Sanchez-Guixe, M.; Cebria-Xart, A.; Fabre, N.; Rodriguez-Hernandez, C. J.; Pinheiro-Santin, M.; Lavarino, C.; Drost, J.; Van Boxtel, R.; Lopez-Bigas, N.; Avgustinova, A.; Gonzalez-Perez, A.

Rhabdoid tumors are very aggressive rare pediatric cancers with poor survival affecting very young children. They are characterized by the bi-allelic loss of SMARCB1 or SMARCA4, which is suspected to occur prenatally. However, their genomic evolution is not well understood. Here we assembled the largest cohort of whole-genome sequenced rhabdoid tumors to date, comprising 97 tumors from 88 children. We discovered that, in 42% of cases, the bi-allelic inactivation of the driver gene occurred via a Copy Number Neutral-Loss of Heterozygosity (CN-LOH). We exploited these CN-LOH events and the steady accumulation of age-related mutations in the tumor genomes to estimate the age of donors at the time of occurrence of the driver event and at the time of emergence of the clonal expansion. Across all cases with CN-LOH, the loss of the driver gene occurred very early during prenatal development. However, the clonal expansion that ultimately gave rise to the tumor occurred at different times during infancy, even several years after the acquisition of the founder event. These results indicate that probably other factors, besides the genetic driver event, are required to promote rhabdoid tumorigenesis.