Molecular characteristics of poorly differentiated chordoma.

Abstract

Pediatric poorly differentiated chordoma is a subtype of chordoma with a much more aggressive clinical course and has been characterized by loss of SMARCB1. This study characterizes the molecular features of these tumors in comparison to conventional chordoma. A search of records between 1990 and 2017 at Massachusetts General Hospital identified two patients with sufficient excess tissue for molecular analysis and a third patient diagnosed with a highly cellular conventional chordoma. The three tumors were sent for array comparative genomic hybridization for genome-wide copy number variants; multiplex PCR for single-nucleotide variants; and RNA-sequencing for fusions. Poorly differentiated chordoma showed chromosome 22q loss, including SMARCB1, with no identifiable mutations on multiplex PCR. The cellular conventional chordoma showed a complex pattern of chromosomal gains and losses involving 12 chromosomes, and an RB1 mutation at low allelic frequency. RNA-Seq identified no disease-defining gene fusion events. Poorly differentiated chordoma appears to represent a distinct type of tumor that is genetically unrelated to conventional chordoma. Recognition of this subtype is important because these malignancies should be treated aggressively with multimodality therapy, and possibly targeted therapy.