Tumour Cell Heterogeneity

The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment.

[1]  J. Drake,et al.  Rates of spontaneous mutation. , 1998, Genetics.

[2]  Robert Axelrod,et al.  Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments. , 2008, Translational oncology.

[3]  Kyle Summers,et al.  Evolutionary biology of cancer. , 2005, Trends in ecology & evolution.

[4]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[5]  C. Maley,et al.  Cancer is a disease of clonal evolution within the body1–3. This has profound clinical implications for neoplastic progression, cancer prevention and cancer therapy. Although the idea of cancer as an evolutionary problem , 2006 .

[6]  A. Bardelli,et al.  Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer , 2014, Science Translational Medicine.

[7]  Gary D Bader,et al.  Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity , 2015, Proceedings of the National Academy of Sciences.

[8]  T. Graeber,et al.  Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma , 2015, Science Translational Medicine.

[9]  E. Inwald,et al.  4-IHC classification of breast cancer subtypes in a large cohort of a clinical cancer registry: use in clinical routine for therapeutic decisions and its effect on survival , 2015, Breast Cancer Research and Treatment.

[10]  Evis Sala,et al.  Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis , 2015, PLoS medicine.

[11]  Z. Szallasi,et al.  Spatial and temporal diversity in genomic instability processes defines lung cancer evolution , 2014, Science.

[12]  M. Calaminici,et al.  Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma , 2013, Nature Genetics.

[13]  A. Børresen-Dale,et al.  Mutational Processes Molding the Genomes of 21 Breast Cancers , 2012, Cell.

[14]  M. Kloor,et al.  Mutations in POLE and survival of colorectal cancer patients – link to disease stage and treatment , 2014, Cancer medicine.

[15]  Matthew N Davies,et al.  Dissecting cancer evolution at the macro-heterogeneity and micro-heterogeneity scale , 2015, Current opinion in genetics & development.

[16]  A. Chapelle,et al.  Mismatch repair genes on chromosomes 2p and 3p account for a major share of hereditary nonpolyposis colorectal cancer families evaluable by linkage. , 1994, American journal of human genetics.

[17]  Naveena Singh,et al.  The clonal evolution of metastases from primary serous epithelial ovarian cancers , 2009, International journal of cancer.

[18]  Scott D. Brown,et al.  Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival , 2014, Genome research.

[19]  Jeff Gore,et al.  Turning ecology and evolution against cancer , 2014, Nature Reviews Cancer.

[20]  Andrew Menzies,et al.  Analysis of the Genetic Phylogeny of Multifocal Prostate Cancer Identifies Multiple Independent Clonal Expansions in Neoplastic and Morphologically Normal Prostate Tissue , 2015, Nature Genetics.

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

[22]  W. Isaacs,et al.  AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. , 2014, The New England journal of medicine.

[23]  H. Johnsen,et al.  Cancer stem cell definitions and terminology: the devil is in the details , 2012, Nature Reviews Cancer.

[24]  Raghu Kalluri,et al.  Fibroblasts in cancer , 2006, Nature Reviews Cancer.

[25]  K. Polyak,et al.  Intra-tumour heterogeneity: a looking glass for cancer? , 2012, Nature Reviews Cancer.

[26]  M. Gerlinger,et al.  How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine , 2010, British Journal of Cancer.

[27]  P. Fitzgerald.  Homogeneity and heterogeneity in pancreas cancer: presence of predominant and minor morphological types and implications , 1986, International journal of pancreatology : official journal of the International Association of Pancreatology.

[28]  Marc J. Williams,et al.  Identification of neutral tumor evolution across cancer types , 2016, Nature Genetics.

[29]  Jiri Bartek,et al.  Replication stress links structural and numerical cancer chromosomal instability , 2013, Nature.

[30]  Alexander G. Fletcher,et al.  Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance , 2015, PLoS Comput. Biol..

[31]  A. Tward,et al.  High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma , 2013, Cancer.

[32]  H. Clevers,et al.  Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties , 2013, Cell.

[33]  James R. Downing,et al.  Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic Leukemia , 2008, Science.

[34]  H. Park,et al.  Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry. , 2012, Breast.

[35]  M. Gönen,et al.  Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. , 2010, The Journal of clinical investigation.

[36]  K. Polyak,et al.  Non-cell autonomous tumor-growth driving supports sub-clonal heterogeneity , 2014, Nature.

[37]  B. Frieden,et al.  Adaptive therapy. , 2009, Cancer research.

[38]  C. Ponting,et al.  G&T-seq: parallel sequencing of single-cell genomes and transcriptomes , 2015, Nature Methods.

[39]  Tzong-Shiue Yu,et al.  A restricted cell population propagates glioblastoma growth after chemotherapy , 2012 .

[40]  J A Jankowski,et al.  Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus , 2008, Gut.

[41]  Rhian Gabe,et al.  Therapeutic Targeting of Integrin αvβ6 in Breast Cancer , 2014, Journal of the National Cancer Institute.

[42]  Joshua F. McMichael,et al.  Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing , 2011, Nature.

[43]  S. Nelson,et al.  Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation , 2010, Nature.

[44]  Johannes G. Reiter,et al.  The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers , 2012, Nature.

[45]  Philipp M. Altrock,et al.  The mathematics of cancer: integrating quantitative models , 2015, Nature Reviews Cancer.

[46]  K. Polyak,et al.  Tumorigenesis: it takes a village , 2015, Nature Reviews Cancer.

[47]  Ken Chen,et al.  Clonal architecture of secondary acute myeloid leukemia. , 2012, The New England journal of medicine.

[48]  K. Polyak,et al.  Oncogene-like induction of cellular invasion from centrosome amplification , 2014, Nature.

[49]  Z. Szallasi,et al.  Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[50]  W. Sellers,et al.  Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance , 2013, Nature.

[51]  Peter Donnelly,et al.  Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas , 2012, Nature Genetics.

[52]  L. Matthews,et al.  Corrigendum: Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue , 2015, Nature Genetics.

[53]  P. Laird,et al.  Association between molecular subtypes of colorectal cancer and patient survival. , 2015, Gastroenterology.

[54]  A. Aguilera,et al.  Replication stress and cancer , 2015, Nature Reviews Cancer.

[55]  S. Gestl,et al.  Tumor cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers , 2014, Nature.

[56]  P. Nowell.  The clonal evolution of tumor cell populations. , 1976, Science.

[57]  Krishnendu Chatterjee,et al.  Evolutionary dynamics of cancer in response to targeted combination therapy , 2013, eLife.

[58]  Rebecca A Betensky,et al.  Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. , 2011, Cancer cell.

[59]  C. Curtis,et al.  A Big Bang model of human colorectal tumor growth , 2015, Nature Genetics.

[60]  R. Bernards,et al.  Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR , 2012, Nature.

[61]  I. Jacobs,et al.  Genetic intra‐tumour heterogeneity in epithelial ovarian cancer and its implications for molecular diagnosis of tumours , 2007, The Journal of pathology.

[62]  I. Tomlinson,et al.  Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas. , 2010, Gastroenterology.

[63]  Gary D Bader,et al.  SINGLE CELL DERIVED CLONAL ANALYSIS OF HUMAN GLIOBLASTOMA LINKS FUNCTIONAL AND GENOMIC HETEROGENEITY. , 2014 .

[64]  Carissa A. Sanchez,et al.  Temporal and Spatial Evolution of Somatic Chromosomal Alterations: A Case-Cohort Study of Barrett's Esophagus , 2013, Cancer Prevention Research.

[65]  Steven J. M. Jones,et al.  Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. , 2014, Cancer cell.

[66]  O. Sartor,et al.  Metastatic Prostate Cancer. , 2018, The New England journal of medicine.

[67]  Carlos Caldas,et al.  Analysis of circulating tumor DNA to monitor metastatic breast cancer. , 2013, The New England journal of medicine.

[68]  Shawn M. Gillespie,et al.  Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma , 2014, Science.

[69]  Jane Fridlyand,et al.  Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors , 2012, Nature.

[70]  C. Maley,et al.  Spatial structure increases the waiting time for cancer , 2011, New journal of physics.

[71]  Amos Tanay,et al.  Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. , 2014, Cell reports.

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

[73]  A. Jauch,et al.  Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  M. Esteller,et al.  Modeling lung cancer evolution and preclinical response by orthotopic mouse allografts. , 2014, Cancer research.

[75]  L. Loeb,et al.  Human cancers express mutator phenotypes: origin, consequences and targeting , 2011, Nature Reviews Cancer.

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

[77]  Ville Mustonen,et al.  The value of monitoring to control evolving populations , 2014, Proceedings of the National Academy of Sciences.

[78]  David Basanta,et al.  Exploiting evolution to treat drug resistance: combination therapy and the double bind. , 2012, Molecular pharmaceutics.

[79]  Robert J Gillies,et al.  Impact of metabolic heterogeneity on tumor growth, invasion, and treatment outcomes. , 2015, Cancer research.

[80]  F. Hirsch,et al.  Tumor heterogeneity in lung cancer based on light microscopic features , 1983, Virchows Archiv A.

[81]  L. Pusztai,et al.  Cancer heterogeneity: implications for targeted therapeutics , 2013, British Journal of Cancer.

[82]  Tae-Min Kim,et al.  Subclonal Genomic Architectures of Primary and Metastatic Colorectal Cancer Based on Intratumoral Genetic Heterogeneity , 2015, Clinical Cancer Research.

[83]  H T Lynch,et al.  Hereditary Nonpolyposis Colorectal Cancer Patients Replication Errors in Benign and Malignant Tumors from , 2006 .

[84]  Enzo Medico,et al.  Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer , 2012, Nature.

[85]  N. Navin,et al.  Clonal Evolution in Breast Cancer Revealed by Single Nucleus Genome Sequencing , 2014, Nature.

[86]  T. Kunkel,et al.  The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases , 2008, Cell Research.

[87]  K. Anderson,et al.  Genetic variegation of clonal architecture and propagating cells in leukaemia , 2011, Nature.

[88]  Pradeep S Rajendran,et al.  Single-cell dissection of transcriptional heterogeneity in human colon tumors , 2011, Nature Biotechnology.

[89]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[90]  S. Richard,et al.  Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis. , 2014, Cancer research.

[91]  Christopher A. Miller,et al.  The Role of TP53 Mutations in the Origin and Evolution of Therapy-Related AML , 2014, Nature.

[92]  Ali Bashashati,et al.  Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling , 2013, The Journal of pathology.

[93]  D. Adams,et al.  Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts , 2015, EMBO molecular medicine.

[94]  Guy S. Salvesen,et al.  SnapShot: Caspases , 2011, Cell.

[95]  Yu Cao,et al.  Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing , 2014, Science.

[96]  Carissa A. Sanchez,et al.  Genetic clonal diversity predicts progression to esophageal adenocarcinoma , 2006, Nature Genetics.

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

[98]  R. Gatenby.  A change of strategy in the war on cancer , 2009, Nature.

[99]  K. Pienta,et al.  Evolution of cooperation among tumor cells , 2006, Proceedings of the National Academy of Sciences.

[100]  Judith Campisi,et al.  Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B , 2012, Nature Medicine.

[101]  W. Bodmer,et al.  Polyclonal Origin of Colonic Adenomas in an XO/XY Patient with FAP , 1996, Science.

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

[103]  Faraz Hach,et al.  Spatial genomic heterogeneity within localized, multifocal prostate cancer , 2015, Nature Genetics.

[104]  M. Nykter,et al.  The Evolutionary History of Lethal Metastatic Prostate Cancer , 2015, Nature.

[105]  F. Markowetz,et al.  Quantitative Image Analysis of Cellular Heterogeneity in Breast Tumors Complements Genomic Profiling , 2012, Science Translational Medicine.

[106]  G. Stamp,et al.  Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[107]  Simon Wan,et al.  Tumor Heterogeneity and Permeability as Measured on the CT Component of PET/CT Predict Survival in Patients with Non–Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[108]  N. Restifo,et al.  Natural selection of tumor variants in the generation of “tumor escape” phenotypes , 2002, Nature Immunology.

[109]  R. Houlston,et al.  Systematic review of microsatellite instability and colorectal cancer prognosis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[110]  Margarita Lopatin,et al.  A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. , 2015, The Lancet. Oncology.

[111]  Andrew M. K. Brown,et al.  Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer , 2013, Science.

[112]  N. Carter,et al.  Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development , 2011, Cell.

[113]  H. Do,et al.  Intratumoral genetic heterogeneity in metastatic melanoma is accompanied by variation in malignant behaviors , 2013, BMC Medical Genomics.

[114]  Alissa M. Weaver,et al.  Tumor Morphology and Phenotypic Evolution Driven by Selective Pressure from the Microenvironment , 2006, Cell.

[115]  J. C. Pastor-Pareja,et al.  Interaction between RasV12 and scribble clones induces tumour growth and invasion , 2009, Nature.

[116]  H. Johnsen,et al.  Cancer stem cells and the cellular hierarchy in haematological malignancies. , 2009, European journal of cancer.

[117]  Xiaohong Li,et al.  A Comprehensive Survey of Clonal Diversity Measures in Barrett's Esophagus as Biomarkers of Progression to Esophageal Adenocarcinoma , 2010, Cancer Prevention Research.