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PhyloWGS: reconstructing subclonal composition and evolution from whole-genome sequencing of tumors.

Deshwar AG, Vembu S, Yung CK, Jang GH, Stein L, Morris Q - Genome Biol. (2015)

Bottom Line: Tumors often contain multiple subpopulations of cancerous cells defined by distinct somatic mutations.We describe a new method, PhyloWGS, which can be applied to whole-genome sequencing data from one or more tumor samples to reconstruct complete genotypes of these subpopulations based on variant allele frequencies (VAFs) of point mutations and population frequencies of structural variations.We introduce a principled phylogenic correction for VAFs in loci affected by copy number alterations and we show that this correction greatly improves subclonal reconstruction compared to existing methods.

View Article: PubMed Central - PubMed

ABSTRACT
Tumors often contain multiple subpopulations of cancerous cells defined by distinct somatic mutations. We describe a new method, PhyloWGS, which can be applied to whole-genome sequencing data from one or more tumor samples to reconstruct complete genotypes of these subpopulations based on variant allele frequencies (VAFs) of point mutations and population frequencies of structural variations. We introduce a principled phylogenic correction for VAFs in loci affected by copy number alterations and we show that this correction greatly improves subclonal reconstruction compared to existing methods. PhyloWGS is free, open-source software, available at https://github.com/morrislab/phylowgs.

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Example of copy number variations affecting the distribution of variant allele frequencies.
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Fig2: Example of copy number variations affecting the distribution of variant allele frequencies.

Mentions: Subclonal reconstruction algorithms define mutation sets, and their associated subpopulations, by analyzing the population frequencies of somatic mutations detected in a tumor sample. In Figure 1, all mutations are SSMs, and all SSMs occur on one copy in diploid regions of the genome. In this case, the estimated population frequency of an SSM is simply twice its VAF. Figure 2, discussed in the next section, shows how CNVs overlapping SSM loci change this relationship. Note that although each VAF cluster corresponds to a subclonal lineage, and a subpopulation that was present at some point during the tumor’s evolution, this subpopulation need not be present when the tumor is sampled. In Figure 1, subpopulation B is no longer present in the tumor, although its two descendant subpopulations are. These vestigial VAF clusters, if they exist, always correspond to subpopulations at branchpoints in the phylogeny, however, not every branchpoint generates a vestigial cluster.Figure 2


PhyloWGS: reconstructing subclonal composition and evolution from whole-genome sequencing of tumors.

Deshwar AG, Vembu S, Yung CK, Jang GH, Stein L, Morris Q - Genome Biol. (2015)

Example of copy number variations affecting the distribution of variant allele frequencies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359439&req=5

Fig2: Example of copy number variations affecting the distribution of variant allele frequencies.
Mentions: Subclonal reconstruction algorithms define mutation sets, and their associated subpopulations, by analyzing the population frequencies of somatic mutations detected in a tumor sample. In Figure 1, all mutations are SSMs, and all SSMs occur on one copy in diploid regions of the genome. In this case, the estimated population frequency of an SSM is simply twice its VAF. Figure 2, discussed in the next section, shows how CNVs overlapping SSM loci change this relationship. Note that although each VAF cluster corresponds to a subclonal lineage, and a subpopulation that was present at some point during the tumor’s evolution, this subpopulation need not be present when the tumor is sampled. In Figure 1, subpopulation B is no longer present in the tumor, although its two descendant subpopulations are. These vestigial VAF clusters, if they exist, always correspond to subpopulations at branchpoints in the phylogeny, however, not every branchpoint generates a vestigial cluster.Figure 2

Bottom Line: Tumors often contain multiple subpopulations of cancerous cells defined by distinct somatic mutations.We describe a new method, PhyloWGS, which can be applied to whole-genome sequencing data from one or more tumor samples to reconstruct complete genotypes of these subpopulations based on variant allele frequencies (VAFs) of point mutations and population frequencies of structural variations.We introduce a principled phylogenic correction for VAFs in loci affected by copy number alterations and we show that this correction greatly improves subclonal reconstruction compared to existing methods.

View Article: PubMed Central - PubMed

ABSTRACT
Tumors often contain multiple subpopulations of cancerous cells defined by distinct somatic mutations. We describe a new method, PhyloWGS, which can be applied to whole-genome sequencing data from one or more tumor samples to reconstruct complete genotypes of these subpopulations based on variant allele frequencies (VAFs) of point mutations and population frequencies of structural variations. We introduce a principled phylogenic correction for VAFs in loci affected by copy number alterations and we show that this correction greatly improves subclonal reconstruction compared to existing methods. PhyloWGS is free, open-source software, available at https://github.com/morrislab/phylowgs.

Show MeSH
Related in: MedlinePlus