Clonality and Evolutionary History of Rhabdomyosarcoma

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To decipher the dynamic mutational process and identify the causative genomic events in rhabdomyosarcoma (RMS), we developed a systematic method that incorporates multiple types of genomic information to estimate normal cell contamination, tumor clonality, and a timeline of somatic events that occurred prior to the tumor presentation. Our results demonstrate two distinct evolutionary paths resulting in PAX-fusion-negative-rhabdomyosarcoma (PFN-RMS) and PAX-fusion-positive-rhabdomyosarcoma (PFP-RMS): (1) In PFN-RMS, genomic loss of heterozygosity on chromosome 11p15.5 and non-synonymous mutations in RAS pathway and cell cycle genes (FGFR4, KRAS, NRAS, HRAS and CCDN1), as well as several genes not previously known to be drivers of RMS, including PKN1, CUL2, and TTK, occurs early in the evolutionary history of tumor; (2) In contrast, the PAX gene fusion event in PFP-RMS tumors is an early detectable event which consistently occurs prior to a whole genome duplication event. These findings provide new insights into the biology and molecular events that initiate RMS tumorigenesis and may help identify actionable drivers for targeted therapies.

Vyšlo v časopise: Clonality and Evolutionary History of Rhabdomyosarcoma. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005075
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005075

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