A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing

Tyler S. Alioto; Ivo Buchhalter; Sophia Derdak; Barbara Hutter; Matthew D. Eldridge; Eivind Hovig; Lawrence E. Heisler; Timothy A. Beck; Jared T. Simpson; Laurie Tonon; Anne-Sophie Sertier; Ann-Marie Patch; Natalie Jaeger; Philip Ginsbach; Ruben Drews; Nagarajan Paramasivam; Rolf Kabbe; Sasithorn Chotewutmontri; Nicolle Diessl; Christopher Previti; Sabine Schmidt; Benedikt Brors; Lars Feuerbach; Michael Heinold; Susanne Groebner; Andrey Korshunov; Patrick S. Tarpey; Adam P. Butler; Jonathan Hinton; David Jones; Andrew Menzies; Keiran Raine; Rebecca Shepherd; Lucy Stebbings; Jon W. Teague; Paolo Ribeca; Francesc Castro Giner; Sergi Beltran; Emanuele Raineri; Marc Dabad; Simon C. Heath; Marta Gut; Robert E. Denroche; Nicholas J. Harding; Takafumi N. Yamaguchi; Akihiro Fujimoto; Hidewaki Nakagawa; Ctor Quesada; Rafael Valdes-Mas; Sigve Nakken; Daniel Vodak; Lawrence Bower; Andrew G. Lynch; Charlotte L. Anderson; Nicola Waddell; John V. Pearson; Sean M. Grimmond; Myron Peto; Paul Spellman; Minghui He; Cyriac Kandoth; Semin Lee; John Zhang; Louis Letourneau; Singer Ma; Sahil Seth; David Torrents; Liu Xi; David A. Wheeler; Carlos Lopez-Otin; Elias Campo; Peter J. Campbell; Paul C. Boutros; Xose S. Puente; Daniela S. Gerhard; Stefan M. Pfister; John D. McPherson; Thomas J. Hudson; Matthias Schlesner; Peter Lichter; Roland Eils; David T. W. Jones; Ivo G. Gut

doi:10.1038/ncomms10001

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing

Tyler S. Alioto, Ivo Buchhalter, Sophia Derdak, Barbara Hutter, Matthew D. Eldridge, Eivind Hovig, Lawrence E. Heisler, Timothy A. Beck, Jared T. Simpson, Laurie Tonon, Anne-Sophie Sertier, Ann-Marie Patch, Natalie Jaeger, Philip Ginsbach, Ruben Drews, Nagarajan Paramasivam, Rolf Kabbe, Sasithorn Chotewutmontri, Nicolle Diessl, Christopher PrevitiSabine Schmidt, Benedikt Brors, Lars Feuerbach, Michael Heinold, Susanne Groebner, Andrey Korshunov, Patrick S. Tarpey, Adam P. Butler, Jonathan Hinton, David Jones, Andrew Menzies, Keiran Raine, Rebecca Shepherd, Lucy Stebbings, Jon W. Teague, Paolo Ribeca, Francesc Castro Giner, Sergi Beltran, Emanuele Raineri, Marc Dabad, Simon C. Heath, Marta Gut, Robert E. Denroche, Nicholas J. Harding, Takafumi N. Yamaguchi, Akihiro Fujimoto, Hidewaki Nakagawa, Ctor Quesada, Rafael Valdes-Mas, Sigve Nakken, Daniel Vodak, Lawrence Bower, Andrew G. Lynch, Charlotte L. Anderson, Nicola Waddell, John V. Pearson, Sean M. Grimmond, Myron Peto, Paul Spellman, Minghui He, Cyriac Kandoth, Semin Lee, John Zhang, Louis Letourneau, Singer Ma, Sahil Seth, David Torrents, Liu Xi, David A. Wheeler, Carlos Lopez-Otin, Elias Campo, Peter J. Campbell, Paul C. Boutros, Xose S. Puente, Daniela S. Gerhard, Stefan M. Pfister, John D. McPherson, Thomas J. Hudson, Matthias Schlesner, Peter Lichter, Roland Eils, David T. W. Jones, Ivo G. Gut^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to similar to 100 x shows benefits, as long as the tumour: control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

Original language	English
Article number	10001
Number of pages	13
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms10001
Publication status	Published - 9 Dec 2015

Keywords

Cancer genetics
DNA sequencing
Genome informatics
Mutation

UN SDGs

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

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Cite this

Alioto, T. S., Buchhalter, I., Derdak, S., Hutter, B., Eldridge, M. D., Hovig, E., Heisler, L. E., Beck, T. A., Simpson, J. T., Tonon, L., Sertier, A.-S., Patch, A.-M., Jaeger, N., Ginsbach, P., Drews, R., Paramasivam, N., Kabbe, R., Chotewutmontri, S., Diessl, N., ... Gut, I. G. (2015). A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing. Nature Communications, 6, Article 10001. https://doi.org/10.1038/ncomms10001

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title = "A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing",

abstract = "As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to similar to 100 x shows benefits, as long as the tumour: control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.",

keywords = "Cancer genetics, DNA sequencing, Genome informatics, Mutation",

author = "Alioto, {Tyler S.} and Ivo Buchhalter and Sophia Derdak and Barbara Hutter and Eldridge, {Matthew D.} and Eivind Hovig and Heisler, {Lawrence E.} and Beck, {Timothy A.} and Simpson, {Jared T.} and Laurie Tonon and Anne-Sophie Sertier and Ann-Marie Patch and Natalie Jaeger and Philip Ginsbach and Ruben Drews and Nagarajan Paramasivam and Rolf Kabbe and Sasithorn Chotewutmontri and Nicolle Diessl and Christopher Previti and Sabine Schmidt and Benedikt Brors and Lars Feuerbach and Michael Heinold and Susanne Groebner and Andrey Korshunov and Tarpey, {Patrick S.} and Butler, {Adam P.} and Jonathan Hinton and David Jones and Andrew Menzies and Keiran Raine and Rebecca Shepherd and Lucy Stebbings and Teague, {Jon W.} and Paolo Ribeca and Giner, {Francesc Castro} and Sergi Beltran and Emanuele Raineri and Marc Dabad and Heath, {Simon C.} and Marta Gut and Denroche, {Robert E.} and Harding, {Nicholas J.} and Yamaguchi, {Takafumi N.} and Akihiro Fujimoto and Hidewaki Nakagawa and Ctor Quesada and Rafael Valdes-Mas and Sigve Nakken and Daniel Vodak and Lawrence Bower and Lynch, {Andrew G.} and Anderson, {Charlotte L.} and Nicola Waddell and Pearson, {John V.} and Grimmond, {Sean M.} and Myron Peto and Paul Spellman and Minghui He and Cyriac Kandoth and Semin Lee and John Zhang and Louis Letourneau and Singer Ma and Sahil Seth and David Torrents and Liu Xi and Wheeler, {David A.} and Carlos Lopez-Otin and Elias Campo and Campbell, {Peter J.} and Boutros, {Paul C.} and Puente, {Xose S.} and Gerhard, {Daniela S.} and Pfister, {Stefan M.} and McPherson, {John D.} and Hudson, {Thomas J.} and Matthias Schlesner and Peter Lichter and Roland Eils and Jones, {David T. W.} and Gut, {Ivo G.}",

note = "Sequence data for this study have been deposited in the European Genome-phenome Archive (EGA) under the accession number EGAS00001001539.",

year = "2015",

month = dec,

day = "9",

doi = "10.1038/ncomms10001",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature publishing group",

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Alioto, TS, Buchhalter, I, Derdak, S, Hutter, B, Eldridge, MD, Hovig, E, Heisler, LE, Beck, TA, Simpson, JT, Tonon, L, Sertier, A-S, Patch, A-M, Jaeger, N, Ginsbach, P, Drews, R, Paramasivam, N, Kabbe, R, Chotewutmontri, S, Diessl, N, Previti, C, Schmidt, S, Brors, B, Feuerbach, L, Heinold, M, Groebner, S, Korshunov, A, Tarpey, PS, Butler, AP, Hinton, J, Jones, D, Menzies, A, Raine, K, Shepherd, R, Stebbings, L, Teague, JW, Ribeca, P, Giner, FC, Beltran, S, Raineri, E, Dabad, M, Heath, SC, Gut, M, Denroche, RE, Harding, NJ, Yamaguchi, TN, Fujimoto, A, Nakagawa, H, Quesada, C, Valdes-Mas, R, Nakken, S, Vodak, D, Bower, L, Lynch, AG, Anderson, CL, Waddell, N, Pearson, JV, Grimmond, SM, Peto, M, Spellman, P, He, M, Kandoth, C, Lee, S, Zhang, J, Letourneau, L, Ma, S, Seth, S, Torrents, D, Xi, L, Wheeler, DA, Lopez-Otin, C, Campo, E, Campbell, PJ, Boutros, PC, Puente, XS, Gerhard, DS, Pfister, SM, McPherson, JD, Hudson, TJ, Schlesner, M, Lichter, P, Eils, R, Jones, DTW & Gut, IG 2015, 'A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing', Nature Communications, vol. 6, 10001. https://doi.org/10.1038/ncomms10001

TY - JOUR

T1 - A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing

AU - Alioto, Tyler S.

AU - Buchhalter, Ivo

AU - Derdak, Sophia

AU - Hutter, Barbara

AU - Eldridge, Matthew D.

AU - Hovig, Eivind

AU - Heisler, Lawrence E.

AU - Beck, Timothy A.

AU - Simpson, Jared T.

AU - Tonon, Laurie

AU - Sertier, Anne-Sophie

AU - Patch, Ann-Marie

AU - Jaeger, Natalie

AU - Ginsbach, Philip

AU - Drews, Ruben

AU - Paramasivam, Nagarajan

AU - Kabbe, Rolf

AU - Chotewutmontri, Sasithorn

AU - Diessl, Nicolle

AU - Previti, Christopher

AU - Schmidt, Sabine

AU - Brors, Benedikt

AU - Feuerbach, Lars

AU - Heinold, Michael

AU - Groebner, Susanne

AU - Korshunov, Andrey

AU - Tarpey, Patrick S.

AU - Butler, Adam P.

AU - Hinton, Jonathan

AU - Jones, David

AU - Menzies, Andrew

AU - Raine, Keiran

AU - Shepherd, Rebecca

AU - Stebbings, Lucy

AU - Teague, Jon W.

AU - Ribeca, Paolo

AU - Giner, Francesc Castro

AU - Beltran, Sergi

AU - Raineri, Emanuele

AU - Dabad, Marc

AU - Heath, Simon C.

AU - Gut, Marta

AU - Denroche, Robert E.

AU - Harding, Nicholas J.

AU - Yamaguchi, Takafumi N.

AU - Fujimoto, Akihiro

AU - Nakagawa, Hidewaki

AU - Quesada, Ctor

AU - Valdes-Mas, Rafael

AU - Nakken, Sigve

AU - Vodak, Daniel

AU - Bower, Lawrence

AU - Lynch, Andrew G.

AU - Anderson, Charlotte L.

AU - Waddell, Nicola

AU - Pearson, John V.

AU - Grimmond, Sean M.

AU - Peto, Myron

AU - Spellman, Paul

AU - He, Minghui

AU - Kandoth, Cyriac

AU - Lee, Semin

AU - Zhang, John

AU - Letourneau, Louis

AU - Ma, Singer

AU - Seth, Sahil

AU - Torrents, David

AU - Xi, Liu

AU - Wheeler, David A.

AU - Lopez-Otin, Carlos

AU - Campo, Elias

AU - Campbell, Peter J.

AU - Boutros, Paul C.

AU - Puente, Xose S.

AU - Gerhard, Daniela S.

AU - Pfister, Stefan M.

AU - McPherson, John D.

AU - Hudson, Thomas J.

AU - Schlesner, Matthias

AU - Lichter, Peter

AU - Eils, Roland

AU - Jones, David T. W.

AU - Gut, Ivo G.

N1 - Sequence data for this study have been deposited in the European Genome-phenome Archive (EGA) under the accession number EGAS00001001539.

PY - 2015/12/9

Y1 - 2015/12/9

N2 - As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to similar to 100 x shows benefits, as long as the tumour: control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

AB - As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to similar to 100 x shows benefits, as long as the tumour: control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

KW - Cancer genetics

KW - DNA sequencing

KW - Genome informatics

KW - Mutation

UR - https://www.nature.com/articles/ncomms10001#supplementary-information

U2 - 10.1038/ncomms10001

DO - 10.1038/ncomms10001

M3 - Article

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 10001

ER -

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing

Abstract

Keywords

UN SDGs

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