Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing — NEJM
Original Article
Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing
Marco
Gerlinger, M.D., Andrew J. Rowan, B.Sc., Stuart Horswell, M.Math.,
James Larkin, M.D., Ph.D., David Endesfelder, Dip.Math., Eva Gronroos,
Ph.D., Pierre Martinez, Ph.D., Nicholas Matthews, B.Sc., Aengus Stewart,
M.Sc., Patrick Tarpey, Ph.D., Ignacio Varela, Ph.D., Benjamin
Phillimore, B.Sc., Sharmin Begum, M.Sc., Neil Q. McDonald, Ph.D., Adam
Butler, B.Sc., David Jones, M.Sc., Keiran Raine, M.Sc., Calli Latimer,
B.Sc., Claudio R. Santos, Ph.D., Mahrokh Nohadani, H.N.C., Aron C.
Eklund, Ph.D., Bradley Spencer-Dene, Ph.D., Graham Clark, B.Sc., Lisa
Pickering, M.D., Ph.D., Gordon Stamp, M.D., Martin Gore, M.D., Ph.D.,
Zoltan Szallasi, M.D., Julian Downward, Ph.D., P. Andrew Futreal, Ph.D.,
and Charles Swanton, M.D., Ph.D.
Background
Intratumor
heterogeneity may foster tumor evolution and adaptation and hinder
personalized-medicine strategies that depend on results from single
tumor-biopsy samples.
Methods
To
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.)
Comments
open through March 14, 2012 
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