title: Epigenetic Homogeneity Within Colorectal Tumors Predicts Shorter Relapse-Free and Overall Survival Times for Patients With Locoregional Cancer.
abstract: There are few validated biomarkers that can be used to predict outcomes for patients with colorectal cancer. Part of the challenge is the genetic and molecular heterogeneity of colorectal tumors not only among patients, but also within tumors. We have explored intratumor heterogeneity at the epigenetic level, due to its dynamic nature. We analyzed DNA methylation profiles of the digestive tract surface and the central bulk and invasive front regions of colorectal tumors.
  
  
  
  We determined the DNA methylation profiles of >450,000 CpG sites in 3 macrodissected regions of 79 colorectal tumors and 23 associated liver metastases, obtained from 2 hospitals in Spain. We also analyzed samples for KRAS and BRAF mutations, 499,170 single nucleotide polymorphisms, and performed immunohistochemical analyses.
  
  
  
  We observed differences in DNA methylation among the 3 tumor sections; regions of tumor-host interface differed the most from the other tumor sections. Interestingly, tumor samples collected from areas closer to the gastrointestinal transit most frequently shared methylation events with metastases. When we calculated individual coefficients to quantify heterogeneity, we found that epigenetic homogeneity was significantly associated with short time of relapse-free survival (log-rank P = .037) and short time of overall survival (log-rank P = .026) in patients with locoregional colorectal cancer.
  
  
  
  In an analysis of 79 colorectal tumors, we found significant heterogeneity in patterns of DNA methylation within each tumor; the level of heterogeneity correlates with times of relapse-free and overall survival.
authors: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors: Anna
authors: A
authors: Martínez-Cardús
authors: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors: Sebastian
authors: S
authors: Moran
authors: Pathology Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain.
authors: Eva
authors: E
authors: Musulen
authors: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors: Cátia
authors: C
authors: Moutinho
authors: Medical Oncology Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain.
authors: Jose L
authors: JL
authors: Manzano
authors: Catalan Institute of Oncology, Health Sciences Research Institute of the Germans Trias i Pujol Foundation, Barcelona, Catalonia, Spain.
authors: Eva
authors: E
authors: Martinez-Balibrea
authors: Catalan Institute of Oncology, Health Sciences Research Institute of the Germans Trias i Pujol Foundation, Barcelona, Catalonia, Spain.
authors: Montserrat
authors: M
authors: Tierno
authors: Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Center affiliated with the Spanish Cancer Research Network (Institute of Health Carlos III), Spain.
authors: Elena
authors: E
authors: Élez
authors: Pathology Department, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain.
authors: Stefania
authors: S
authors: Landolfi
authors: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors: Patricia
authors: P
authors: Lorden
authors: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors: Carles
authors: C
authors: Arribas
authors: Max Planck Institute for Informatics, Saarbrücken, Germany.
authors: Fabian
authors: F
authors: Müller
authors: Max Planck Institute for Informatics, Saarbrücken, Germany; Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors: Christoph
authors: C
authors: Bock
authors: Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Center affiliated with the Spanish Cancer Research Network (Institute of Health Carlos III), Spain.
authors: Josep
authors: J
authors: Tabernero
authors: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain; Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain; Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain. Electronic address: mesteller@idibell.cat.
authors: Manel
authors: M
authors: Esteller
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor
keywords: Colorectal Cancer; DNA Methylation; Epigenetics; Heterogeneity