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

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

109 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

Bibliographical note

Publisher Copyright:
© 2017 Nature America, Inc.

Funding

We thank C. Mayer for supplying and supporting the PHOBOS tool. G.G. was partially funded by the Paul C. Zamecnick, MD, Chair in Oncology at MGH and the NIH TCGA Genome Data Analysis Center (NIH U24CA143845). Y.E.M., P. Polak, and A. Kamburov were funded by G.G.’s start-up funds at Massachusetts General Hospital. K.W.M. was partially funded by an American Society of Radiation Oncology (ASTRO) Junior Faculty Career Research Training Award and a Harvard Catalyst KL2/CMeRIT Award. F.M. gratefully acknowledges support from the Dana-Farber Cancer Institute Physical Sciences Oncology Center (NIH U54CA193461). R.K. was supported by the European Commission Seventh Framework Programme (Integra-Life; grant 315997) and the Croatian Science Foundation (grant IP-2014-09-6400).

Funders	Funder number
Dana-Farber Cancer Institute Physical Sciences Oncology Center	U54CA193461
National Institutes of Health	U24CA143845
National Cancer Institute	K08CA219504
American Society for Radiation Oncology
Massachusetts General Hospital
Hrvatska Zaklada za Znanost	IP-2014-09-6400
Seventh Framework Programme	315997

UN SDGs

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

SDG 3 Good Health and Well-being

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10.1038/nbt.3966

Cite this

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

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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.",

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day = "1",

doi = "10.1038/nbt.3966",

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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

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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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Analysis of somatic microsatellite indels identifies driver events in human tumors

Abstract

Bibliographical note

Funding

UN SDGs

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