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.).

0 Bookmarks
 · 
464 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: This year the American association for cancer research meeting was held in San Diego. "Harnessing breakthroughs and targeting cures" was the title of this meeting where the major recent scientific data on cancer research were discussed. This year was undoubtedly the year of immunotherapy and immunology of tumors. With the aim of sharing the data presented at this congress, AERIO (Association d'Enseignement et de Recherche des Internes d'Oncologie) and Oncologie joined to propose a digest of this outstanding congress. Of course, exhaustivity is not an objective of this type of digest which reflects the choices of young researchers and physicians, with the help of the editorial board, among the multiple themes and researches presented and discussed during this meeting. Tumor immunology and immunotherapy data from the congress are reported. Moreover, autophagy, microbiome, liquid biopsy, tumoral heterogeneity, and cancer stem cells data from this congress are reported, as a reflection of the diversity of this meeting and cancer research. From a clinical point of view, new targets and molecules and the new design of clinical trial are also reported.
    Oncologie 08/2014; 16(7-8):341-366. DOI:10.1007/s10269-014-2414-y · 0.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity).We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P¼0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.
    Nature Communications 01/2015; 6. DOI:10.1038/ncomms7125 · 10.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The mitochondrial respiratory chain is organized into dynamic high molecular weight complexes that associate to form supercomplexes. The function of these SCs is to minimize the production of reactive oxygen species (ROS) generated during electron transfer within them and to efficiently transfer electrons to complex IV. These supra-molecular structures as well as whole mitochondria are stress-responsive and respond to mitochondrially targeted anti-cancer agent by destabilization and induction of massive production of ROS leading to apoptosis. We have recently developed mitochondrially targeted anti-cancer agents epitomized by the mitochondrially targeted analogue of the redox-silent compound vitamin E succinate, which belongs to the group of agents that kill cancer cells via their mitochondria-destabilizing activity, referred to as mitocans. To understand the molecular mechanism of the effect of such agents, the use of native blue gel electrophoresis and clear native electrophoresis coupled with in-gel activity assays, are methods of choice. The relevant methodology is described in this chapter.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1265:195-208. DOI:10.1007/978-1-4939-2288-8_15 · 1.29 Impact Factor

Full-text

Download
29 Downloads
Available from
Oct 12, 2014