Open Access Research2008NaxerovaetVolume al. 9, Issue 7, Article R108 Analysis of gene expression in a developmental context emphasizes distinct biological leitmotifs in human cancers Kamila Naxerova*, Carol J Bult†, Anne Peaston†, Karen Fancher†, Barbara B Knowles†, Simon Kasif*‡ and Isaac S Kohane* Addresses: *Children's Hospital Informatics Program, Harvard-MIT Division of Health Sciences and Technology, Longwood Avenue, Boston, MA 02115, USA. †The Jackson Laboratory, Main Street, Bar Harbor, ME 04609, USA. ‡Department of Biomedical Engineering, Boston University, Cummington Street, Boston, MA 02215, USA. Correspondence: Isaac S Kohane. Email: [email protected] Published: 8 July 2008 Received: 4 March 2008 Revised: 31 May 2008 Genome Biology 2008, 9:R108 (doi:10.1186/gb-2008-9-7-r108) Accepted: 8 July 2008 The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2008/9/7/R108 © 2008 Naxerova et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Development<p>Ain cancer systematic gene and expression.</p> analysis cancer signaturesof the relationship between the neoplastic and developmental transcriptome provides an outline of global trends Abstract Background: In recent years, the molecular underpinnings of the long-observed resemblance between neoplastic and immature tissue have begun to emerge. Genome-wide transcriptional profiling has revealed similar gene expression signatures in several tumor types and early developmental stages of their tissue of origin. However, it remains unclear whether such a relationship is a universal feature of malignancy, whether heterogeneities exist in the developmental component of different tumor types and to which degree the resemblance between cancer and development is a tissue-specific phenomenon. Results: We defined a developmental landscape by summarizing the main features of ten developmental time courses and projected gene expression from a variety of human tumor types onto this landscape. This comparison demonstrates a clear imprint of developmental gene expression in a wide range of tumors and with respect to different, even non-cognate developmental backgrounds. Our analysis reveals three classes of cancers with developmentally distinct transcriptional patterns. We characterize the biological processes dominating these classes and validate the class distinction with respect to a new time series of murine embryonic lung development. Finally, we identify a set of genes that are upregulated in most cancers and we show that this signature is active in early development. Conclusion: This systematic and quantitative overview of the relationship between the neoplastic and developmental transcriptome spanning dozens of tissues provides a reliable outline of global trends in cancer gene expression, reveals potentially clinically relevant differences in the gene expression of different cancer types and represents a reference framework for interpretation of smaller-scale functional studies. Genome Biology 2008, 9:R108 http://genomebiology.com/2008/9/7/R108 Genome Biology 2008, Volume 9, Issue 7, Article R108 Naxerova et al. R108.2 Background other hand, highly lineage-specific mechanisms govern The historical roots of our understanding of the intimate con- malignant growth and behavior, focus has to be put on iden- nection between tumorigenesis and developmental processes tifying and targeting tissue-specific regulators. reach back to 1858, when Rudolf Virchow first suggested that neoplasms arise "in accordance with the same law, which reg- The results from the integrative analysis of gene expression in ulates embryonic development" [1]. Since then, his idea has cancer and development presented here suggest that the profoundly influenced medicine and still remains highly rele- developmental information content of most human cancers vant today. The similarities between cancer and development indeed is significant. The developmental signature of cancers are evident on many levels of observation: microscopically, originating from various tissues exhibits low tissue-specifi- cancerous tissues appear as undifferentiated masses, with city, indicating that a large portion of the cancer transcrip- some tumor types even exhibiting embryonic tissue organiza- tome is composed of general developmental modules. tion. The increased mobility of malignant cells, leading to Furthermore, we describe three developmentally distinct invasion of the local environment with the potential for sub- groups of cancer, validate the class distinction on a new time sequent travel to distant organs (representing one of the most series of embryonic development in the mouse and show that problematic clinical aspects of cancer), is reminiscent of the behavior of genes in lung development is predictable by migratory behavior during development. On the molecular their expression across the three groups. We explore the bio- level, the shared characteristics between certain malignant logical themes dominating the expression profiles of these tumors and developing tissues with respect to transcription classes and demonstrate that one group recapitulates early factor activity [2], regulation of chromatin structure [3] and developmental gene expression patterns and is characterized signaling [4] have been documented. In particular, several by an 'individualistic' signature with upregulation of pluripo- studies have suggested that part of the cancer transcriptome tency genes and suppression of genes involved in cell-cell represents a 'developmental signature', that is, it contains a communication and signal transduction. A second group set of genes that are collectively active during development. exhibits a 'communicative' gene expression signature that is For lung cancer [5,6], liver cancer [7], Wilms' tumor [8], active in late development, is enriched in genes involved in colon cancer [9,10] and medulloblastoma [11], gene expres- immune response, cell-cell and cell-matrix interactions and sion patterns resembling early developmental stages of the resembles a wound healing signature. A third group connects corresponding organ have been identified in the tumor pro- the previous two with a transition phenotype. While social file. The results of these transcriptome-scale analyses are and anti-social aspects of cancer have been widely popular- important because they offer a glimpse into fundamental bio- ized, this study points out the possibility of a more subtle clas- logical processes underlying tumorigenesis and provide a nat- sification of different cancers that tend to evoke different ural framework for understanding complex cancer gene types of 'survival mechanisms'. Finally, we identify a core pro- expression signatures that are difficult to interpret otherwise. gram of genes that are upregulated in most cancers and show Moreover, developmental signatures harbor a clinical rele- that these genes are coexpressed in early development. vance that we are only beginning to discover. For example, lung cancers can be risk-stratified by their similarity to lung development and pluripotency gene signatures can be used to Results predict outcome in breast cancer [6,12]. Placing human cancers on a developmental landscape Our analysis is based on a large-scale comparison of gene In the present study, we paint a novel picture of the oncolog- expression in 10 developmental processes and 32 cancer data ical landscape by comparing a variety of human cancers based sets. To paint an unbiased picture of the association between on their developmental signature. Our analysis was inspired gene expression in development and oncogenesis, we selected by the following questions: to which extent can the transcrip- data from a wide biological range. Our development database tome of a tumor, which is oftentimes perceived as an aberra- encompasses gene expression time series characterizing tion, be 'explained' by developmental gene expression? Does processes as diverse as heart development in the mouse, the developmental signature represent a feature of most, and human T cell development and in vitro differentiation of possibly all, human cancers or does gene expression in differ- murine embryonic stem cells (see Additional data file 6 for a ent tumors fall into distinct groups with respect to develop- list of all data sets). Cancer gene expression data include ment? Is recapitulation of developmental gene expression tumors from most commonly affected anatomical locations programs a tissue-specific phenomenon or is the develop- and corresponding normal tissue as a reference. mental signature largely composed of general transcriptional modules that play a ubiquitous role in developmental proc- The approach for analysis of this large data compendium esses? The answers to these open questions have therapeutic (consisting of 1,094 individual arrays) is depicted in Figure 1. implications [13]. If a broad range of tumors employs primi- We first simplified the complex, high-dimensional expression tive developmental mechanisms that are shared across tis- profiles characterizing each developmental process into a sues to sustain their growth and survival, a certain drug or one-dimensional developmental timeline (DT). To under- class of drugs could