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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 subclonal structure and inferred phylogenies using different methods.(A) Example of tumor subclonal structure. (B) Tumor phylogeny recovered by PhyloWGS. (C) Tumor phylogeny recovered by PhyloSub. (D) Subclonal structure implied by only CNVs. CNV, copy number variation; SSM, simple somatic mutation.
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Fig4: Example subclonal structure and inferred phylogenies using different methods.(A) Example of tumor subclonal structure. (B) Tumor phylogeny recovered by PhyloWGS. (C) Tumor phylogeny recovered by PhyloSub. (D) Subclonal structure implied by only CNVs. CNV, copy number variation; SSM, simple somatic mutation.

Mentions: Consider a tumor where 25% of the cells are normal (no SSMs and diploid, population A), 25% come from a subpopulation with only SSMs (SSM1 to 4, population B) and 50% belong to a descendant subpopulation of B containing all the SSMs from B and adding new simple somatic variants (SSM5 to 8) and a homozygous deletion (CNV1) in the region containing SSM4, labeled population C. The evolutionary tree of this population is shown in Figure 4A. In reads sampled from this population, the expected VAFs for SSM1 to 3 are 37.5% (i.e. half of their population frequency) and for SSM5 to 8 they are 25%; however, based on the rules described in the Materials and methods section, the expected VAF of SSM4 is 25%. This is because all the copies of the genome at that position come from population A or B. Populations A and B are present in equal proportions and only one copy in population B contains variant reads, so 25% of the genomes contain the variant allele. As such, methods that do not incorporate the CNV change at the SSM4 locus will incorrectly assign SSM4 to population C. Also, methods that incorporate only CNV information cannot detect the subpopulation B, which is defined by SSM alone.Figure 4


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 subclonal structure and inferred phylogenies using different methods.(A) Example of tumor subclonal structure. (B) Tumor phylogeny recovered by PhyloWGS. (C) Tumor phylogeny recovered by PhyloSub. (D) Subclonal structure implied by only CNVs. CNV, copy number variation; SSM, simple somatic mutation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Example subclonal structure and inferred phylogenies using different methods.(A) Example of tumor subclonal structure. (B) Tumor phylogeny recovered by PhyloWGS. (C) Tumor phylogeny recovered by PhyloSub. (D) Subclonal structure implied by only CNVs. CNV, copy number variation; SSM, simple somatic mutation.
Mentions: Consider a tumor where 25% of the cells are normal (no SSMs and diploid, population A), 25% come from a subpopulation with only SSMs (SSM1 to 4, population B) and 50% belong to a descendant subpopulation of B containing all the SSMs from B and adding new simple somatic variants (SSM5 to 8) and a homozygous deletion (CNV1) in the region containing SSM4, labeled population C. The evolutionary tree of this population is shown in Figure 4A. In reads sampled from this population, the expected VAFs for SSM1 to 3 are 37.5% (i.e. half of their population frequency) and for SSM5 to 8 they are 25%; however, based on the rules described in the Materials and methods section, the expected VAF of SSM4 is 25%. This is because all the copies of the genome at that position come from population A or B. Populations A and B are present in equal proportions and only one copy in population B contains variant reads, so 25% of the genomes contain the variant allele. As such, methods that do not incorporate the CNV change at the SSM4 locus will incorrectly assign SSM4 to population C. Also, methods that incorporate only CNV information cannot detect the subpopulation B, which is defined by SSM alone.Figure 4

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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Related in: MedlinePlus