Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma
Menée sur des échantillons de tumeurs primitives et récidivantes prélevés sur 23 patients atteints d'un gliome, cette étude de séquençage de l'exome met en évidence l'absence fréquente, dans les tumeurs récidivantes, de mutations de plusieurs gènes, notamment TP53, ATRX, SMARCA4 et BRAF, détectées dans les tumeurs primitives
Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF, suggesting recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB and AKT-mTOR pathways that bore the signature of TMZ-induced mutagenesis.