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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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The development of intratumor heterogeneity and subclonal reconstruction. Tumor composition over time (i), the resulting distribution of variant allele frequencies (VAFs) (ii), the result of successful inference of the VAF clusters (iii), and the desired output of subclonal inference (iiii). SSM, simple somatic mutation; VAF, variant allelic frequency.
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Fig1: The development of intratumor heterogeneity and subclonal reconstruction. Tumor composition over time (i), the resulting distribution of variant allele frequencies (VAFs) (ii), the result of successful inference of the VAF clusters (iii), and the desired output of subclonal inference (iiii). SSM, simple somatic mutation; VAF, variant allelic frequency.

Mentions: Figure 1 provides an overview of an evolving tumor, the measurement of somatic VAFs and the resulting subclonal reconstruction process. Panel (i) of this figure shows a visualization of the evolution of a tumor over time as non-cancerous cells (subpopulation A, shown in grey) are replaced by, at first, one clonal cancerous population (subpopulation B, shown in green), which then further develops into multiple cancerous subpopulations (C and D, shown in blue and yellow, respectively). Tumor cells define new subpopulations by acquiring new oncogenic mutations that allow their descendants to expand relative to the other tumor subpopulations. Each circle in panel (i) refers to a subpopulation. We associate subpopulations with the set of shared somatic mutations that distinguish it from its parent subpopulation (or, in the case of A, from the germ line (or reference) genome); this mutation set is indicated by the corresponding lower case letter (e.g. mutation set b first appears in subpopulation B). However, each subpopulation also inherits all of its parent’s mutations; the subclonal lineage of a mutation is the set of all subpopulations that contain it (e.g., the subclonal lineage of a is A, B, C and D).Figure 1


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)

The development of intratumor heterogeneity and subclonal reconstruction. Tumor composition over time (i), the resulting distribution of variant allele frequencies (VAFs) (ii), the result of successful inference of the VAF clusters (iii), and the desired output of subclonal inference (iiii). SSM, simple somatic mutation; VAF, variant allelic frequency.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: The development of intratumor heterogeneity and subclonal reconstruction. Tumor composition over time (i), the resulting distribution of variant allele frequencies (VAFs) (ii), the result of successful inference of the VAF clusters (iii), and the desired output of subclonal inference (iiii). SSM, simple somatic mutation; VAF, variant allelic frequency.
Mentions: Figure 1 provides an overview of an evolving tumor, the measurement of somatic VAFs and the resulting subclonal reconstruction process. Panel (i) of this figure shows a visualization of the evolution of a tumor over time as non-cancerous cells (subpopulation A, shown in grey) are replaced by, at first, one clonal cancerous population (subpopulation B, shown in green), which then further develops into multiple cancerous subpopulations (C and D, shown in blue and yellow, respectively). Tumor cells define new subpopulations by acquiring new oncogenic mutations that allow their descendants to expand relative to the other tumor subpopulations. Each circle in panel (i) refers to a subpopulation. We associate subpopulations with the set of shared somatic mutations that distinguish it from its parent subpopulation (or, in the case of A, from the germ line (or reference) genome); this mutation set is indicated by the corresponding lower case letter (e.g. mutation set b first appears in subpopulation B). However, each subpopulation also inherits all of its parent’s mutations; the subclonal lineage of a mutation is the set of all subpopulations that contain it (e.g., the subclonal lineage of a is A, B, C and D).Figure 1

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