Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer.

Despite much evidence on epigenetic abnormalities in cancer, it is currently unclear to what extent epigenetic alterations can be associated with tumors' clonal genetic origins. Here, we show that the prostate intratumor heterogeneity in DNA methylation and copy-number patterns can be explained by a unified evolutionary process. By assaying multiple topographically distinct tumor sites, premalignant lesions, and lymph node metastases within five cases of prostate cancer, we demonstrate that both DNA methylation and copy-number heterogeneity consistently reflect the life history of the tumors. Furthermore, we show cases of genetic or epigenetic convergent evolution and highlight the diversity in the evolutionary origins and aberration spectrum between tumor and metastatic subclones. Importantly, DNA methylation can complement genetic data by serving as a proxy for activity at regulatory domains, as we show through identification of high epigenetic heterogeneity at androgen-receptor-bound enhancers. Epigenome variation thereby expands on the current genome-centric view on tumor heterogeneity.

[1]  N. Navin,et al.  Tumor evolution in response to chemotherapy: phenotype versus genotype. , 2014, Cell reports.

[2]  Sarat Chandarlapaty,et al.  Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. , 2011, Cancer cell.

[3]  R. Arceci.  Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing , 2012 .

[4]  Huanming Yang,et al.  Single-Cell Exome Sequencing Reveals Single-Nucleotide Mutation Characteristics of a Kidney Tumor , 2012, Cell.

[5]  Steven J. M. Jones,et al.  Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma , 2014, Science.

[6]  Zhaohui S. Qin,et al.  An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. , 2010, Cancer cell.

[7]  K. Pienta,et al.  Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets , 2013, Proceedings of the National Academy of Sciences.

[8]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[9]  Clifford A. Meyer,et al.  Androgen Receptor Regulates a Distinct Transcription Program in Androgen-Independent Prostate Cancer , 2009, Cell.

[10]  A. Sivachenko,et al.  Punctuated Evolution of Prostate Cancer Genomes , 2013, Cell.

[11]  A. McKenna,et al.  Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. , 2014, Cancer cell.

[12]  T. Meehan,et al.  An atlas of active enhancers across human cell types and tissues , 2014, Nature.

[13]  Robin L. Jones,et al.  Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. , 2014, Cell reports.

[14]  Gavin Sherlock,et al.  DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer. , 2011, Genome research.

[15]  J. Ferlay,et al.  Global estimates of cancer prevalence for 27 sites in the adult population in 2008 , 2013, International journal of cancer.

[16]  Benjamin J. Raphael,et al.  The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer , 2016 .

[17]  Martin J. Aryee,et al.  DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases , 2013, Science Translational Medicine.

[18]  Olivier Gascuel,et al.  Fast and Accurate Phylogeny Reconstruction Algorithms Based on the Minimum-Evolution Principle , 2002, WABI.

[19]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[20]  Simon G. Coetzee,et al.  Comprehensive Functional Annotation of 77 Prostate Cancer Risk Loci , 2014, PLoS genetics.

[21]  M. Rubin,et al.  Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. , 2012, Cancer discovery.

[22]  A. Børresen-Dale,et al.  The Life History of 21 Breast Cancers , 2012, Cell.

[23]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[24]  Eric S. Lander,et al.  The genomic complexity of primary human prostate cancer , 2010, Nature.

[25]  Jun Luo,et al.  Copy Number Analysis Indicates Monoclonal Origin of Lethal Metastatic Prostate Cancer , 2009, Nature Medicine.

[26]  A. D. De Marzo,et al.  Epigenetic alterations in human prostate cancers. , 2009, Endocrinology.

[27]  M. Shen,et al.  Molecular genetics of prostate cancer: new prospects for old challenges. , 2010, Genes & development.

[28]  A. Teschendorff,et al.  Using high-density DNA methylation arrays to profile copy number alterations , 2014, Genome Biology.

[29]  N. Friedman,et al.  Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells , 2014, Nature.

[30]  E. Letouzé,et al.  Analysis of the copy number profiles of several tumor samples from the same patient reveals the successive steps in tumorigenesis , 2010, Genome Biology.

[31]  A. Sivachenko,et al.  Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer , 2012, Nature Genetics.

[32]  M. Graefen,et al.  Tumour grade, proliferation, apoptosis, microvessel density, p53, and bcl-2 in prostate cancers: differences between tumours located in the transition zone and in the peripheral zone. , 2002, European urology.

[33]  Lukas Burger,et al.  Transcription Factor Occupancy Can Mediate Active Turnover of DNA Methylation at Regulatory Regions , 2013, PLoS genetics.

[34]  J. Troge,et al.  Tumour evolution inferred by single-cell sequencing , 2011, Nature.

[35]  Christopher R. Schmidt,et al.  Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. , 2014, Cancer discovery.

[36]  V. Beneš,et al.  Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. , 2013, Cancer cell.

[37]  A. McKenna,et al.  Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia , 2012, Cell.

[38]  V. P. Collins,et al.  Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics , 2013, Proceedings of the National Academy of Sciences.

[39]  P. A. Futreal,et al.  Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing , 2014, Nature Genetics.

[40]  David T. W. Jones,et al.  Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. , 2012, Cancer cell.

[41]  Long-Cheng Li,et al.  Epigenetics of prostate cancer. , 2007, Frontiers in bioscience : a journal and virtual library.