Abstract
There is a lack of well validated prognostic biomarkers in osteosarcoma, a rare, recalcitrant disease for which treatment standards have not changed in over 20 years. We performed microRNA sequencing in 74 frozen osteosarcoma biopsy samples, constituting the largest single center translationally analyzed osteosarcoma cohort to date, and we separately analyzed a multi-omic dataset from a large NCI supported national cooperative group cohort. We validated the prognostic value of candidate microRNA signatures and contextualized them in relevant transcriptomic and epigenomic networks. Our results reveal the existence of molecularly defined phenotypes associated with outcome independent of clinicopathologic features. Through machine learning based integrative pharmacogenomic analysis, the microRNA biomarkers identify novel therapeutics for stratified application in osteosarcoma. The previously unrecognized osteosarcoma subtypes with distinct clinical courses and response to therapy could be translatable for discerning patients appropriate for more intensified, less intensified, or alternate therapeutic regimens.
Highlights
There is a lack of well validated prognostic biomarkers in osteosarcoma, a rare, recalcitrant disease for which treatment standards have not changed in over 20 years
While chemotherapy with the standard cisplatin/doxorubicin/methotrexate regimen, combined with surgical resection has markedly improved prognosis in patients with localized tumors, up to 40–50% of patients experience relapse and eventually succumb to the disease and the prognosis for patients presenting with metastatic disease is even poorer[1,2]
Osteosarcoma treatment is based on a combined modality approach consisting of surgery and neoadjuvant and adjuvant chemotherapy with the MAP regimen
Summary
There is a lack of well validated prognostic biomarkers in osteosarcoma, a rare, recalcitrant disease for which treatment standards have not changed in over 20 years. A recent large randomized international trial (EURAMOS6), using pathologic necrosis to stratify patients for the addition of ifosfamide/etoposide or interferon to the adjuvant treatment, failed to produce a survival benefit underscoring both the need for novel therapeutics as well as the limitations of currently available prognostic/stratification markers leading to an increased interest in molecular markers of outcome. In this context, miRNAs have recently gained attention, due to their recognized regulatory role for large numbers of downstream genes in cancer. We explore possible novel therapeutic implications by analyzing connections of the molecular profiles with new drugs that may be effective in osteosarcoma
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