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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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Proposed evolutionary model of rhabdomyosarcoma.(a) PFN samples. (b) PFP samples.
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pgen.1005075.g006: Proposed evolutionary model of rhabdomyosarcoma.(a) PFN samples. (b) PFP samples.

Mentions: From the analyses described here, we can begin to understand the dynamics of RMS development. LOH of 11p15.5 has long been described as recurrent feature of several pediatric conditions including the overgrowth phenotype of Beckwith-Wiedemann Syndrome [37], Wilms tumor [38] and embryonal RMS. The proposed mechanism for oncogenesis of this lesion is loss of imprinting control over the IGF2 locus resulting in over-expression of this developmentally regulated growth factor. In this study, we find that not only is this lesion highly recurrent (>90%), it also appears to be the key early landmark in the evolution of fusion-negative tumors. The discovery of a somatic mutation of IGF2 within a fusion negative sample that does not harbor LOH of 11p15.5 (RMS2037) provides additional support to the role of dysregulation of IGF2 in PFN-RMS. In evolutionary terms, the presence of 11p15.5 LOH defines the “most recent common ancestor” when combined with a mutation in a gene in the RAS pathway (NRAS, KRAS, HRAS, FGFR4). While the progression we describe in this study indicates a possible common sequence of events (S1 Table), in some tumors it is equally as likely that the oncogenic mutation of a RAS pathway gene is the founding lesion. This corroborates the finding that patient’s with Costello Syndrome (HRAS germline mutation) [39], Noonan Syndrome (NRAS, KRAS, PTPN11 germline mutations) [40] and Neurofibromatosis (NF1 germline mutation) [41] all have increased risk of developing fusion-negative RMS. Interestingly, while RMS is certainly described in patients with Beckwith-Wiedemann Syndrome (germline uniparental disomy of 11p15.5), these patients appear to have a higher relative risk of developing Wilms’ tumor and hepatoblastoma than RMS [42]. Regardless of which lesion comes first, the combination of LOH of 11p15.5 with a RAS pathway mutation appears to set a clone on the course towards developing a fusion negative RMS tumor (Fig. 6A).


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)

Proposed evolutionary model of rhabdomyosarcoma.(a) PFN samples. (b) PFP samples.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005075.g006: Proposed evolutionary model of rhabdomyosarcoma.(a) PFN samples. (b) PFP samples.
Mentions: From the analyses described here, we can begin to understand the dynamics of RMS development. LOH of 11p15.5 has long been described as recurrent feature of several pediatric conditions including the overgrowth phenotype of Beckwith-Wiedemann Syndrome [37], Wilms tumor [38] and embryonal RMS. The proposed mechanism for oncogenesis of this lesion is loss of imprinting control over the IGF2 locus resulting in over-expression of this developmentally regulated growth factor. In this study, we find that not only is this lesion highly recurrent (>90%), it also appears to be the key early landmark in the evolution of fusion-negative tumors. The discovery of a somatic mutation of IGF2 within a fusion negative sample that does not harbor LOH of 11p15.5 (RMS2037) provides additional support to the role of dysregulation of IGF2 in PFN-RMS. In evolutionary terms, the presence of 11p15.5 LOH defines the “most recent common ancestor” when combined with a mutation in a gene in the RAS pathway (NRAS, KRAS, HRAS, FGFR4). While the progression we describe in this study indicates a possible common sequence of events (S1 Table), in some tumors it is equally as likely that the oncogenic mutation of a RAS pathway gene is the founding lesion. This corroborates the finding that patient’s with Costello Syndrome (HRAS germline mutation) [39], Noonan Syndrome (NRAS, KRAS, PTPN11 germline mutations) [40] and Neurofibromatosis (NF1 germline mutation) [41] all have increased risk of developing fusion-negative RMS. Interestingly, while RMS is certainly described in patients with Beckwith-Wiedemann Syndrome (germline uniparental disomy of 11p15.5), these patients appear to have a higher relative risk of developing Wilms’ tumor and hepatoblastoma than RMS [42]. Regardless of which lesion comes first, the combination of LOH of 11p15.5 with a RAS pathway mutation appears to set a clone on the course towards developing a fusion negative RMS tumor (Fig. 6A).

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