Targeted Next-Generation Sequencing Identifies Molecular and Genetic Events in Dedifferentiated Chondrosarcoma
| Autor: | James P. Grenert, Andrew E. Horvai, Calixto-Hope G Lucas |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine IDH1 DNA Copy Number Variations DNA Mutational Analysis Chondrosarcoma Gene Dosage Bone Neoplasms Biology IDH2 DNA sequencing Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Predictive Value of Tests Biomarkers Tumor medicine Humans Missense mutation Genetic Predisposition to Disease Collagen Type II Telomerase Aged High-Throughput Nucleotide Sequencing Sequence Analysis DNA General Medicine Cell Dedifferentiation Middle Aged medicine.disease Phenotype Isocitrate Dehydrogenase Medical Laboratory Technology 030104 developmental biology Tumor progression 030220 oncology & carcinogenesis Mutation Cancer research Immunohistochemistry Female Sarcoma |
| Zdroj: | Archives of Pathology & Laboratory Medicine. 145:1009-1017 |
| ISSN: | 1543-2165 0003-9985 |
| DOI: | 10.5858/arpa.2020-0379-oa |
| Popis: | Context.— Dedifferentiated chondrosarcoma is a rare adult bone tumor with a dismal prognosis and is composed of a conventional chondrosarcoma juxtaposed to high-grade nonchondrogenic sarcoma. Dedifferentiated chondrosarcomas may represent tumor progression from a differentiated to a primitive histotype. Objective.— To determine the genetic and molecular events that drive progression from a conventional chondrosarcoma to high grade nonchondrogenic sarcoma. Design.— We analyzed the genomic landscape of paired conventional and dedifferentiated components of 11 dedifferentiated chondrosarcoma using targeted next-generation DNA sequencing with immunohistochemical validation. Clinical, radiographic, and pathologic features of tumors were reviewed. Capture-based DNA sequencing targeting the coding regions of 479 cancer genes and select introns was performed. Results.— The tumors arose in the femur (n = 4; 36%), scapula (n = 3; 27%), pelvis (n = 3; 27%), and humerus (n = 1; 9%) of 7 men (64%) and 4 women (36%; median age, 61 years). DNA was adequate for sequencing from all 11 dedifferentiated components (100%) and 9 paired conventional chondrosarcoma components (82%). All tumors (100%) harbored either IDH1 p.R132 or IDH2 p.R172S hotspot mutations. Seven tumors (64%) displayed COL2A1 alterations. TERT promoter mutations were present in 5 of 9 pairs (56%) and 2 (22%) additional unpaired dedifferentiated components. IDH1/2, COL2A1, and TERT mutations were identical in both components of the paired samples. Pathogenic missense or truncating mutations in TP53 and large-scale copy number alterations were more common in dedifferentiated components than in those of matched conventional components. Conclusions.— The results support IDH1/2, COL2A1, and TERT promoter mutations being common in dedifferentiated chondrosarcoma and as likely early events in progression, whereas inactivating mutation of TP53 and high-level copy number alterations may be later events in the dedifferentiated phenotype. |
| Databáze: | OpenAIRE |
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