Tampere University of Technology

TUTCRIS Research Portal

Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

Research output: Contribution to journalArticleScientificpeer-review

Standard

Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. / Ju, Young S.eok; Alexandrov, Ludmil B.; Gerstung, Moritz; Martincorena, Inigo; Nik-Zainal, Serena; Ramakrishna, Manasa; Davies, Helen R.; Papaemmanuil, Elli; Gundem, Gunes; Shlien, Adam; Bolli, Niccolo; Behjati, Sam; Tarpey, Patrick S.; Nangalia, Jyoti; Massie, Charles E.; Butler, Adam P.; Teague, Jon W.; Vassiliou, George S.; Green, Anthony R.; Du, Ming Qing; Unnikrishnan, Ashwin; Pimanda, John E.; Teh, Bin T.ean; Munshi, Nikhil; Greaves, Mel; Vyas, Paresh; El-Naggar, Adel K.; Santarius, Tom; Collins, V. Peter; Grundy, Richard; Taylor, Jack A.; Hayes, D. Neil; Malkin, David; Foster, Christopher S.; Warren, Anne Y.; Whitaker, Hayley C.; Brewer, Daniel; Eeles, Rosalind; Cooper, Colin; Neal, David; Visakorpi, Tapio; Isaacs, William B.; Bova, G. Steven; Flanagan, Adrienne M.; Futreal, P. Andrew; Lynch, Andy G.; Chinnery, Patrick F.; McDermott, Ultan; Stratton, Michael R.; Campbell, Peter J.

In: eLIFE, Vol. 3, 2014.

Research output: Contribution to journalArticleScientificpeer-review

Harvard

Ju, YSE, Alexandrov, LB, Gerstung, M, Martincorena, I, Nik-Zainal, S, Ramakrishna, M, Davies, HR, Papaemmanuil, E, Gundem, G, Shlien, A, Bolli, N, Behjati, S, Tarpey, PS, Nangalia, J, Massie, CE, Butler, AP, Teague, JW, Vassiliou, GS, Green, AR, Du, MQ, Unnikrishnan, A, Pimanda, JE, Teh, BTE, Munshi, N, Greaves, M, Vyas, P, El-Naggar, AK, Santarius, T, Collins, VP, Grundy, R, Taylor, JA, Hayes, DN, Malkin, D, Foster, CS, Warren, AY, Whitaker, HC, Brewer, D, Eeles, R, Cooper, C, Neal, D, Visakorpi, T, Isaacs, WB, Bova, GS, Flanagan, AM, Futreal, PA, Lynch, AG, Chinnery, PF, McDermott, U, Stratton, MR & Campbell, PJ 2014, 'Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer', eLIFE, vol. 3. https://doi.org/10.7554/eLife.02935

APA

Ju, Y. S. E., Alexandrov, L. B., Gerstung, M., Martincorena, I., Nik-Zainal, S., Ramakrishna, M., ... Campbell, P. J. (2014). Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLIFE, 3. https://doi.org/10.7554/eLife.02935

Vancouver

Ju YSE, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLIFE. 2014;3. https://doi.org/10.7554/eLife.02935

Author

Ju, Young S.eok ; Alexandrov, Ludmil B. ; Gerstung, Moritz ; Martincorena, Inigo ; Nik-Zainal, Serena ; Ramakrishna, Manasa ; Davies, Helen R. ; Papaemmanuil, Elli ; Gundem, Gunes ; Shlien, Adam ; Bolli, Niccolo ; Behjati, Sam ; Tarpey, Patrick S. ; Nangalia, Jyoti ; Massie, Charles E. ; Butler, Adam P. ; Teague, Jon W. ; Vassiliou, George S. ; Green, Anthony R. ; Du, Ming Qing ; Unnikrishnan, Ashwin ; Pimanda, John E. ; Teh, Bin T.ean ; Munshi, Nikhil ; Greaves, Mel ; Vyas, Paresh ; El-Naggar, Adel K. ; Santarius, Tom ; Collins, V. Peter ; Grundy, Richard ; Taylor, Jack A. ; Hayes, D. Neil ; Malkin, David ; Foster, Christopher S. ; Warren, Anne Y. ; Whitaker, Hayley C. ; Brewer, Daniel ; Eeles, Rosalind ; Cooper, Colin ; Neal, David ; Visakorpi, Tapio ; Isaacs, William B. ; Bova, G. Steven ; Flanagan, Adrienne M. ; Futreal, P. Andrew ; Lynch, Andy G. ; Chinnery, Patrick F. ; McDermott, Ultan ; Stratton, Michael R. ; Campbell, Peter J. / Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. In: eLIFE. 2014 ; Vol. 3.

Bibtex - Download

@article{d181112c71f449368e2e12e5c2fbffbc,
title = "Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer",
abstract = "Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.",
keywords = "cancer genome, evolution, evolutionary biology, genomics, human, mitochondrial DNA, mutational signature, sequencing, somatic mutation",
author = "Ju, {Young S.eok} and Alexandrov, {Ludmil B.} and Moritz Gerstung and Inigo Martincorena and Serena Nik-Zainal and Manasa Ramakrishna and Davies, {Helen R.} and Elli Papaemmanuil and Gunes Gundem and Adam Shlien and Niccolo Bolli and Sam Behjati and Tarpey, {Patrick S.} and Jyoti Nangalia and Massie, {Charles E.} and Butler, {Adam P.} and Teague, {Jon W.} and Vassiliou, {George S.} and Green, {Anthony R.} and Du, {Ming Qing} and Ashwin Unnikrishnan and Pimanda, {John E.} and Teh, {Bin T.ean} and Nikhil Munshi and Mel Greaves and Paresh Vyas and El-Naggar, {Adel K.} and Tom Santarius and Collins, {V. Peter} and Richard Grundy and Taylor, {Jack A.} and Hayes, {D. Neil} and David Malkin and Foster, {Christopher S.} and Warren, {Anne Y.} and Whitaker, {Hayley C.} and Daniel Brewer and Rosalind Eeles and Colin Cooper and David Neal and Tapio Visakorpi and Isaacs, {William B.} and Bova, {G. Steven} and Flanagan, {Adrienne M.} and Futreal, {P. Andrew} and Lynch, {Andy G.} and Chinnery, {Patrick F.} and Ultan McDermott and Stratton, {Michael R.} and Campbell, {Peter J.}",
year = "2014",
doi = "10.7554/eLife.02935",
language = "English",
volume = "3",
journal = "eLIFE",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

AU - Ju, Young S.eok

AU - Alexandrov, Ludmil B.

AU - Gerstung, Moritz

AU - Martincorena, Inigo

AU - Nik-Zainal, Serena

AU - Ramakrishna, Manasa

AU - Davies, Helen R.

AU - Papaemmanuil, Elli

AU - Gundem, Gunes

AU - Shlien, Adam

AU - Bolli, Niccolo

AU - Behjati, Sam

AU - Tarpey, Patrick S.

AU - Nangalia, Jyoti

AU - Massie, Charles E.

AU - Butler, Adam P.

AU - Teague, Jon W.

AU - Vassiliou, George S.

AU - Green, Anthony R.

AU - Du, Ming Qing

AU - Unnikrishnan, Ashwin

AU - Pimanda, John E.

AU - Teh, Bin T.ean

AU - Munshi, Nikhil

AU - Greaves, Mel

AU - Vyas, Paresh

AU - El-Naggar, Adel K.

AU - Santarius, Tom

AU - Collins, V. Peter

AU - Grundy, Richard

AU - Taylor, Jack A.

AU - Hayes, D. Neil

AU - Malkin, David

AU - Foster, Christopher S.

AU - Warren, Anne Y.

AU - Whitaker, Hayley C.

AU - Brewer, Daniel

AU - Eeles, Rosalind

AU - Cooper, Colin

AU - Neal, David

AU - Visakorpi, Tapio

AU - Isaacs, William B.

AU - Bova, G. Steven

AU - Flanagan, Adrienne M.

AU - Futreal, P. Andrew

AU - Lynch, Andy G.

AU - Chinnery, Patrick F.

AU - McDermott, Ultan

AU - Stratton, Michael R.

AU - Campbell, Peter J.

PY - 2014

Y1 - 2014

N2 - Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.

AB - Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.

KW - cancer genome

KW - evolution

KW - evolutionary biology

KW - genomics

KW - human

KW - mitochondrial DNA

KW - mutational signature

KW - sequencing

KW - somatic mutation

UR - http://www.scopus.com/inward/record.url?scp=84994324806&partnerID=8YFLogxK

U2 - 10.7554/eLife.02935

DO - 10.7554/eLife.02935

M3 - Article

VL - 3

JO - eLIFE

JF - eLIFE

SN - 2050-084X

ER -