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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    • "Advances in pharmaceutical biotechnology and genetic engineering has made it possible to discover and/or develop potent anticancer drugs that may directly target the cancer cells without affecting the neighboring healthy cells [8]. These potent anticancer drugs have to face a variety of challenges in order to achieve desired targeted-specific therapeutic efficacy [9]. "
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    • "Heterogeneity in cancer tissue has been hypothesized over the past few decades [Wersto et al. (1991)] and has been demonstrated elegantly using NGS technology over the past few years [Gerlinger et al. (2012)]. Genetic variation in a tumor occurs due to evolutionary processes that drive tumor progression. "
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    ABSTRACT: We develop a feature allocation model for inference on genetic tumor variation using next-generation sequencing data. Specifically, we record single nucleotide variants (SNVs) based on short reads mapped to human reference genome and characterize tumor heterogeneity by latent haplotypes defined as a scaffold of SNVs on the same homologous genome. For multiple samples from a single tumor, assuming that each sample is composed of some sample-specific proportions of these haplotypes, we then fit the observed variant allele fractions of SNVs for each sample and estimate the proportions of haplotypes. Varying proportions of haplotypes across samples is evidence of tumor heterogeneity since it implies varying composition of cell subpopulations. Taking a Bayesian perspective, we proceed with a prior probability model for all relevant unknown quantities, including, in particular, a prior probability model on the binary indicators that characterize the latent haplotypes. Such prior models are known as feature allocation models. Specifically, we define a simplified version of the Indian buffet process, one of the most traditional feature allocation models. The proposed model allows overlapping clustering of SNVs in defining latent haplotypes, which reflects the evolutionary process of subclonal expansion in tumor samples.
    The Annals of Applied Statistics 09/2015; 9(2). DOI:10.1214/15-AOAS817
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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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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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