Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Publication: Research - peer-reviewJournal article – Annual report year: 2012

Standard

Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. / Gerlinger, Marco; Rowan, Andrew J.; Horswell, Stuart; Larkin, James; Endesfelder, David; Gronroos, Eva; Martinez, Pierre; Matthews, Nicholas; Stewart, Aengus; Tarpey, Patrick; Varela, Ignacio; Phillimore, Benjamin; Begum, Sharmin; McDonald, Neil Q.; Butler, Adam; Jones, David; Raine, Keiran; Latimer, Calli; Santos, Claudio R.; Nohadani, Mahrokh; Eklund, Aron Charles; Spencer-Dene, Bradley; Clark, Graham; Pickering, Lisa; Stamp, Gordon; Gore, Martin; Szallasi, Zoltan Imre; Downward, Julian; Futreal, P. Andrew; Swanton, Charles.

In: New England Journal of Medicine, Vol. 366, No. 10, 2012, p. 883-892.

Publication: Research - peer-reviewJournal article – Annual report year: 2012

Harvard

Gerlinger, M, Rowan, AJ, Horswell, S, Larkin, J, Endesfelder, D, Gronroos, E, Martinez, P, Matthews, N, Stewart, A, Tarpey, P, Varela, I, Phillimore, B, Begum, S, McDonald, NQ, Butler, A, Jones, D, Raine, K, Latimer, C, Santos, CR, Nohadani, M, Eklund, AC, Spencer-Dene, B, Clark, G, Pickering, L, Stamp, G, Gore, M, Szallasi, ZI, Downward, J, Futreal, PA & Swanton, C 2012, 'Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing' New England Journal of Medicine, vol 366, no. 10, pp. 883-892.

APA

Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., ... Swanton, C. (2012). Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. New England Journal of Medicine, 366(10), 883-892.

CBE

Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi ZI, Downward J, Futreal PA, Swanton C. 2012. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. New England Journal of Medicine. 366(10):883-892.

MLA

Vancouver

Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. New England Journal of Medicine. 2012;366(10):883-892.

Author

Gerlinger, Marco; Rowan, Andrew J.; Horswell, Stuart; Larkin, James; Endesfelder, David; Gronroos, Eva; Martinez, Pierre; Matthews, Nicholas; Stewart, Aengus; Tarpey, Patrick; Varela, Ignacio; Phillimore, Benjamin; Begum, Sharmin; McDonald, Neil Q.; Butler, Adam; Jones, David; Raine, Keiran; Latimer, Calli; Santos, Claudio R.; Nohadani, Mahrokh; Eklund, Aron Charles; Spencer-Dene, Bradley; Clark, Graham; Pickering, Lisa; Stamp, Gordon; Gore, Martin; Szallasi, Zoltan Imre; Downward, Julian; Futreal, P. Andrew; Swanton, Charles / Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing.

In: New England Journal of Medicine, Vol. 366, No. 10, 2012, p. 883-892.

Publication: Research - peer-reviewJournal article – Annual report year: 2012

Bibtex

@article{73ca94b7e51045779971fe057a2283ec,
title = "Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing",
keywords = "Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common, human KDM5C gene [Hominidae], human PTEN gene [Hominidae], human SETD2 gene [Hominidae], mammalian target of rapamycin kinase, messenger RNA mRNA, 03502, Genetics - General, 03508, Genetics - Human, 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines, 15506, Urinary system - Pathology, 24004, Neoplasms - Pathology, clinical aspects and systemic effects, Molecular Genetics, Nephrology, Oncology, renal carcinoma Kidney Neoplasms (MeSH) Carcinoma (MeSH) urologic disease, neoplastic disease, branched evolution, intratumor heterogeneity, Biochemistry and Molecular Biophysics, Human Medicine, Medical Sciences, chromosome aberration analysis laboratory techniques, genetic techniques, exome sequencing laboratory techniques, genetic techniques, immunohistochemical analysis laboratory techniques, immunologic techniques, multiregion sequencing laboratory techniques, genetic techniques, mutation functional analysis laboratory techniques, genetic techniques, ploidy profiling laboratory techniques, genetic techniques",
publisher = "Massachusetts Medical Society",
author = "Marco Gerlinger and Rowan, {Andrew J.} and Stuart Horswell and James Larkin and David Endesfelder and Eva Gronroos and Pierre Martinez and Nicholas Matthews and Aengus Stewart and Patrick Tarpey and Ignacio Varela and Benjamin Phillimore and Sharmin Begum and McDonald, {Neil Q.} and Adam Butler and David Jones and Keiran Raine and Calli Latimer and Santos, {Claudio R.} and Mahrokh Nohadani and Eklund, {Aron Charles} and Bradley Spencer-Dene and Graham Clark and Lisa Pickering and Gordon Stamp and Martin Gore and Szallasi, {Zoltan Imre} and Julian Downward and Futreal, {P. Andrew} and Charles Swanton",
year = "2012",
volume = "366",
number = "10",
pages = "883--892",
journal = "New England Journal of Medicine",
issn = "0028-4793",

}

RIS

TY - JOUR

T1 - Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

A1 - Gerlinger,Marco

A1 - Rowan,Andrew J.

A1 - Horswell,Stuart

A1 - Larkin,James

A1 - Endesfelder,David

A1 - Gronroos,Eva

A1 - Martinez,Pierre

A1 - Matthews,Nicholas

A1 - Stewart,Aengus

A1 - Tarpey,Patrick

A1 - Varela,Ignacio

A1 - Phillimore,Benjamin

A1 - Begum,Sharmin

A1 - McDonald,Neil Q.

A1 - Butler,Adam

A1 - Jones,David

A1 - Raine,Keiran

A1 - Latimer,Calli

A1 - Santos,Claudio R.

A1 - Nohadani,Mahrokh

A1 - Eklund,Aron Charles

A1 - Spencer-Dene,Bradley

A1 - Clark,Graham

A1 - Pickering,Lisa

A1 - Stamp,Gordon

A1 - Gore,Martin

A1 - Szallasi,Zoltan Imre

A1 - Downward,Julian

A1 - Futreal,P. Andrew

A1 - Swanton,Charles

AU - Gerlinger,Marco

AU - Rowan,Andrew J.

AU - Horswell,Stuart

AU - Larkin,James

AU - Endesfelder,David

AU - Gronroos,Eva

AU - Martinez,Pierre

AU - Matthews,Nicholas

AU - Stewart,Aengus

AU - Tarpey,Patrick

AU - Varela,Ignacio

AU - Phillimore,Benjamin

AU - Begum,Sharmin

AU - McDonald,Neil Q.

AU - Butler,Adam

AU - Jones,David

AU - Raine,Keiran

AU - Latimer,Calli

AU - Santos,Claudio R.

AU - Nohadani,Mahrokh

AU - Eklund,Aron Charles

AU - Spencer-Dene,Bradley

AU - Clark,Graham

AU - Pickering,Lisa

AU - Stamp,Gordon

AU - Gore,Martin

AU - Szallasi,Zoltan Imre

AU - Downward,Julian

AU - Futreal,P. Andrew

AU - Swanton,Charles

PB - Massachusetts Medical Society

PY - 2012

Y1 - 2012

N2 - BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.METHODSTo examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression.RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors.CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)

AB - BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.METHODSTo examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression.RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors.CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)

KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common

KW - human KDM5C gene [Hominidae]

KW - human PTEN gene [Hominidae]

KW - human SETD2 gene [Hominidae]

KW - mammalian target of rapamycin kinase

KW - messenger RNA mRNA

KW - 03502, Genetics - General

KW - 03508, Genetics - Human

KW - 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines

KW - 15506, Urinary system - Pathology

KW - 24004, Neoplasms - Pathology, clinical aspects and systemic effects

KW - Molecular Genetics

KW - Nephrology

KW - Oncology

KW - renal carcinoma Kidney Neoplasms (MeSH) Carcinoma (MeSH) urologic disease, neoplastic disease

KW - branched evolution

KW - intratumor heterogeneity

KW - Biochemistry and Molecular Biophysics

KW - Human Medicine, Medical Sciences

KW - chromosome aberration analysis laboratory techniques, genetic techniques

KW - exome sequencing laboratory techniques, genetic techniques

KW - immunohistochemical analysis laboratory techniques, immunologic techniques

KW - multiregion sequencing laboratory techniques, genetic techniques

KW - mutation functional analysis laboratory techniques, genetic techniques

KW - ploidy profiling laboratory techniques, genetic techniques

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 10

VL - 366

SP - 883

EP - 892

ER -