosis in Saos2 cells. We also show that exogenous expression of 14q32 miRNAs in Saos2 cells significantly downregulated miR-17∼92, a transcriptional target of cMYC. The pro-apoptotic effect of 14q32 miRNAs in Saos2 cells was rescued either by overexpression of cMYC cDNA without the 3′UTR or with miR-17∼92 cluster. Further, array comparative genomic hybridization studies showed no DNA copy number changes at 14q32 locus in OS patient samples suggesting that downregulation of 14q32 miRNAs are not due to deletion at this locus. Together, our data support a model where the deregulation of a network involving 14q32 miRNAs, cMYC and miR-17∼92 miRNAs could contribute to osteosarcoma pathogenesis.

Osteosarcoma (OS) is the most commonly diagnosed malignant bone tumor in humans and dogs, characterized in both species by extremely complex karyotypes exhibiting high frequencies of genomic imbalance. Evaluation of genomic signatures in human OS using array comparative genomic hybridization (aCGH) has assisted in uncovering genetic mechanisms that result in disease phenotype. Previous low-resolution (10-20 Mb) aCGH analysis of canine OS identified a wide range of recurrent DNA copy number aberrations, indicating extensive genomic instability. In this study, we profiled 123 canine OS tumors by 1 Mb-resolution aCGH to generate a dataset for direct comparison with current data for human OS, concluding that several high frequency aberrations in canine and human OS are orthologous. To ensure complete coverage of gene annotation, we identified the human refseq genes that map to these orthologous aberrant dog regions and found several candidate genes warranting evaluation for OS involvement. Specifically, subsequenct FISH and qRT-PCR analysis of RUNX2, TUSC3, and PTEN indicated that expression levels correlated with genomic copy number status, showcasing RUNX2 as an OS associated gene and TUSC3 as a possible tumor suppressor candidate. Together these data demonstrate the ability of genomic comparative oncology to identify genetic abberations which may be important for OS progression. Large scale screening of genomic imbalance in canine OS further validates the use of the dog as a suitable model for human cancers, supporting the idea that dysregulation discovered in canine cancers will provide an avenue for complementary study in human counterparts.

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Background Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include phase II detoxification enzymes, UGT2B17 and UGT2B28, which are two of the most commonly deleted genes in the genome. Methods To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk we genotyped 665 Caucasian CRC cases and 621 Caucasian controls that had completed extensive demographics and lifestyle questionnaires. Results A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when analyzing the entire population (p = 0.044). Stratification by sex yielded a decreased risk (p = 0.020) in men with the UGT2B17 (0/0), but no association was observed in women (p = 0.724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (p = 0.0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk. Conclusions The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men not women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. As UGT2B17 metabolizes certain NSAIDs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components.