Clonality and evolutionary history of rhabdomyosarcoma

PLoS Genetics
Li ChenJaved Khan

Abstract

To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. We discover several early mutations in non-RAS mutated samples and predict them to be drivers in PFN-RMS including recurrent mutation of PKN1. In contrast, we find that PAX-fusion-positive (PFP) subtype tumors have undergone whole-genome duplication in the late stage of cancer evolutionary history and have acquired fewer mutations and subclones than PFN-RMS. Moreover we predict that the PAX3-FOXO1 fusion event occurs earlier than the whole genome duplication. Our findings provide information critical to the understanding of tumorigenesis of RMS.

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Methods Mentioned

BETA
biopsies
PCR
dissect
RNAseq
GTPases
flow cytometry
genotyping
exome sequencing

Software Mentioned

Ion Ampliseq
NEXUS
SOLiD
CGA
CASAVA
Cufflinks
RNAseq
Complete Genomics
TopHat2
GSEA

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