Clear Cell Chondrosarcoma With Somatic VHL Inactivation: A Case Report With Integrated Genomic and Transcriptomic...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Clear cell chondrosarcoma (CCC) is a rare, low-grade malignant bone tumor, distinct from IDH-mutated conventional chondrosarcomas.
• The genomic profile of CCC is largely uncharacterized, with no prior demonstration of somatic VHL alterations.
• While VHL disease association is known, somatic VHL mutations in CCC were not previously established.

Purpose of the Study:

• To molecularly characterize a recurrent clear cell chondrosarcoma.
• To investigate the genomic alterations in IDH-wildtype CCC.
• To determine if somatic VHL alterations contribute to CCC development.

Main Methods:

• Comprehensive DNA/RNA next-generation sequencing was performed on a recurrent distal femoral CCC.
• Matched germline testing was utilized to differentiate somatic from germline alterations.
• Analysis included variant detection, tumor mutational burden, loss of heterozygosity, karyotyping, and gene expression profiling.

Main Results:

• The recurrent tumor exhibited classic CCC morphology with no IDH1/2 mutations.
• Pathogenic loss-of-function variants in COL2A1 and VHL were identified as somatic alterations.
• Somatic VHL inactivation was confirmed, with decreased VHL mRNA expression and a complex karyotype.

Conclusions:

• This is the first report of a molecularly profiled CCC with somatic VHL inactivation.
• The findings expand the genomic understanding of CCC beyond its IDH-wildtype status.
• VHL pathway dysregulation is suggested as a potential driver of tumorigenesis in a subset of CCC cases.