Abstract
Transcriptional profile-based subtypes of cancer are often viewed as identifying different diseases from the same tissue origin. Understanding the mechanisms driving the subtypes may be key in development of novel therapeutics but is challenged by lineage-specific expression signals. Using a t-test statistics approach, we compared gene expression subtypes across 12 tumor types, which identified eight transcriptional superclusters characterized by commonly activated disease pathways and similarities in gene expression. One of the largest superclusters was determined by the upregulation of a proliferation signature, significant enrichment in TP53 mutations, genomic loss of CDKN2A (p16ARF), evidence of increased numbers of DNA double strand breaks and high expression of cyclin B1 protein. These correlations suggested that abrogation of the P53-mediated apoptosis response to DNA damage results in activation of cell cycle pathways and represents a common theme in cancer. A second consistent pattern, observed in 9 of 11 solid tumor types, was a subtype related to an activated tumor-associated stroma. The similarity in transcriptional footprints across cancers suggested that tumor subtypes are commonly unified by a limited number of molecular themes.
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Acknowledgements
The results published here are in whole or part based upon data generated by The Cancer Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at ‘http://cancergenome.nih.gov’. This work was supported in part by U.S. National Cancer Institute (NCI; MD Anderson TCGA Genome Data Analysis Center) grant numbers CA143883 and CA083639, and MD Anderson Cancer Center Support Grant P30 CA016672. HK is supported in part by the Odyssey Program and the Theodore N, Law Endowment for Scientific Achievement at The University of Texas MD Anderson Cancer Center.
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Martínez, E., Yoshihara, K., Kim, H. et al. Comparison of gene expression patterns across 12 tumor types identifies a cancer supercluster characterized by TP53 mutations and cell cycle defects. Oncogene 34, 2732–2740 (2015). https://doi.org/10.1038/onc.2014.216
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DOI: https://doi.org/10.1038/onc.2014.216