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: 55.87). 03/2012; 366(10):883-92. DOI: 10.1056/NEJMoa1113205
Source: PubMed


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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Available from: Charles Swanton, Oct 12, 2014
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    • "In contrast, clinical efforts to restore PTEN functionality have instead focused on targeting kinases in the PI3K pathway, including PI3K, Akt, and the mammalian target of rapamycin (Hopkins and Parsons, 2014). However, the development of PI3K targeting drugs has been complicated by the limited tolerability of current pharmacological treatments as well as tumor heterogeneity (Gerlinger et al., 2012; Bauer et al., 2014). *For correspondence: tim@ "
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    ABSTRACT: The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from 'A coding-independent function of gene and pseudogene mRNAs regulates tumour biology' by Poliseno et al. (2010), published in Nature in 2010. The key experiments to be replicated are reported in Figures 1D, 2F-H, and 4A. In these experiments, Poliseno and colleagues report microRNAs miR-19b and miR-20a transcriptionally suppress both PTEN and PTENP1 in prostate cancer cells (Figure 1D; Poliseno et al., 2010). Decreased expression of PTEN and/or PTENP1 resulted in downregulated PTEN protein levels (Figure 2H), downregulation of both mRNAs (Figure 2G), and increased tumor cell proliferation (Figure 2F; Poliseno et al., 2010). Furthermore, overexpression of the PTEN 3' UTR enhanced PTENP1 mRNA abundance limiting tumor cell proliferation, providing additional evidence for the co-regulation of PTEN and PTENP1 (Figure 4A; Poliseno et al., 2010). The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published in eLife.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.08245
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    • "As with many of such prognostic biomarker studies, many of them lack an independent validation and almost all of them are retrospective in their nature. The problems of aforementioned intratumoral and cellular heterogeneity apply also for prognostic biomarkers (Gerlinger et al, 2012; Kent et al, 2014). For these and other reasons, microRNA-based prognostic assays are far away from approval in clinical routine use and, similar to diagnostic microRNA-based biomarkers, large prospective studies are needed to evaluate their true value in a particular clinical scenario. "
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    ABSTRACT: Several discoveries have paved the way to personalise cancer medicine and a tremendous gain of knowledge in genomics and molecular mechanisms of cancer progression cumulated over the last years. Big stories in biology commonly start in a simple model system. No wonder microRNAs have been identified as regulators of embryonic development in the nematode Caenorhabditis elegans. From the first identification in worms to the first-in-man microRNA-based clinical trial in humans, almost 20 years passed. In this review we follow the story of understanding microRNA alterations in cancer, describe recent developments in the microRNA field and critically discuss their potential as diagnostic, prognostic and therapeutics factors in cancer medicine. We will explain the rationale behind the use of microRNAs in cancer diagnosis and prognosis prediction, but also discuss the limitations and pitfalls associated with this. Novel developments of combined microRNA/siRNA pharmacological approaches will be discussed and most recently data about MXR34, the first-tested microRNA drug will be described.British Journal of Cancer advance online publication 9 July 2015; doi:10.1038/bjc.2015.253
    British Journal of Cancer 07/2015; 113(4). DOI:10.1038/bjc.2015.253
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    • "The presence of distinct peaks suggests (but does not prove) multistability. Such non-genetic heterogeneity must be distinguished from genetic heterogeneity caused by genomic instability (Gerlinger et al, 2012; Pisco et al, 2013). "
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    ABSTRACT: Therapy resistance and tumour relapse after drug therapy are commonly explained by Darwinian selection of pre-existing drug-resistant, often stem-like cancer cells resulting from random mutations. However, the ubiquitous non-genetic heterogeneity and plasticity of tumour cell phenotype raises the question: are mutations really necessary and sufficient to promote cell phenotype changes during tumour progression? Cancer therapy inevitably spares some cancer cells, even in the absence of resistant mutants. Accumulating observations suggest that the non-killed, residual tumour cells actively acquire a new phenotype simply by exploiting their developmental potential. These surviving cells are stressed by the cytotoxic treatment, and owing to phenotype plasticity, exhibit a variety of responses. Some are pushed into nearby, latent attractor states of the gene regulatory network which resemble evolutionary ancient or early developmental gene expression programs that confer stemness and resilience. By entering such stem-like, stress-response states, the surviving cells strengthen their capacity to cope with future noxious agents. Considering non-genetic cell state dynamics and the relative ease with which surviving but stressed cells can be tipped into latent attractors provides a foundation for exploring new therapeutic approaches that seek not only to kill cancer cells but also to avoid promoting resistance and relapse that are inherently linked to the attempts to kill them.British Journal of Cancer advance online publication 12 May 2015. doi:10.1038/bjc.2015.146
    British Journal of Cancer 05/2015; 112(11). DOI:10.1038/bjc.2015.146
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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

    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.  

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