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Clonality and evolutionary history of rhabdomyosarcoma.

Chen L, Shern JF, Wei JS, Yohe ME, Song YK, Hurd L, Liao H, Catchpoole D, Skapek SX, Barr FG, Hawkins DS, Khan J - PLoS Genet. (2015)

Bottom Line: 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.Our findings provide information critical to the understanding of tumorigenesis of RMS.

View Article: PubMed Central - PubMed

Affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 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.

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Related in: MedlinePlus

Subclonality in in 44 rhabdomyosarcoma samples.(a) Only a small number of somatic mutations are subclonal while the majority of them were present in all tumor cells. (b) The top panel shows the distribution of VAF of somatic mutations on chromosomes without aneuploidy for selected PFN-RMS samples, where a dominant clone is accompanied with a subclone(s). The lower panel shows the distribution of VAF of somatic mutations for selected PFP-RMS samples. Because these samples have undergone whole-genome duplication, the VAF of somatic mutations on tetraploid chromosomes is distributed around 0.5 and 0.25. (c) PFN samples have more detectable subclonal copy number alterations than PFP samples (p = 0.05, from Mann-Whitney test). It is possible that there are additional subclones that possess subclonal mutations or copy number alterations undetectable with our sequencing depth.
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pgen.1005075.g002: Subclonality in in 44 rhabdomyosarcoma samples.(a) Only a small number of somatic mutations are subclonal while the majority of them were present in all tumor cells. (b) The top panel shows the distribution of VAF of somatic mutations on chromosomes without aneuploidy for selected PFN-RMS samples, where a dominant clone is accompanied with a subclone(s). The lower panel shows the distribution of VAF of somatic mutations for selected PFP-RMS samples. Because these samples have undergone whole-genome duplication, the VAF of somatic mutations on tetraploid chromosomes is distributed around 0.5 and 0.25. (c) PFN samples have more detectable subclonal copy number alterations than PFP samples (p = 0.05, from Mann-Whitney test). It is possible that there are additional subclones that possess subclonal mutations or copy number alterations undetectable with our sequencing depth.

Mentions: The method was then applied to all the 44 RMS tumors. Looking across all 44 genomes revealed that a dominant clonal lineage was present in each tumor sample (Fig. 2A). The dominant clone carried a large proportion (from 81–96%) of somatic mutations regardless of PAX-fusion status of the tumor. Meanwhile, a small percentage of the cells in each tumor did display evidence of subclonal changes (Fig. 2B). In addition, we observed more subclonal aneuploidy events in PFN tumors (more than half of the tumors have detectable subclones) than PFP tumors (Fig. 2C). The inferred subclonal aneuploidy and mutational events were listed in S1 and S2 Tables, respectively.


Clonality and evolutionary history of rhabdomyosarcoma.

Chen L, Shern JF, Wei JS, Yohe ME, Song YK, Hurd L, Liao H, Catchpoole D, Skapek SX, Barr FG, Hawkins DS, Khan J - PLoS Genet. (2015)

Subclonality in in 44 rhabdomyosarcoma samples.(a) Only a small number of somatic mutations are subclonal while the majority of them were present in all tumor cells. (b) The top panel shows the distribution of VAF of somatic mutations on chromosomes without aneuploidy for selected PFN-RMS samples, where a dominant clone is accompanied with a subclone(s). The lower panel shows the distribution of VAF of somatic mutations for selected PFP-RMS samples. Because these samples have undergone whole-genome duplication, the VAF of somatic mutations on tetraploid chromosomes is distributed around 0.5 and 0.25. (c) PFN samples have more detectable subclonal copy number alterations than PFP samples (p = 0.05, from Mann-Whitney test). It is possible that there are additional subclones that possess subclonal mutations or copy number alterations undetectable with our sequencing depth.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358975&req=5

pgen.1005075.g002: Subclonality in in 44 rhabdomyosarcoma samples.(a) Only a small number of somatic mutations are subclonal while the majority of them were present in all tumor cells. (b) The top panel shows the distribution of VAF of somatic mutations on chromosomes without aneuploidy for selected PFN-RMS samples, where a dominant clone is accompanied with a subclone(s). The lower panel shows the distribution of VAF of somatic mutations for selected PFP-RMS samples. Because these samples have undergone whole-genome duplication, the VAF of somatic mutations on tetraploid chromosomes is distributed around 0.5 and 0.25. (c) PFN samples have more detectable subclonal copy number alterations than PFP samples (p = 0.05, from Mann-Whitney test). It is possible that there are additional subclones that possess subclonal mutations or copy number alterations undetectable with our sequencing depth.
Mentions: The method was then applied to all the 44 RMS tumors. Looking across all 44 genomes revealed that a dominant clonal lineage was present in each tumor sample (Fig. 2A). The dominant clone carried a large proportion (from 81–96%) of somatic mutations regardless of PAX-fusion status of the tumor. Meanwhile, a small percentage of the cells in each tumor did display evidence of subclonal changes (Fig. 2B). In addition, we observed more subclonal aneuploidy events in PFN tumors (more than half of the tumors have detectable subclones) than PFP tumors (Fig. 2C). The inferred subclonal aneuploidy and mutational events were listed in S1 and S2 Tables, respectively.

Bottom Line: 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.Our findings provide information critical to the understanding of tumorigenesis of RMS.

View Article: PubMed Central - PubMed

Affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 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.

Show MeSH
Related in: MedlinePlus