title: An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients.
abstract: BACKGROUND
  Despite therapeutic innovations, metastatic colorectal cancer (mCRC) is still characterized by poor prognosis and few molecular markers predict the risk of progression. Polycomb group genes (PcGs) are epigenetic modifiers involved in tumor suppressor gene silencing. PcG member EZH2 mediates gene silencing through histone-H3 lysine-27 methylation. In colorectal cancer (CRC), EZH2 overexpression predicts shorter survival. Recently, four EZH2 single-nucleotide polymorphisms (SNPs) have been described. The present study was aimed at evaluating the correlation between EZH2 SNPs and outcome parameters in mCRC patients.
  
  
  METHODS
  DNA was extracted from blood samples of 110 mCRC patients treated with first-line 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) and bevacizumab. Genotyping was carried out by real-time PCR. Genotype was used to predict objective response, progression-free survival (PFS) and overall survival (OS). EZH2 messenger RNA levels were evaluated on lymphocytes of a parallel cohort of 50 CRC patients.
  
  
  RESULTS
  One allelic variant (rs3757441 C/C versus C/T or T/T) was significantly associated with shorter PFS and OS (P < 0.01 and P < 0.05, respectively). At multivariate analysis, the same variant resulted an independent predictor of PFS and OS (P < 0.05). The C/C variant was associated with significantly higher EZH2 expression (P < 0.05).
  
  
  CONCLUSIONS
  An EZH2 SNP may be useful to predict clinical outcome in mCRC patients.
authors.affiliation: Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa. Electronic address: fr.crea@gmail.com.
authors.forename: F
authors.initials: F
authors.lastname: Crea
authors.affiliation: Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fornaro
authors.affiliation: Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa.
authors.forename: E
authors.initials: E
authors.lastname: Paolicchi
authors.affiliation: Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Masi
authors.affiliation: Unit of Biostatistics, Institute of Environmental Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Frumento
authors.affiliation: Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Salvatore
authors.affiliation: Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Schirripa
authors.affiliation: Medical Oncology Unit, Department of Onco-Hematology, Azienda Ospedaliera S. Salvatore, Pesaro.
authors.forename: F
authors.initials: F
authors.lastname: Graziano
authors.affiliation: Division of Medical Oncology, S. Raffaele Scientific Institute, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ronzoni
authors.affiliation: Division of Medical Oncology, S. Raffaele Scientific Institute, Milano, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Ricci
authors.affiliation: Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Institute of Cancer-Frederick, Frederick, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Farrar
authors.affiliation: Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa.
authors.forename: R
authors.initials: R
authors.lastname: Danesi
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D018572:Disease-Free Survival; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D063151:Polycomb Repressive Complex 2; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011379:Prognosis; D012189:Retrospective Studies; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D000068258:Bevacizumab; D000077146:Irinotecan; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin