Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

被引:6013
作者
Gerlinger, Marco [4 ]
Rowan, Andrew J.
Horswell, Stuart
Larkin, James [2 ]
Endesfelder, David
Gronroos, Eva
Martinez, Pierre
Matthews, Nicholas
Stewart, Aengus
Tarpey, Patrick [3 ]
Varela, Ignacio [3 ]
Phillimore, Benjamin
Begum, Sharmin
McDonald, Neil Q.
Butler, Adam [3 ]
Jones, David [3 ]
Raine, Keiran [3 ]
Latimer, Calli [3 ]
Santos, Claudio R.
Nohadani, Mahrokh [2 ]
Eklund, Aron C. [6 ]
Spencer-Dene, Bradley
Clark, Graham
Pickering, Lisa [2 ]
Stamp, Gordon [2 ]
Gore, Martin [2 ]
Szallasi, Zoltan [6 ,7 ]
Downward, Julian
Futreal, P. Andrew [3 ]
Swanton, Charles [1 ,5 ]
机构
[1] Canc Res UK London Res Inst, Translat Canc Therapeut Lab, London WC2A 3LY, England
[2] Royal Marsden Hosp, Dept Med, London SW3 6JJ, England
[3] Wellcome Trust Sanger Inst, London, England
[4] Barts & London Queen Marys Sch Med & Dent, Barts Canc Inst, London, England
[5] UCL, Inst Canc, London, England
[6] Tech Univ Denmark, DK-2800 Lyngby, Denmark
[7] Harvard Univ, Sch Med, Boston, MA USA
基金
英国惠康基金; 英国医学研究理事会;
关键词
CHRONIC MYELOID-LEUKEMIA; RENAL-CELL CARCINOMA; PANCREATIC-CANCER; GENOMIC ANALYSIS; LUNG-CANCER; MUTATIONS; NEPHRECTOMY; GENE; INSTABILITY; METASTASIS;
D O I
10.1056/NEJMoa1113205
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.)
引用
收藏
页码:883 / 892
页数:10
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