Genes, chromosomes & cancer · 2026
Clear Cell Chondrosarcoma With Somatic VHL Inactivation: A Case Report With Integrated Genomic and Transcriptomic Analysis.
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Patel Lalit R, Wong Philip, Oskouei Shervin, Bahrami Armita
Аннотация
BACKGROUND: Clear cell chondrosarcoma (CCC) is a rare, low-grade malignant bone tumor and a specific subtype of chondrosarcoma. In contrast to conventional central chondrosarcoma, which often exhibits recurrent IDH1/2 mutations, CCC is IDH-wildtype, and its genomic profile remains uncharacterized. Sporadic cases have been described in association with von Hippel-Lindau (VHL) disease, but somatic VHL alterations have not been demonstrated in this tumor.
METHODS: A 35-year-old man presented with local recurrence of a distal femoral tumor 5 years after curettage and allograft reconstruction for a tumor that was initially diagnosed as clear cell chondrosarcoma. The recurrent tumor was resected and analyzed using a comprehensive DNA/RNA next-generation sequencing assay with matched germline testing to distinguish somatic from germline alterations.
RESULTS: The recurrent tumor measured 5.0 cm and showed classic CCC morphology with focal areas of conventional chondrosarcoma-like differentiation. No IDH1/2 mutations were identified. Two pathogenic loss-of-function variants were detected: COL2A1 c.1262_1266+2delinsTCC (variant allele frequency [VAF], 34%) and VHL c.341-2A>C (VAF, 45%). The tumor had a low tumor mutational burden, low loss of heterozygosity, and a complex karyotype with monosomy of chromosome 3. Gene expression profiling revealed decreased VHL mRNA expression. Germline testing showed no germline VHL alteration, confirming somatic VHL inactivation.
CONCLUSION: To our knowledge, this report is the first to describe a molecularly profiled CCC with somatic VHL inactivation. These results expand the evolving genomic spectrum of CCC beyond its previously known IDH-wildtype status and suggest that VHL pathway dysregulation may contribute to tumorigenesis in a subset of cases.
METHODS: A 35-year-old man presented with local recurrence of a distal femoral tumor 5 years after curettage and allograft reconstruction for a tumor that was initially diagnosed as clear cell chondrosarcoma. The recurrent tumor was resected and analyzed using a comprehensive DNA/RNA next-generation sequencing assay with matched germline testing to distinguish somatic from germline alterations.
RESULTS: The recurrent tumor measured 5.0 cm and showed classic CCC morphology with focal areas of conventional chondrosarcoma-like differentiation. No IDH1/2 mutations were identified. Two pathogenic loss-of-function variants were detected: COL2A1 c.1262_1266+2delinsTCC (variant allele frequency [VAF], 34%) and VHL c.341-2A>C (VAF, 45%). The tumor had a low tumor mutational burden, low loss of heterozygosity, and a complex karyotype with monosomy of chromosome 3. Gene expression profiling revealed decreased VHL mRNA expression. Germline testing showed no germline VHL alteration, confirming somatic VHL inactivation.
CONCLUSION: To our knowledge, this report is the first to describe a molecularly profiled CCC with somatic VHL inactivation. These results expand the evolving genomic spectrum of CCC beyond its previously known IDH-wildtype status and suggest that VHL pathway dysregulation may contribute to tumorigenesis in a subset of cases.