TY - JOUR
T1 - DNA methylation-based classifier for accurate molecular diagnosis of bone sarcomas
AU - Peter Wu, S.
AU - Cooper, Benjamin T.
AU - Bu, Fang
AU - Bowman, Christopher J.
AU - Keith Killian, J.
AU - Serrano, Jonathan
AU - Wang, Shiyang
AU - Jackson, Twana M.
AU - Gorovets, Daniel
AU - Shukla, Neerav
AU - Meyers, Paul A.
AU - Pisapia, David J.
AU - Gorlick, Richard
AU - Ladanyi, Marc
AU - Thomas, Kristen
AU - Snuderl, Matija
AU - Karajannis, Matthias A.
N1 - Publisher Copyright:
© 2018 American Society of Clinical Oncology.
PY - 2017
Y1 - 2017
N2 - Purpose Pediatric sarcomas provide a unique diagnostic challenge. There is considerable morphologic overlap between entities, increasing the importance of molecular studies in the diagnosis, treatment, and identification of therapeutic targets. We developed and validated a genome-wideDNAmethylation-based classifier to differentiate between osteosarcoma, Ewing sarcoma, and synovial sarcoma. Methods DNA methylation status of 482,421 CpG sites in 10 Ewing sarcoma, 11 synovial sarcoma, and 15 osteosarcoma samples were determined using the Illumina Infinium HumanMethylation450 array. We developed a random forest classifier trained from the 400 most differentially methylated CpG sites within the training set of 36 sarcoma samples. This classifier was validated on data drawn from The Cancer Genome Atlas synovial sarcoma, TARGET-Osteosarcoma, and a recently published series of Ewing sarcoma. Results Methylation profiling revealed three distinct patterns, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from The Cancer Genome Atlas were accurately classified as synovial sarcoma (10 of 10; sensitivity and specificity, 100%), all but one sample from TARGET-Osteosarcoma were classified as osteosarcoma (85 of 86; sensitivity, 98%; specificity, 100%), and 14 of 15 Ewing sarcoma samples were classified correctly (sensitivity, 93%; specificity, 100%). The single misclassified osteosarcoma sample demonstrated high EWSR1 and ETV1 expression on RNA sequencing, although no fusion was found on manual curation of the transcript sequence.Twoadditional clinical samples that were difficult to classify by morphology and molecular methods were classified as osteosarcoma; one had been suspected of being a synovial sarcoma and the other of being Ewing sarcoma on initial diagnosis. Conclusion Osteosarcoma, synovial sarcoma, and Ewing sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide diagnostic assistance when histologic and standard techniques are inconclusive.
AB - Purpose Pediatric sarcomas provide a unique diagnostic challenge. There is considerable morphologic overlap between entities, increasing the importance of molecular studies in the diagnosis, treatment, and identification of therapeutic targets. We developed and validated a genome-wideDNAmethylation-based classifier to differentiate between osteosarcoma, Ewing sarcoma, and synovial sarcoma. Methods DNA methylation status of 482,421 CpG sites in 10 Ewing sarcoma, 11 synovial sarcoma, and 15 osteosarcoma samples were determined using the Illumina Infinium HumanMethylation450 array. We developed a random forest classifier trained from the 400 most differentially methylated CpG sites within the training set of 36 sarcoma samples. This classifier was validated on data drawn from The Cancer Genome Atlas synovial sarcoma, TARGET-Osteosarcoma, and a recently published series of Ewing sarcoma. Results Methylation profiling revealed three distinct patterns, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from The Cancer Genome Atlas were accurately classified as synovial sarcoma (10 of 10; sensitivity and specificity, 100%), all but one sample from TARGET-Osteosarcoma were classified as osteosarcoma (85 of 86; sensitivity, 98%; specificity, 100%), and 14 of 15 Ewing sarcoma samples were classified correctly (sensitivity, 93%; specificity, 100%). The single misclassified osteosarcoma sample demonstrated high EWSR1 and ETV1 expression on RNA sequencing, although no fusion was found on manual curation of the transcript sequence.Twoadditional clinical samples that were difficult to classify by morphology and molecular methods were classified as osteosarcoma; one had been suspected of being a synovial sarcoma and the other of being Ewing sarcoma on initial diagnosis. Conclusion Osteosarcoma, synovial sarcoma, and Ewing sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide diagnostic assistance when histologic and standard techniques are inconclusive.
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U2 - 10.1200/PO.17.00031
DO - 10.1200/PO.17.00031
M3 - Article
C2 - 29354796
AN - SCOPUS:85077490288
SN - 2473-4284
VL - 2017
SP - 1
EP - 11
JO - JCO Precision Oncology
JF - JCO Precision Oncology
IS - 1
ER -