Colorectal Cancer Classification and Cell Heterogeneity: A Systems Oncology Approach

Colorectal cancer is a heterogeneous disease that manifests through diverse clinical scenarios. During many years, our knowledge about the variability of colorectal tumors was limited to the histopathological analysis from which generic classifications associated with different clinical expectations are derived. However, currently we are beginning to understand that under the intense pathological and clinical variability of these tumors there underlies strong genetic and biological heterogeneity. Thus, with the increasing available information of inter-tumor and intra-tumor heterogeneity, the classical pathological approach is being displaced in favor of novel molecular classifications. In the present article, we summarize the most relevant proposals of molecular classifications obtained from the analysis of colorectal tumors using powerful high throughput techniques and devices. We also discuss the role that cancer systems biology may play in the integration and interpretation of the high amount of data generated and the challenges to be addressed in the future development of precision oncology. In addition, we review the current state of implementation of these novel tools in the pathological laboratory and in clinical practice.

[1]  R. Labianca,et al.  Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[3]  K. Michels,et al.  Epigenetic epidemiology of cancer. , 2014, Biochemical and biophysical research communications.

[4]  Martin A Nowak,et al.  Timing and heterogeneity of mutations associated with drug resistance in metastatic cancers , 2014, Proceedings of the National Academy of Sciences.

[5]  Melanie A. Huntley,et al.  Recurrent R-spondin fusions in colon cancer , 2012, Nature.

[6]  S. Hanash,et al.  Mining the plasma proteome for cancer biomarkers , 2008, Nature.

[7]  F. Bosch,et al.  Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer , 2012, Nature Medicine.

[8]  J. Barrett,et al.  KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Renzo Boldorini,et al.  Increased Detection Sensitivity for KRAS Mutations Enhances the Prediction of Anti-EGFR Monoclonal Antibody Resistance in Metastatic Colorectal Cancer , 2011, Clinical Cancer Research.

[10]  R. Gillies,et al.  Evolutionary dynamics of carcinogenesis and why targeted therapy does not work , 2012, Nature Reviews Cancer.

[11]  Sabine Tejpar,et al.  Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  I. Nagtegaal,et al.  Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies , 2014, Clinical Cancer Research.

[13]  A. Bardelli,et al.  Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor–Targeted Therapy in Metastatic Colorectal Cancer , 2009, Journal of the National Cancer Institute.

[14]  S. Tavazoie,et al.  Extracellular Metabolic Energetics Can Promote Cancer Progression , 2015, Cell.

[15]  P. Stern,et al.  Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. , 1997, Immunology today.

[16]  Parantu K. Shah,et al.  canEvolve: A Web Portal for Integrative Oncogenomics , 2013, PloS one.

[17]  A. G. de Herreros,et al.  Functional Heterogeneity of Cancer-Associated Fibroblasts from Human Colon Tumors Shows Specific Prognostic Gene Expression Signature , 2013, Clinical Cancer Research.

[18]  Sabine Tejpar,et al.  KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. , 2011, The Lancet. Oncology.

[19]  J. Pagès,et al.  Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  Ken Kato,et al.  Clinical impact of c-MET expression and genetic mutational status in colorectal cancer patients after liver resection , 2014, Cancer science.

[21]  Sabine Tejpar,et al.  Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Georg Krupitza,et al.  Initial steps of metastasis: Cell invasion and endothelial transmigration , 2011, Mutation research.

[23]  Daniel J Sargent,et al.  Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. , 2003, The New England journal of medicine.

[24]  M. Kloor,et al.  Distinctive Spatiotemporal Stability of Somatic Mutations in Metastasized Microsatellite-stable Colorectal Cancer , 2015, The American journal of surgical pathology.

[25]  Prahlad T. Ram,et al.  Cancer Systems Biology: a peek into the future of patient care? , 2014, Nature Reviews Clinical Oncology.

[26]  F. Clavel-Chapelon,et al.  Dietary Fibre Intake and Risks of Cancers of the Colon and Rectum in the European Prospective Investigation into Cancer and Nutrition (EPIC) , 2012, PloS one.

[27]  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.

[28]  Gregory J Goodall,et al.  Down-regulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. , 2013, Neoplasia.

[29]  S. Friend,et al.  Colorectal Cancer Subtyping Consortium (CRCSC) identification of a consensus of molecular subtypes. , 2014 .

[30]  Bruno Landi,et al.  Clinical Relevance of KRAS-Mutated Subclones Detected with Picodroplet Digital PCR in Advanced Colorectal Cancer Treated with Anti-EGFR Therapy , 2014, Clinical Cancer Research.

[31]  Florian Markowetz,et al.  Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions , 2013, Nature Medicine.

[32]  A. Frigessi,et al.  Principles and methods of integrative genomic analyses in cancer , 2014, Nature Reviews Cancer.

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

[34]  B. Uzzan,et al.  Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. , 2009, European journal of cancer.

[35]  Mark J. Ratain,et al.  Tumour heterogeneity in the clinic , 2013, Nature.

[36]  G. Botti,et al.  Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  M. Tzardi,et al.  KRAS Genotypic Changes of Circulating Tumor Cells during Treatment of Patients with Metastatic Colorectal Cancer , 2014, PloS one.

[38]  C. Swanton Intratumor heterogeneity: evolution through space and time. , 2012, Cancer research.

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

[40]  T. Yeatman,et al.  Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer , 2011, Gut.

[41]  F. Marincola,et al.  Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours , 2013, The Journal of pathology.

[42]  A. Carrato,et al.  Role of Kras Status in Patients with Metastatic Colorectal Cancer Receiving First-Line Chemotherapy plus Bevacizumab: A TTD Group Cooperative Study , 2012, PloS one.

[43]  P. Delvenne,et al.  Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies , 2014, Hepatology.

[44]  C. Bokemeyer,et al.  Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. , 2012, European journal of cancer.

[45]  Kebin Liu,et al.  Epigenetics and Colorectal Cancer Pathogenesis , 2013, Cancers.

[46]  C. Sander,et al.  MLH1‐silenced and non‐silenced subgroups of hypermutated colorectal carcinomas have distinct mutational landscapes , 2013, The Journal of pathology.

[47]  Mira Ayadi,et al.  Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value , 2013, PLoS medicine.

[48]  V. Mootha,et al.  Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation , 2012, Science.

[49]  Hong Ding,et al.  BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis , 2011, Molecular Biology Reports.

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

[51]  H. Lehrach,et al.  Somatic Mutation Profiles of MSI and MSS Colorectal Cancer Identified by Whole Exome Next Generation Sequencing and Bioinformatics Analysis , 2010, PloS one.

[52]  D. Sargent,et al.  Molecular Pathways: Microsatellite Instability in Colorectal Cancer: Prognostic, Predictive, and Therapeutic Implications , 2012, Clinical Cancer Research.

[53]  Céline Lefebvre,et al.  Comparative analysis of primary tumour and matched metastases in colorectal cancer patients: evaluation of concordance between genomic and transcriptional profiles. , 2015, European journal of cancer.

[54]  M. Disis,et al.  TNM staging in colorectal cancer: T is for T cell and M is for memory. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  F. Bazzoli,et al.  Molecular Pathways Involved in Colorectal Cancer: Implications for Disease Behavior and Prevention , 2013, International journal of molecular sciences.

[56]  M. Bertagnolli,et al.  Molecular origins of cancer: Molecular basis of colorectal cancer. , 2009, The New England journal of medicine.

[57]  J. Herman,et al.  CpG island methylator phenotype in colorectal cancer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Javier Sastre,et al.  Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior , 2012, BMC Cancer.

[59]  Bert Vogelstein,et al.  DETECTION OF CIRCULATING TUMOR DNA IN EARLY AND LATE STAGE HUMAN MALIGNANCIES , 2014 .

[60]  Zlatko Trajanoski,et al.  In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[62]  Xi-shan Wang,et al.  EGFR Gene Copy Number as a Prognostic Marker in Colorectal Cancer Patients Treated with Cetuximab or Panitumumab: A Systematic Review and Meta Analysis , 2013, PloS one.

[63]  Lewis C Cantley,et al.  A colorectal cancer classification system that associates cellular phenotype and responses to therapy , 2013, Nature Medicine.

[64]  S. Veronese,et al.  Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[66]  M. Ychou,et al.  Mutational analysis of biomarker samples from the CORRECT study: Correlating mutation status with clinical response to regorafenib , 2013 .

[67]  J. Lamb,et al.  A Comprehensive Characterization of Genome-Wide Copy Number Aberrations in Colorectal Cancer Reveals Novel Oncogenes and Patterns of Alterations , 2012, PloS one.

[68]  Shuji Ogino,et al.  How many molecular subtypes? Implications of the unique tumor principle in personalized medicine , 2012, Expert review of molecular diagnostics.

[69]  Alexander Meissner,et al.  Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease , 2013, Modern Pathology.

[70]  L. V. van't Veer,et al.  Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  R. Schilsky,et al.  Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  Sabine Tejpar,et al.  Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  P. Stern,et al.  Natural history of HLA expression during tumour development. , 1993, Immunology today.

[74]  William M. Grady,et al.  Epigenetics and colorectal cancer , 2011, Nature Reviews Gastroenterology &Hepatology.

[75]  F. Garrido,et al.  “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: Implications for immunotherapy , 2010, International journal of cancer.

[76]  Louis Vermeulen,et al.  Wnt activity defines colon cancer stem cells and is regulated by the microenvironment , 2010, Nature Cell Biology.

[77]  G. Orphanides,et al.  Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines , 2012, BMC Medical Genomics.

[78]  N. McGranahan,et al.  The causes and consequences of genetic heterogeneity in cancer evolution , 2013, Nature.

[79]  E. Nice,et al.  Proteomics, genomics and transcriptomics: their emerging roles in the discovery and validation of colorectal cancer biomarkers , 2014, Expert review of proteomics.

[80]  Zlatko Trajanoski,et al.  Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[81]  R. Salazar,et al.  The evolution of our molecular understanding of colorectal cancer: what we are doing now, what the future holds, and how tumor profiling is just the beginning. , 2014, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[82]  F. Clavel-Chapelon,et al.  Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition , 2011, Gut.

[83]  M. Wiese,et al.  Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[84]  A. Sparks,et al.  The Genomic Landscapes of Human Breast and Colorectal Cancers , 2007, Science.

[85]  A. Concha,et al.  Leukocyte infiltrate in gastrointestinal adenocarcinomas is strongly associated with tumor microsatellite instability but not with tumor immunogenicity , 2011, Cancer Immunology, Immunotherapy.

[86]  F. Clavel-Chapelon,et al.  Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study , 2010, BMJ : British Medical Journal.

[87]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[88]  Andreas Schlicker,et al.  Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition , 2013, International journal of cancer.

[89]  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.

[90]  Jing Yang,et al.  Epithelial–mesenchymal plasticity in carcinoma metastasis , 2013, Genes & development.

[91]  D. Kerr,et al.  Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[92]  I. Nagtegaal,et al.  KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients , 2011, British Journal of Cancer.

[93]  Charles J. Vaske,et al.  Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing , 2014, Proceedings of the National Academy of Sciences.

[94]  J. Tabernero,et al.  Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. , 2013, The New England journal of medicine.

[95]  K. Hemminki,et al.  Consensus Pathways Implicated in Prognosis of Colorectal Cancer Identified Through Systematic Enrichment Analysis of Gene Expression Profiling Studies , 2011, PloS one.

[96]  Corbin E. Meacham,et al.  Tumour heterogeneity and cancer cell plasticity , 2013, Nature.

[97]  Jin-Ling Tang,et al.  Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases , 2015, Scientific Reports.

[98]  E. Riboli,et al.  Adult weight change and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition. , 2013, European journal of cancer.

[99]  Sabine Tejpar,et al.  Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer , 2013, The Journal of pathology.

[100]  Deficient mismatch repair system in patients with sporadic advanced colorectal cancer , 2009, British Journal of Cancer.

[101]  C. Compton,et al.  Characterization of sporadic colon cancer by patterns of genomic instability. , 2003, Cancer research.

[102]  R. Sanz-Pamplona,et al.  Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information , 2014, Molecular oncology.

[103]  M. Leitzmann,et al.  Television viewing and time spent sedentary in relation to cancer risk: a meta-analysis. , 2014, Journal of the National Cancer Institute.

[104]  Vladimir Vacic,et al.  Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions , 2014, Genome Biology.

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

[106]  Y. Ohkura,et al.  Overexpression of MET is a new predictive marker for anti-EGFR therapy in metastatic colorectal cancer with wild-type KRAS , 2014, Cancer Chemotherapy and Pharmacology.

[107]  C. Compton,et al.  Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[108]  J. L. Tang,et al.  PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[109]  G. Calin,et al.  Clinical relevance of circulating cell-free microRNAs in cancer , 2014, Nature Reviews Clinical Oncology.

[110]  Steven J. M. Jones,et al.  Meta-analysis of Colorectal Cancer Gene Expression Profiling Studies Identifies Consistently Reported Candidate Biomarkers , 2008, Cancer Epidemiology Biomarkers & Prevention.

[111]  R. Labianca,et al.  DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. , 2011, Journal of the National Cancer Institute.

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

[113]  A. Viale,et al.  Comparative genomic analysis of primary versus metastatic colorectal carcinomas. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[114]  Baorui Liu,et al.  Colorectal Cancer Patients with Low Abundance of KRAS Mutation May Benefit from EGFR Antibody Therapy , 2013, PloS one.

[115]  Carlos Caldas,et al.  The implications of clonal genome evolution for cancer medicine. , 2013, The New England journal of medicine.

[116]  Sridhar Ramaswamy,et al.  Circulating Breast Tumor Cells Exhibit Dynamic Changes in Epithelial and Mesenchymal Composition , 2013, Science.

[117]  Reiko Nishihara,et al.  Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. , 2013, Journal of the National Cancer Institute.

[118]  D. Spiegelman,et al.  Predictive and Prognostic Roles of BRAF Mutation in Stage III Colon Cancer: Results from Intergroup Trial CALGB 89803 , 2011, Clinical Cancer Research.

[119]  C. Cano,et al.  Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape , 2012, Cancer Immunology, Immunotherapy.