Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Matthew H. Bailey; William U. Meyerson; Lewis Jonathan Dursi; Liang Bo Wang; Guanlan Dong; Wen Wei Liang; Amila Weerasinghe; Shantao Li; Yize Li; Sean Kelso; MC3 Working Group; PCAWG novel somatic mutation calling methods working group; Gordon Saksena; Kyle Ellrott; Michael C. Wendl; David A. Wheeler; Gad Getz; Jared T. Simpson; Mark B. Gerstein; Li Ding; PCAWG Consortium

doi:10.1038/s41467-020-18151-y

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Matthew H. Bailey, William U. Meyerson, Lewis Jonathan Dursi, Liang Bo Wang, Guanlan Dong, Wen Wei Liang, Amila Weerasinghe, Shantao Li, Yize Li, Sean Kelso, MC3 Working Group, PCAWG novel somatic mutation calling methods working group, Gordon Saksena, Kyle Ellrott, Michael C. Wendl, David A. Wheeler, Gad Getz, Jared T. Simpson, Mark B. Gerstein (Lead / Corresponding author), Li Ding (Lead / Corresponding author)PCAWG Consortium

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Abstract

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.

Original language	English
Article number	4748
Number of pages	27
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-18151-y
Publication status	Published - 21 Sept 2020

Keywords

Cancer genomics
Communication and replication
Comparative genomics
Genetic databases

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-18151-yLicence: CC BY

Final Published VersionFinal published version, 2.42 MBLicence: CC BY

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Bailey, M. H., Meyerson, W. U., Dursi, L. J., Wang, L. B., Dong, G., Liang, W. W., Weerasinghe, A., Li, S., Li, Y., Kelso, S., MC3 Working Group, PCAWG novel somatic mutation calling methods working group, Saksena, G., Ellrott, K., Wendl, M. C., Wheeler, D. A., Getz, G., Simpson, J. T., Gerstein, M. B., ... PCAWG Consortium (2020). Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples. Nature Communications, 11, Article 4748. https://doi.org/10.1038/s41467-020-18151-y

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title = "Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples",

abstract = "The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.",

keywords = "Cancer genomics, Communication and replication, Comparative genomics, Genetic databases",

author = "Bailey, {Matthew H.} and Meyerson, {William U.} and Dursi, {Lewis Jonathan} and Wang, {Liang Bo} and Guanlan Dong and Liang, {Wen Wei} and Amila Weerasinghe and Shantao Li and Yize Li and Sean Kelso and {MC3 Working Group} and {PCAWG novel somatic mutation calling methods working group} and Gordon Saksena and Kyle Ellrott and Wendl, {Michael C.} and Wheeler, {David A.} and Gad Getz and Simpson, {Jared T.} and Gerstein, {Mark B.} and Li Ding and {PCAWG Consortium} and Purdie, {Colin A.} and Thompson, {Alastair M.}",

year = "2020",

month = sep,

day = "21",

doi = "10.1038/s41467-020-18151-y",

language = "English",

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journal = "Nature Communications",

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Bailey, MH, Meyerson, WU, Dursi, LJ, Wang, LB, Dong, G, Liang, WW, Weerasinghe, A, Li, S, Li, Y, Kelso, S, MC3 Working Group, PCAWG novel somatic mutation calling methods working group, Saksena, G, Ellrott, K, Wendl, MC, Wheeler, DA, Getz, G, Simpson, JT, Gerstein, MB, Ding, L & PCAWG Consortium 2020, 'Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples', Nature Communications, vol. 11, 4748. https://doi.org/10.1038/s41467-020-18151-y

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T1 - Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

AU - Bailey, Matthew H.

AU - Meyerson, William U.

AU - Dursi, Lewis Jonathan

AU - Wang, Liang Bo

AU - Dong, Guanlan

AU - Liang, Wen Wei

AU - Weerasinghe, Amila

AU - Li, Shantao

AU - Li, Yize

AU - Kelso, Sean

AU - MC3 Working Group

AU - PCAWG novel somatic mutation calling methods working group

AU - Saksena, Gordon

AU - Ellrott, Kyle

AU - Wendl, Michael C.

AU - Wheeler, David A.

AU - Getz, Gad

AU - Simpson, Jared T.

AU - Gerstein, Mark B.

AU - Ding, Li

AU - PCAWG Consortium

AU - Purdie, Colin A.

AU - Thompson, Alastair M.

PY - 2020/9/21

Y1 - 2020/9/21

N2 - The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.

AB - The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.

KW - Cancer genomics

KW - Communication and replication

KW - Comparative genomics

KW - Genetic databases

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U2 - 10.1038/s41467-020-18151-y

DO - 10.1038/s41467-020-18151-y

M3 - Article

C2 - 32958763

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 4748

ER -

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Author Correction: Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples (Nature Communications, (2020), 11, 1, (4748), 10.1038/s41467-020-18151-y)

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