Targeted Next-Generation Sequencing Identifies Molecular and Genetic Events in Dedifferentiated Chondrosarcoma.
PMID 33147331 · Archives of pathology & laboratory medicine · 2021 · DOI 10.5858/arpa.2020-0379-OA
Authors: Calixto-Hope G Lucas; James P Grenert; Andrew Horvai
Abstract
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. To determine the genetic and molecular events that drive progression from a conventional chondrosarcoma to high grade nonchondrogenic sarcoma. 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. 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. 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.
Adult; Aged; Biomarkers, Tumor; Bone Neoplasms; Cell Dedifferentiation; Chondrosarcoma; Collagen Type II; DNA Copy Number Variations; DNA Mutational Analysis; Female; Gene Dosage; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Phenotype; Predictive Value of Tests; Sequence Analysis, DNA; Telomerase
Cite
Calixto-Hope G Lucas; James P Grenert; Andrew Horvai. Targeted Next-Generation Sequencing Identifies Molecular and Genetic Events in Dedifferentiated Chondrosarcoma. Archives of pathology & laboratory medicine (2021). PMID 33147331. DOI 10.5858/arpa.2020-0379-OA.