Article

Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Cancer Research UK London Research Institute, London, United Kingdom.
New England Journal of Medicine (Impact Factor: 54.42). 03/2012; 366(10):883-92. DOI: 10.1056/NEJMoa1113205
Source: PubMed

ABSTRACT Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.
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.
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.
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.).

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Questions & Answers about this publication

  • Go J Yoshida added an answer in Heterogeneity:
    Is the Darwinian model the only one able to explain the heterogeneity in tumor tissues by clonal selection?

    Is the Darwinian model the only one able to explain the heterogeneity in tumor tissues by clonal selection?

    Go J Yoshida · Tokyo Medical and Dental University

    Several sub-clones contribute to the development of cancer, and then as Darwinian evolutionary model tells, the sub-clone survive suitable for the microenvironment and cellular competition including the competitive occupation of the limited number of niche. Thus, the selective pressure makes heterogeneous cancer cells undergo transient "bottleneck effect," in which relatively homogeneous malignant cells selectively survive and proliferate, and after that the heterogeneity due to the epigenetic modification or additional genetic mutations again appear in the metastatic tissues.