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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

Summary of recurrent somatic lesions found across the 44 tumors and the estimates of their occurrence time.The heatmap denotes the occurrence of the lesions and their timing (the brightness of grids represents the percentage of cancer lifetime when the lesion occurred). The occurrence time of a mutation is represented as the median of its inferred time interval. Note that within a single chromosome, there may be multiple segments with different copy number status, and we only show the arm-level copy number alterations in this figure. 11p15.5 LOH with copy gain and the mutations in RAS pathway are consistently early events during the development of PFN rhabdomyosarcoma.
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pgen.1005075.g004: Summary of recurrent somatic lesions found across the 44 tumors and the estimates of their occurrence time.The heatmap denotes the occurrence of the lesions and their timing (the brightness of grids represents the percentage of cancer lifetime when the lesion occurred). The occurrence time of a mutation is represented as the median of its inferred time interval. Note that within a single chromosome, there may be multiple segments with different copy number status, and we only show the arm-level copy number alterations in this figure. 11p15.5 LOH with copy gain and the mutations in RAS pathway are consistently early events during the development of PFN rhabdomyosarcoma.

Mentions: This method was applied to all the 44 tumor-normal sample pairs to build the evolutionary history of RMS (Fig. 4, S9 Fig., and S1 Table). In summary, our results showed three major findings. First, LOH of 11p15.5 was a consistent early founding event (in average occurred at 35% of molecular cancer lifetime) in PFN-RMS. In comparison, other highly recurrent aneuploidy events such as the copy gain of chromosome 8 and 2 were not consistent early occurring events (time ranges from 1%∼95% and 16%∼96%, respectively). Second, mutations in RAS pathway genes, including FGFR4, KRAS, NRAS and HRAS, were recurrent early events in PFN-RMS. In addition, mutations in other genes (PKN1, CCND1, CUL2, and TTK) occurred early suggesting their role in tumorigenesis. Third, PFP-RMS tumors in general had much fewer somatic alterations and few of them occurred early in the tumor’s molecular lifetime. Of note, a whole-genome duplication event consistently occurred at the middle or late point in the molecular lifetime of these tumors. The high recurrence suggests that this event might be crucial for the presentation of this cancer subtype. We will discuss these findings in more details in the following sections.


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)

Summary of recurrent somatic lesions found across the 44 tumors and the estimates of their occurrence time.The heatmap denotes the occurrence of the lesions and their timing (the brightness of grids represents the percentage of cancer lifetime when the lesion occurred). The occurrence time of a mutation is represented as the median of its inferred time interval. Note that within a single chromosome, there may be multiple segments with different copy number status, and we only show the arm-level copy number alterations in this figure. 11p15.5 LOH with copy gain and the mutations in RAS pathway are consistently early events during the development of PFN rhabdomyosarcoma.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005075.g004: Summary of recurrent somatic lesions found across the 44 tumors and the estimates of their occurrence time.The heatmap denotes the occurrence of the lesions and their timing (the brightness of grids represents the percentage of cancer lifetime when the lesion occurred). The occurrence time of a mutation is represented as the median of its inferred time interval. Note that within a single chromosome, there may be multiple segments with different copy number status, and we only show the arm-level copy number alterations in this figure. 11p15.5 LOH with copy gain and the mutations in RAS pathway are consistently early events during the development of PFN rhabdomyosarcoma.
Mentions: This method was applied to all the 44 tumor-normal sample pairs to build the evolutionary history of RMS (Fig. 4, S9 Fig., and S1 Table). In summary, our results showed three major findings. First, LOH of 11p15.5 was a consistent early founding event (in average occurred at 35% of molecular cancer lifetime) in PFN-RMS. In comparison, other highly recurrent aneuploidy events such as the copy gain of chromosome 8 and 2 were not consistent early occurring events (time ranges from 1%∼95% and 16%∼96%, respectively). Second, mutations in RAS pathway genes, including FGFR4, KRAS, NRAS and HRAS, were recurrent early events in PFN-RMS. In addition, mutations in other genes (PKN1, CCND1, CUL2, and TTK) occurred early suggesting their role in tumorigenesis. Third, PFP-RMS tumors in general had much fewer somatic alterations and few of them occurred early in the tumor’s molecular lifetime. Of note, a whole-genome duplication event consistently occurred at the middle or late point in the molecular lifetime of these tumors. The high recurrence suggests that this event might be crucial for the presentation of this cancer subtype. We will discuss these findings in more details in the following sections.

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