Genetic alteration and clonal evolution of primary glioblastoma into secondary gliosarcoma

Aims Secondary gliosarcoma (SGS) rarely arises post treatment of primary glioblastoma multiforme (GBM), and contains gliomatous and sarcomatous components. The origin and clonal evolution of SGS sarcomatous components remain uncharacterized. Therapeutic radiation is mutagenic and can induce sarcomas in patients with other tumor phenotypes, but possible causal relationships between radiotherapy and induction of SGS sarcomatous components remain unexplored. Herein, we investigated the clonal origin of SGS in a patient with primary GBM progressing into SGS post‐radiochemotherapy. Methods Somatic mutation profile in GBM and SGS was examined using whole‐genome sequencing and deep‐whole‐exome sequencing. Mutation signatures were characterized to investigate relationships between radiochemotherapy and SGS pathogenesis. Results A mutation cluster containing two founding mutations in tumor‐suppressor genes NF1 (variant allele frequency [VAF]: 50.0% in GBM and 51.1% in SGS) and TP53 (VAF: 26.7% in GBM and 50.8% in SGS) was shared in GBM and SGS. SGS exhibited an overpresented C>A (G>T) transversion (oxidative DNA damage signature) but no signature 11 mutations (alkylating‐agents – exposure signature). Since radiation induces DNA lesions by generating reactive oxygen species, the mutations observed in this case of SGS were likely the result of radiotherapy rather than chemotherapy. Conclusions Secondary gliosarcoma components likely have a monoclonal origin, and the clone possessing mutations in NF1 and TP53 was likely the founding clone in this case of SGS. This study presents the first comprehensive genomic profile and clonal architecture of tumor evolution from glioblastoma multiforme to Secondary gliosarcoma (SGS). The data support not only the monoclonal origin of gliomatous and sarcomatous components in SGS but also the causal relationship between therapeutic radiation and SGS pathogenesis.