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DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells

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DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells. / Chung, Jiil; Maruvka, Yosef E; Sudhaman, Sumedha; Kelly, Jacalyn; Haradhvala, Nicholas J; Bianchi, Vanessa; Edwards, Melissa; Forster, Victoria J; Nunes, Nuno M; Galati, Melissa A; Komosa, Martin; Deshmukh, Shriya; Cabric, Vanja; Davidson, Scott; Zatzman, Matthew; Light, Nicholas; Hayes, Reid; Brunga, Ledia; Anderson, Nathaniel D; Ho, Ben; Hodel, Karl P; Siddaway, Robert; Morrissy, A Sorana; Bowers, Daniel C; Larouche, Valérie; Bronsema, Annika; Osborn, Michael; Cole, Kristina A; Opocher, Enrico; Mason, Gary; Thomas, Gregory A; George, Ben; Ziegler, David S; Lindhorst, Scott; Vanan, Magimairajan; Yalon-Oren, Michal; Reddy, Alyssa T; Massimino, Maura; Tomboc, Patrick; Van Damme, An; Lossos, Alexander; Durno, Carol; Aronson, Melyssa; Morgenstern, Daniel A; Bouffet, Eric; Huang, Annie; Taylor, Michael D; Villani, Anita; Malkin, David; Hawkins, Cynthia E; Pursell, Zachary F; Shlien, Adam; Kunkel, Thomas A; Getz, Gad; Tabori, Uri.

in: CANCER DISCOV, Jahrgang 11, Nr. 5, 05.2021, S. 1176-1191.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Chung, J, Maruvka, YE, Sudhaman, S, Kelly, J, Haradhvala, NJ, Bianchi, V, Edwards, M, Forster, VJ, Nunes, NM, Galati, MA, Komosa, M, Deshmukh, S, Cabric, V, Davidson, S, Zatzman, M, Light, N, Hayes, R, Brunga, L, Anderson, ND, Ho, B, Hodel, KP, Siddaway, R, Morrissy, AS, Bowers, DC, Larouche, V, Bronsema, A, Osborn, M, Cole, KA, Opocher, E, Mason, G, Thomas, GA, George, B, Ziegler, DS, Lindhorst, S, Vanan, M, Yalon-Oren, M, Reddy, AT, Massimino, M, Tomboc, P, Van Damme, A, Lossos, A, Durno, C, Aronson, M, Morgenstern, DA, Bouffet, E, Huang, A, Taylor, MD, Villani, A, Malkin, D, Hawkins, CE, Pursell, ZF, Shlien, A, Kunkel, TA, Getz, G & Tabori, U 2021, 'DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells', CANCER DISCOV, Jg. 11, Nr. 5, S. 1176-1191. https://doi.org/10.1158/2159-8290.CD-20-0790

APA

Chung, J., Maruvka, Y. E., Sudhaman, S., Kelly, J., Haradhvala, N. J., Bianchi, V., Edwards, M., Forster, V. J., Nunes, N. M., Galati, M. A., Komosa, M., Deshmukh, S., Cabric, V., Davidson, S., Zatzman, M., Light, N., Hayes, R., Brunga, L., Anderson, N. D., ... Tabori, U. (2021). DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells. CANCER DISCOV, 11(5), 1176-1191. https://doi.org/10.1158/2159-8290.CD-20-0790

Vancouver

Chung J, Maruvka YE, Sudhaman S, Kelly J, Haradhvala NJ, Bianchi V et al. DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells. CANCER DISCOV. 2021 Mai;11(5):1176-1191. https://doi.org/10.1158/2159-8290.CD-20-0790

Bibtex

@article{17997ea8666e4ed1ba2bf7f48dc3bc67,
title = "DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells",
abstract = "Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.",
keywords = "Cell Transformation, Neoplastic, DNA Mismatch Repair, DNA-Directed DNA Polymerase, Gene Expression Regulation, Neoplastic, Humans, Microsatellite Instability, Neoplasms/genetics, Exome Sequencing",
author = "Jiil Chung and Maruvka, {Yosef E} and Sumedha Sudhaman and Jacalyn Kelly and Haradhvala, {Nicholas J} and Vanessa Bianchi and Melissa Edwards and Forster, {Victoria J} and Nunes, {Nuno M} and Galati, {Melissa A} and Martin Komosa and Shriya Deshmukh and Vanja Cabric and Scott Davidson and Matthew Zatzman and Nicholas Light and Reid Hayes and Ledia Brunga and Anderson, {Nathaniel D} and Ben Ho and Hodel, {Karl P} and Robert Siddaway and Morrissy, {A Sorana} and Bowers, {Daniel C} and Val{\'e}rie Larouche and Annika Bronsema and Michael Osborn and Cole, {Kristina A} and Enrico Opocher and Gary Mason and Thomas, {Gregory A} and Ben George and Ziegler, {David S} and Scott Lindhorst and Magimairajan Vanan and Michal Yalon-Oren and Reddy, {Alyssa T} and Maura Massimino and Patrick Tomboc and {Van Damme}, An and Alexander Lossos and Carol Durno and Melyssa Aronson and Morgenstern, {Daniel A} and Eric Bouffet and Annie Huang and Taylor, {Michael D} and Anita Villani and David Malkin and Hawkins, {Cynthia E} and Pursell, {Zachary F} and Adam Shlien and Kunkel, {Thomas A} and Gad Getz and Uri Tabori",
note = "{\textcopyright}2020 American Association for Cancer Research.",
year = "2021",
month = may,
doi = "10.1158/2159-8290.CD-20-0790",
language = "English",
volume = "11",
pages = "1176--1191",
journal = "CANCER DISCOV",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

RIS

TY - JOUR

T1 - DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells

AU - Chung, Jiil

AU - Maruvka, Yosef E

AU - Sudhaman, Sumedha

AU - Kelly, Jacalyn

AU - Haradhvala, Nicholas J

AU - Bianchi, Vanessa

AU - Edwards, Melissa

AU - Forster, Victoria J

AU - Nunes, Nuno M

AU - Galati, Melissa A

AU - Komosa, Martin

AU - Deshmukh, Shriya

AU - Cabric, Vanja

AU - Davidson, Scott

AU - Zatzman, Matthew

AU - Light, Nicholas

AU - Hayes, Reid

AU - Brunga, Ledia

AU - Anderson, Nathaniel D

AU - Ho, Ben

AU - Hodel, Karl P

AU - Siddaway, Robert

AU - Morrissy, A Sorana

AU - Bowers, Daniel C

AU - Larouche, Valérie

AU - Bronsema, Annika

AU - Osborn, Michael

AU - Cole, Kristina A

AU - Opocher, Enrico

AU - Mason, Gary

AU - Thomas, Gregory A

AU - George, Ben

AU - Ziegler, David S

AU - Lindhorst, Scott

AU - Vanan, Magimairajan

AU - Yalon-Oren, Michal

AU - Reddy, Alyssa T

AU - Massimino, Maura

AU - Tomboc, Patrick

AU - Van Damme, An

AU - Lossos, Alexander

AU - Durno, Carol

AU - Aronson, Melyssa

AU - Morgenstern, Daniel A

AU - Bouffet, Eric

AU - Huang, Annie

AU - Taylor, Michael D

AU - Villani, Anita

AU - Malkin, David

AU - Hawkins, Cynthia E

AU - Pursell, Zachary F

AU - Shlien, Adam

AU - Kunkel, Thomas A

AU - Getz, Gad

AU - Tabori, Uri

N1 - ©2020 American Association for Cancer Research.

PY - 2021/5

Y1 - 2021/5

N2 - Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.

AB - Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.

KW - Cell Transformation, Neoplastic

KW - DNA Mismatch Repair

KW - DNA-Directed DNA Polymerase

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Microsatellite Instability

KW - Neoplasms/genetics

KW - Exome Sequencing

U2 - 10.1158/2159-8290.CD-20-0790

DO - 10.1158/2159-8290.CD-20-0790

M3 - SCORING: Journal article

C2 - 33355208

VL - 11

SP - 1176

EP - 1191

JO - CANCER DISCOV

JF - CANCER DISCOV

SN - 2159-8274

IS - 5

ER -