Analysis of somatic microsatellite indels identifies driver events in human tumors

Yosef E. Maruvka; Kent W. Mouw; Rosa Karlic; Prasanna Parasuraman; Atanas Kamburov; Paz Polak; Nicholas J. Haradhvala; Julian M. Hess; Esther Rheinbay; Yehuda Brody; Amnon Koren; Lior Z. Braunstein; Alan D'Andrea; Michael S. Lawrence; Adam Bass; Andre Bernards; Franziska Michor; Gad Getz

doi:10.1038/nbt.3966

Analysis of somatic microsatellite indels identifies driver events in human tumors

Yosef E. Maruvka, Kent W. Mouw, Rosa Karlic, Prasanna Parasuraman, Atanas Kamburov, Paz Polak, Nicholas J. Haradhvala, Julian M. Hess, Esther Rheinbay, Yehuda Brody, Amnon Koren, Lior Z. Braunstein, Alan D'Andrea, Michael S. Lawrence, Adam Bass, Andre Bernards, Franziska Michor, Gad Getz

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96 Scopus citations

Abstract

Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: Four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).

Original language	English
Pages (from-to)	951-959
Number of pages	9
Journal	Nature Biotechnology
Volume	35
Issue number	10
DOIs	https://doi.org/10.1038/nbt.3966
State	Published - 1 Oct 2017
Externally published	Yes

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Maruvka, Y. E., Mouw, K. W., Karlic, R., Parasuraman, P., Kamburov, A., Polak, P., Haradhvala, N. J., Hess, J. M., Rheinbay, E., Brody, Y., Koren, A., Braunstein, L. Z., D'Andrea, A., Lawrence, M. S., Bass, A., Bernards, A., Michor, F., & Getz, G. (2017). Analysis of somatic microsatellite indels identifies driver events in human tumors. Nature Biotechnology, 35(10), 951-959. https://doi.org/10.1038/nbt.3966

@article{a974127e1d5f4c1da997e36d9989bac3,

title = "Analysis of somatic microsatellite indels identifies driver events in human tumors",

abstract = "Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: Four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).",

author = "Maruvka, {Yosef E.} and Mouw, {Kent W.} and Rosa Karlic and Prasanna Parasuraman and Atanas Kamburov and Paz Polak and Haradhvala, {Nicholas J.} and Hess, {Julian M.} and Esther Rheinbay and Yehuda Brody and Amnon Koren and Braunstein, {Lior Z.} and Alan D'Andrea and Lawrence, {Michael S.} and Adam Bass and Andre Bernards and Franziska Michor and Gad Getz",

note = "Publisher Copyright: {\textcopyright} 2017 Nature America, Inc.",

year = "2017",

month = oct,

day = "1",

doi = "10.1038/nbt.3966",

language = "English",

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Maruvka, YE, Mouw, KW, Karlic, R, Parasuraman, P, Kamburov, A, Polak, P, Haradhvala, NJ, Hess, JM, Rheinbay, E, Brody, Y, Koren, A, Braunstein, LZ, D'Andrea, A, Lawrence, MS, Bass, A, Bernards, A, Michor, F & Getz, G 2017, 'Analysis of somatic microsatellite indels identifies driver events in human tumors', Nature Biotechnology, vol. 35, no. 10, pp. 951-959. https://doi.org/10.1038/nbt.3966

TY - JOUR

T1 - Analysis of somatic microsatellite indels identifies driver events in human tumors

AU - Maruvka, Yosef E.

AU - Mouw, Kent W.

AU - Karlic, Rosa

AU - Parasuraman, Prasanna

AU - Kamburov, Atanas

AU - Polak, Paz

AU - Haradhvala, Nicholas J.

AU - Hess, Julian M.

AU - Rheinbay, Esther

AU - Brody, Yehuda

AU - Koren, Amnon

AU - Braunstein, Lior Z.

AU - D'Andrea, Alan

AU - Lawrence, Michael S.

AU - Bass, Adam

AU - Bernards, Andre

AU - Michor, Franziska

AU - Getz, Gad

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: Four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).

AB - Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: Four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).

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U2 - 10.1038/nbt.3966

DO - 10.1038/nbt.3966

M3 - Article

C2 - 28892075

AN - SCOPUS:85031106017

SN - 1087-0156

VL - 35

SP - 951

EP - 959

JO - Nature Biotechnology

JF - Nature Biotechnology

IS - 10

ER -

Analysis of somatic microsatellite indels identifies driver events in human tumors

Abstract

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