Children without known germline cancer predisposing mutations that present with a second malignancy during their young age are extremely rare. In this study, Sánchez-Guixé and colleagues investigated four children with second tumors through whole genome sequencing and error-corrected ultra-deep duplex sequencing. Using mutational signatures to time the clonal expansion, three different routes of origin for the second malignancy were uncovered: a leukemia secondary to the exposure to the cytotoxic therapy, a mosaic somatic mutation acquired early during embryonic development, and completely independent clones diverging during embryogenesis. Importantly, this study also describes the mutational impact of platinum-based therapies in healthy tissues.

See article, p. 953.

The EZH2 methyltransferase tazemetostat has recently been approved as the first targeted therapy for SMARCB1-deficient epithelioid sarcomas, but resistance is common. In this study, Kazansky and colleagues sought to explore mechanisms of resistance to tazemetostat in SMARCB1-deficient sarcomas and rhabdoid tumors and identified...

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