Clinical and Molecular Analysis of Pathologic Fracture-associated Osteosarcoma: MicroRNA profile Is Different and Correlates with Prognosis.

Santiago A. Lozano Calderón, C. Garbutt, Jason Kim, Christopher E Lietz, Yen-Lin E Chen, K. Bernstein, I. Chebib, G. Nielsen, V. Deshpande, Renee Rubio, Yaoyu E. Wang, John Quackenbush, T. Delaney, K. Raskin, J. Schwab, G. Cote, D. Spentzos
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However, this has not been proved at the biological or molecular level. Currently, there has not been a microRNA profiling study of patients who have osteosarcoma with and without pathologic fractures that has described differences in terms of microRNA profiling between these two groups and their correlation with biologic behavior.\n\n\nQUESTIONS/PURPOSES\n(1) In patients with osteosarcoma of the extremities, how do the microRNA profiles of those with and without pathologic fractures compare? (2) What relationship do microRNAs have with local recurrence, risk of metastasis, disease-specific survival, and overall survival in osteosarcoma patients with pathologic fractures?\n\n\nMETHODS\nBetween 1994 and 2013, 217 patients were diagnosed and treated at our institution for osteosarcoma of the extremities. Patients were excluded if (1) they underwent oncologic resection of the osteosarcoma at an outside institution (two patients) or (2) they were diagnosed with an extraskeletal osteosarcoma (29 patients) or (3) they had less than 1 year of clinical follow-up and no oncologic outcome (local recurrence, metastasis, or death) (four patients). A total of 182 patients were eligible. Of those, 143 were high-grade osteosarcomas. After evaluation of tumor samples before chemotherapy treatment, a total of 80 consecutive samples were selected for sequencing. Demographic and clinical comparison between the sequenced and non-sequenced patients did not demonstrate any differences, confirming that both groups were comparable. Diagnostic samples from the extremities of 80 patients with high-grade extremity osteosarcomas who had not yet received chemotherapy underwent microRNA sequencing for an ongoing large-scale osteosarcoma genome profiling project at our institution. Six samples were removed after a second look by a musculoskeletal pathologist who verified cellularity and quality of samples to be sequenced, leaving a total of 74 patients. Of these, two samples were removed as they were confirmed to be pelvic tumors in a second check after sequencing. The final study sample was 72 patients (11 patients with pathologic fractures and 61 without). Sequencing data were correlated with fractures and local recurrence, risk of metastasis, disease-specific survival, and overall survival through Kaplan-Meier analyses.\n\n\nRESULTS\nSeveral microRNAs were expressed differently between the two groups. Among the markers with the highest differential expression (edgeR and DESeq algorithms), Hsa-mIR 656-3p, hsa-miR 493-5p, and hsa-miR 381-3p were upregulated in patients with pathologic fractures, whereas hsa-miR 363, hsa-miR 885-5p, and has-miR 20b-5p were downregulated. The highest differential expression fracture and nonfracture-associated microRNA markers also distinguished groups of patients with different metastasis risk, a well as different disease-specific and overall survival. Furthermore, the profile of pathologic fractures demonstrated a higher differential expression for microRNA markers that were previously associated with a higher risk of metastasis and lower survival rates in patients with osteosarcoma.\n\n\nCONCLUSIONS\nIn patients who have osteosarcoma, the microRNA profiles of those with pathologic fractures are different than of patients without pathologic fractures. The highest differential expression mircroRNA molecules in patients with pathologic fractures predict also higher risk of metastatic disease as well as worse disease-specific survival and overall survival. Furthermore, we found higher differential expression of microRNAs in the pathologic fracture group previously associated with poor prognosis. The higher risk of metastasis and poorer overall survival in patients with pathologic fractures is inherent to tumor aggressive biologic behavior. It is plausible that the fracture itself is not the direct cause of worse prognosis but another manifestation of tumor biologic aggressiveness. Identification of these molecules through liquid biopsies may help to determine which patients may benefit from surgery before fractures occur. The same technology can be applied to identify patterns of response to conventional chemotherapy, assisting in more specific and accurate systemic therapy.\n\n\nLEVEL OF EVIDENCE LEVEL\nIII, prognostic study.","PeriodicalId":10465,"journal":{"name":"Clinical Orthopaedics & Related Research","volume":"4 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"15","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Orthopaedics & Related Research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1097/CORR.0000000000000867","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 15

Abstract

BACKGROUND MicroRNAs are small, noncoding RNAs that regulate the expression of posttranslational genes. The presence of some specific microRNAs has been associated with increased risk of both local recurrence and metastasis and worse survival in patients with osteosarcoma. Pathologic fractures in osteosarcoma are considered to be more the manifestation of a neoplasm with a more aggressive biological behavior than the cause itself of worse prognosis. However, this has not been proved at the biological or molecular level. Currently, there has not been a microRNA profiling study of patients who have osteosarcoma with and without pathologic fractures that has described differences in terms of microRNA profiling between these two groups and their correlation with biologic behavior. QUESTIONS/PURPOSES (1) In patients with osteosarcoma of the extremities, how do the microRNA profiles of those with and without pathologic fractures compare? (2) What relationship do microRNAs have with local recurrence, risk of metastasis, disease-specific survival, and overall survival in osteosarcoma patients with pathologic fractures? METHODS Between 1994 and 2013, 217 patients were diagnosed and treated at our institution for osteosarcoma of the extremities. Patients were excluded if (1) they underwent oncologic resection of the osteosarcoma at an outside institution (two patients) or (2) they were diagnosed with an extraskeletal osteosarcoma (29 patients) or (3) they had less than 1 year of clinical follow-up and no oncologic outcome (local recurrence, metastasis, or death) (four patients). A total of 182 patients were eligible. Of those, 143 were high-grade osteosarcomas. After evaluation of tumor samples before chemotherapy treatment, a total of 80 consecutive samples were selected for sequencing. Demographic and clinical comparison between the sequenced and non-sequenced patients did not demonstrate any differences, confirming that both groups were comparable. Diagnostic samples from the extremities of 80 patients with high-grade extremity osteosarcomas who had not yet received chemotherapy underwent microRNA sequencing for an ongoing large-scale osteosarcoma genome profiling project at our institution. Six samples were removed after a second look by a musculoskeletal pathologist who verified cellularity and quality of samples to be sequenced, leaving a total of 74 patients. Of these, two samples were removed as they were confirmed to be pelvic tumors in a second check after sequencing. The final study sample was 72 patients (11 patients with pathologic fractures and 61 without). Sequencing data were correlated with fractures and local recurrence, risk of metastasis, disease-specific survival, and overall survival through Kaplan-Meier analyses. RESULTS Several microRNAs were expressed differently between the two groups. Among the markers with the highest differential expression (edgeR and DESeq algorithms), Hsa-mIR 656-3p, hsa-miR 493-5p, and hsa-miR 381-3p were upregulated in patients with pathologic fractures, whereas hsa-miR 363, hsa-miR 885-5p, and has-miR 20b-5p were downregulated. The highest differential expression fracture and nonfracture-associated microRNA markers also distinguished groups of patients with different metastasis risk, a well as different disease-specific and overall survival. Furthermore, the profile of pathologic fractures demonstrated a higher differential expression for microRNA markers that were previously associated with a higher risk of metastasis and lower survival rates in patients with osteosarcoma. CONCLUSIONS In patients who have osteosarcoma, the microRNA profiles of those with pathologic fractures are different than of patients without pathologic fractures. The highest differential expression mircroRNA molecules in patients with pathologic fractures predict also higher risk of metastatic disease as well as worse disease-specific survival and overall survival. Furthermore, we found higher differential expression of microRNAs in the pathologic fracture group previously associated with poor prognosis. The higher risk of metastasis and poorer overall survival in patients with pathologic fractures is inherent to tumor aggressive biologic behavior. It is plausible that the fracture itself is not the direct cause of worse prognosis but another manifestation of tumor biologic aggressiveness. Identification of these molecules through liquid biopsies may help to determine which patients may benefit from surgery before fractures occur. The same technology can be applied to identify patterns of response to conventional chemotherapy, assisting in more specific and accurate systemic therapy. LEVEL OF EVIDENCE LEVEL III, prognostic study.
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病理性骨折相关性骨肉瘤的临床和分子分析:MicroRNA谱不同并与预后相关。
micrornas是调节翻译后基因表达的小的非编码rna。一些特异性microrna的存在与骨肉瘤患者局部复发和转移的风险增加以及生存率降低有关。骨肉瘤的病理性骨折被认为是一种具有更强侵袭性生物学行为的肿瘤的表现,而不是导致预后更差的原因本身。然而,这还没有在生物学或分子水平上得到证实。目前,还没有一项针对伴有和不伴有病理性骨折的骨肉瘤患者的microRNA谱分析研究描述了这两组之间microRNA谱分析的差异及其与生物行为的相关性。(1)在四肢骨肉瘤患者中,有和没有病理性骨折的microRNA谱是如何比较的?(2) microrna与病理性骨折骨肉瘤患者局部复发、转移风险、疾病特异性生存、总生存有何关系?方法1994 ~ 2013年,我院收治肢体骨肉瘤患者217例。如果患者(1)在外部机构接受骨肉瘤肿瘤切除术(2例)或(2)诊断为骨外骨肉瘤(29例)或(3)临床随访时间少于1年且无肿瘤预后(局部复发、转移或死亡)(4例),则排除患者。共有182名患者符合条件。其中143例为高级别骨肉瘤。化疗前对肿瘤样本进行评估后,共选取80个连续样本进行测序。在测序患者和未测序患者之间的人口学和临床比较未显示任何差异,证实两组具有可比性。我们对80例尚未接受化疗的高级别肢体骨肉瘤患者的肢体诊断样本进行了microRNA测序,用于我们机构正在进行的大规模骨肉瘤基因组分析项目。在肌肉骨骼病理学家验证了待测序样本的细胞质量和质量后,在第二次检查后取出了6个样本,总共留下74名患者。其中,两个样本被移除,因为它们在测序后的第二次检查中被确认为盆腔肿瘤。最终研究样本为72例患者(11例有病理性骨折,61例无病理性骨折)。通过Kaplan-Meier分析,测序数据与骨折和局部复发、转移风险、疾病特异性生存和总生存相关。结果两组有几种microrna表达不同。在差异表达最高的标记物(edgeR和DESeq算法)中,Hsa-mIR 656-3p、Hsa-mIR 493-5p和Hsa-mIR 381-3p在病理性骨折患者中上调,而Hsa-mIR 363、Hsa-mIR 885-5p和has-miR 20b-5p下调。骨折和非骨折相关的microRNA标记物的最高差异表达也区分了不同转移风险的患者群体,以及不同的疾病特异性和总生存期。此外,病理性骨折的特征表明,microRNA标记物的差异表达更高,而microRNA标记物先前与骨肉瘤患者的转移风险较高和生存率较低相关。结论在骨肉瘤患者中,病理性骨折患者的microRNA谱与非病理性骨折患者不同。病理性骨折患者中差异表达最高的mirrorna分子也预示着更高的转移性疾病风险以及更差的疾病特异性生存期和总生存期。此外,我们发现在病理性骨折组中microrna的差异表达较高,先前与预后不良相关。病理性骨折患者较高的转移风险和较差的总生存率是肿瘤侵袭性生物学行为所固有的。似乎骨折本身并不是导致预后不良的直接原因,而是肿瘤生物侵袭性的另一种表现。通过液体活检鉴定这些分子可能有助于确定哪些患者可能在骨折发生前从手术中受益。同样的技术可以用于识别对常规化疗的反应模式,帮助更具体和准确的全身治疗。证据等级iii级,预后研究。
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