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PLoS Genet. 2015 Mar 13;11(3):e1005075. doi: 10.1371/journal.pgen.1005075. eCollection 2015 Mar.

Clonality and evolutionary history of rhabdomyosarcoma.

Author information

1
Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
2
Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Pediatric Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America.
3
Biospecimens Research and Tumour Bank, The Kids Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
4
Department of Pediatrics, Division of Pediatric Hematology/Oncology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
5
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
6
Department of Pediatrics, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

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.

PMID:
25768946
PMCID:
PMC4358975
DOI:
10.1371/journal.pgen.1005075
[Indexed for MEDLINE]
Free PMC Article

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