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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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Inferring evolutionary history of a PFN sample, RMS2110.(a) The VAF of germline SNVs on chromosome 11 is distributed around 1, as a result of the uniparental disomy (LOH with duplication). (b) The VAF of somatic mutations is quite different from that of germline SNVs, suggesting majority of somatic mutations happen after the duplication event and thus are present in only one copy of chromosome 11. The earlier occurrence of the duplication of chromosome 11, the more somatic mutations with VAF = 0.5 are detected. S7 Fig. provides a more illustrative explanation. (c) Inferred evolutionary history represented as a phylogenetic tree. The thickness of the branches reflects the proportion of tumor cells in each lineage. The length of the branches reflects how much molecular time it undergoes with each lineage.
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pgen.1005075.g003: Inferring evolutionary history of a PFN sample, RMS2110.(a) The VAF of germline SNVs on chromosome 11 is distributed around 1, as a result of the uniparental disomy (LOH with duplication). (b) The VAF of somatic mutations is quite different from that of germline SNVs, suggesting majority of somatic mutations happen after the duplication event and thus are present in only one copy of chromosome 11. The earlier occurrence of the duplication of chromosome 11, the more somatic mutations with VAF = 0.5 are detected. S7 Fig. provides a more illustrative explanation. (c) Inferred evolutionary history represented as a phylogenetic tree. The thickness of the branches reflects the proportion of tumor cells in each lineage. The length of the branches reflects how much molecular time it undergoes with each lineage.

Mentions: The majority of this cancer genome was the expected diploid status with LAF = 0.5, however regions with aneuploidy or allelic imbalance provided the opportunity to identify the timing of genomic events, by comparing the allelic copy number status with the VAF distribution of somatic mutations (S7 Fig.). For example, chromosome 9p and 11 have 2 copies with LAF of 0 (Fig. 1B), which is likely the loss of one allele followed by a duplication of the remaining allele although we cannot formally exclude the possibility of the duplication of both alleles with subsequent loss of the 2 copies of one allele. This observation was confirmed by the fact that most germline single nucleotide variants on chromosome 9p and 11 had VAF near 1 (Fig. 3A). In this case, the somatic mutations occurring before the “LOH+duplication” event must be present on both copies, with an expected VAF of 1, whereas those occurring after the “LOH+duplication” event would be present on only one copy, with an expected VAF of 0.5. The data confirmed this prediction with the VAF displaying a bi-modal distribution with two peaks at 0.5 and 1, respectively (Fig. 3B). The ratio between the numbers of mutations in the two clusters reflects the fraction of “molecular time” it undergoes to accumulate mutations before and after the “LOH+duplication” event, assuming a constant accumulation rate [2]. We acknowledge that the somatic mutation accumulation rate varies among small genomic segments [5,25–27], but for chromosome-level segments used in this study, the average accumulation rates of somatic mutation were observed to be consistent with one another (r2 > 0.98, S8 Fig.). Therefore, the molecular timing inferred for different aneuploidy events were comparable among the segments within the same tumor sample.


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)

Inferring evolutionary history of a PFN sample, RMS2110.(a) The VAF of germline SNVs on chromosome 11 is distributed around 1, as a result of the uniparental disomy (LOH with duplication). (b) The VAF of somatic mutations is quite different from that of germline SNVs, suggesting majority of somatic mutations happen after the duplication event and thus are present in only one copy of chromosome 11. The earlier occurrence of the duplication of chromosome 11, the more somatic mutations with VAF = 0.5 are detected. S7 Fig. provides a more illustrative explanation. (c) Inferred evolutionary history represented as a phylogenetic tree. The thickness of the branches reflects the proportion of tumor cells in each lineage. The length of the branches reflects how much molecular time it undergoes with each lineage.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005075.g003: Inferring evolutionary history of a PFN sample, RMS2110.(a) The VAF of germline SNVs on chromosome 11 is distributed around 1, as a result of the uniparental disomy (LOH with duplication). (b) The VAF of somatic mutations is quite different from that of germline SNVs, suggesting majority of somatic mutations happen after the duplication event and thus are present in only one copy of chromosome 11. The earlier occurrence of the duplication of chromosome 11, the more somatic mutations with VAF = 0.5 are detected. S7 Fig. provides a more illustrative explanation. (c) Inferred evolutionary history represented as a phylogenetic tree. The thickness of the branches reflects the proportion of tumor cells in each lineage. The length of the branches reflects how much molecular time it undergoes with each lineage.
Mentions: The majority of this cancer genome was the expected diploid status with LAF = 0.5, however regions with aneuploidy or allelic imbalance provided the opportunity to identify the timing of genomic events, by comparing the allelic copy number status with the VAF distribution of somatic mutations (S7 Fig.). For example, chromosome 9p and 11 have 2 copies with LAF of 0 (Fig. 1B), which is likely the loss of one allele followed by a duplication of the remaining allele although we cannot formally exclude the possibility of the duplication of both alleles with subsequent loss of the 2 copies of one allele. This observation was confirmed by the fact that most germline single nucleotide variants on chromosome 9p and 11 had VAF near 1 (Fig. 3A). In this case, the somatic mutations occurring before the “LOH+duplication” event must be present on both copies, with an expected VAF of 1, whereas those occurring after the “LOH+duplication” event would be present on only one copy, with an expected VAF of 0.5. The data confirmed this prediction with the VAF displaying a bi-modal distribution with two peaks at 0.5 and 1, respectively (Fig. 3B). The ratio between the numbers of mutations in the two clusters reflects the fraction of “molecular time” it undergoes to accumulate mutations before and after the “LOH+duplication” event, assuming a constant accumulation rate [2]. We acknowledge that the somatic mutation accumulation rate varies among small genomic segments [5,25–27], but for chromosome-level segments used in this study, the average accumulation rates of somatic mutation were observed to be consistent with one another (r2 > 0.98, S8 Fig.). Therefore, the molecular timing inferred for different aneuploidy events were comparable among the segments within the same tumor sample.

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