Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair

Nicholas J. Haradhvala; Paz Polak; Petar Stojanov; Kyle R. Covington; Eve Shinbrot; Julian M. Hess; Esther Rheinbay; Jaegil Kim; Yosef E. Maruvka; Lior Z. Braunstein; Atanas Kamburov; Philip C. Hanawalt; David A. Wheeler; Amnon Koren; Michael S. Lawrence; Gad Getz

doi:10.1016/j.cell.2015.12.050

Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair

Nicholas J. Haradhvala, Paz Polak, Petar Stojanov, Kyle R. Covington, Eve Shinbrot, Julian M. Hess, Esther Rheinbay, Jaegil Kim, Yosef E. Maruvka, Lior Z. Braunstein, Atanas Kamburov, Philip C. Hanawalt, David A. Wheeler, Amnon Koren, Michael S. Lawrence, Gad Getz

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

294 Scopus citations

Abstract

Summary Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional ("T-class") asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative ("R-class") asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.

Original language	English
Pages (from-to)	538-549
Number of pages	12
Journal	Cell
Volume	164
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2015.12.050
State	Published - 28 Jan 2016
Externally published	Yes

Access to Document

10.1016/j.cell.2015.12.050

Cite this

Haradhvala, N. J., Polak, P., Stojanov, P., Covington, K. R., Shinbrot, E., Hess, J. M., Rheinbay, E., Kim, J., Maruvka, Y. E., Braunstein, L. Z., Kamburov, A., Hanawalt, P. C., Wheeler, D. A., Koren, A., Lawrence, M. S., & Getz, G. (2016). Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair. Cell, 164(3), 538-549. https://doi.org/10.1016/j.cell.2015.12.050

@article{1555ee9167524236a33783630da24315,

title = "Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair",

abstract = "Summary Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional ({"}T-class{"}) asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative ({"}R-class{"}) asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.",

author = "Haradhvala, {Nicholas J.} and Paz Polak and Petar Stojanov and Covington, {Kyle R.} and Eve Shinbrot and Hess, {Julian M.} and Esther Rheinbay and Jaegil Kim and Maruvka, {Yosef E.} and Braunstein, {Lior Z.} and Atanas Kamburov and Hanawalt, {Philip C.} and Wheeler, {David A.} and Amnon Koren and Lawrence, {Michael S.} and Gad Getz",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = jan,

day = "28",

doi = "10.1016/j.cell.2015.12.050",

language = "English",

volume = "164",

pages = "538--549",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "3",

}

Haradhvala, NJ, Polak, P, Stojanov, P, Covington, KR, Shinbrot, E, Hess, JM, Rheinbay, E, Kim, J, Maruvka, YE, Braunstein, LZ, Kamburov, A, Hanawalt, PC, Wheeler, DA, Koren, A, Lawrence, MS & Getz, G 2016, 'Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair', Cell, vol. 164, no. 3, pp. 538-549. https://doi.org/10.1016/j.cell.2015.12.050

TY - JOUR

T1 - Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair

AU - Haradhvala, Nicholas J.

AU - Polak, Paz

AU - Stojanov, Petar

AU - Covington, Kyle R.

AU - Shinbrot, Eve

AU - Hess, Julian M.

AU - Rheinbay, Esther

AU - Kim, Jaegil

AU - Maruvka, Yosef E.

AU - Braunstein, Lior Z.

AU - Kamburov, Atanas

AU - Hanawalt, Philip C.

AU - Wheeler, David A.

AU - Koren, Amnon

AU - Lawrence, Michael S.

AU - Getz, Gad

PY - 2016/1/28

Y1 - 2016/1/28

N2 - Summary Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional ("T-class") asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative ("R-class") asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.

AB - Summary Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional ("T-class") asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative ("R-class") asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.

UR - http://www.scopus.com/inward/record.url?scp=84955592205&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2015.12.050

DO - 10.1016/j.cell.2015.12.050

M3 - Article

C2 - 26806129

AN - SCOPUS:84955592205

SN - 0092-8674

VL - 164

SP - 538

EP - 549

JO - Cell

JF - Cell

IS - 3

ER -

Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair

Abstract

Access to Document

Fingerprint

Cite this