title: Epigenomic characterization of locally advanced anal cancer: a radiation therapy oncology group 98-11 specimen study.
abstract: BACKGROUND
  The Radiation Therapy Oncology Group 98-11 clinical trial demonstrated the superiority of standard 5-fluorouracil/mitomycin-C over 5-fluorouracil/cisplatin in combination with radiation in the treatment of anal squamous cell cancer. Tumor size (>5 cm) and lymph node metastases are associated with disease progression. There may be key molecular differences (eg, DNA methylation changes) in tumors at high risk for progression.
  
  
  OBJECTIVE
  The objectives of this study were to determine whether there are differences in DNA methylation at individual CpG sites and within genes among locally advanced anal cancers, with large tumor size and/or nodal involvement, compared with those that are less advanced.
  
  
  METHODS
  This was a case-case study among 121 patients defined as high risk (tumor size >5 cm and/or nodal involvement; n = 59) or low risk (≤5 cm, node negative; n = 62) within the mitomycin-C arm of the Radiation Therapy Oncology Group 98-11 trial. DNA methylation was measured using the Illumina HumanMethylation450 Array.
  
  
  METHODS
  The study was conducted in a tertiary care cancer center in collaboration with a national clinical trials cooperative group.
  
  
  METHODS
  The patients consisted of 74 women and 47 men with a median age of 54 years (range, 25-79 years).
  
  
  METHODS
  DNA methylation differences at individual CpG sites and within genes between low- and high-risk patients were compared using the Mann-Whitney test (p < 0.001).
  
  
  RESULTS
  A total of 16 CpG loci were differentially methylated (14 increased and 2 decreased) in high- versus low-risk cases. Genes harboring differentially methylated CpG sites included known tumor suppressor genes and novel targets.
  
  
  CONCLUSIONS
  This study only included patients in the mitomycin-C arm with tumor tissue; however, this sample was representative of the trial.
  
  
  CONCLUSIONS
  This is the first study to apply genome-wide methylation analysis to anal cancer. Biologically relevant differences in methylated targets were found to discriminate locally advanced from early anal cancer. Epigenetic events likely play a significant role in the progression of anal cancer and may serve as potential biomarkers.
authors.affiliation: 1Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 2Department of Biomedical Informatics, Moffitt Cancer Center, Tampa, Florida 3Department of Statistics, Radiation Therapy Oncology Group, Philadelphia, Pennsylvania 4Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida 5Biospecimen Resource, Radiation Therapy Oncology Group, San Francisco, California 6Department of Medical Oncology, M.D. Anderson Cancer Center, Houston, TX 7Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, Florida 8Department Radiation Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Siegel
authors.forename: Steven
authors.initials: S
authors.lastname: Eschrich
authors.forename: Kathryn
authors.initials: K
authors.lastname: Winter
authors.forename: Bridget
authors.initials: B
authors.lastname: Riggs
authors.forename: Anders
authors.initials: A
authors.lastname: Berglund
authors.forename: Abidemi
authors.initials: A
authors.lastname: Ajidahun
authors.forename: Jeff
authors.initials: J
authors.lastname: Simko
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moughan
authors.forename: Jaffer
authors.initials: J
authors.lastname: Ajani
authors.forename: Anthony
authors.initials: A
authors.lastname: Magliocco
authors.forename: Abul
authors.initials: A
authors.lastname: Elahi
authors.forename: Sarah
authors.initials: S
authors.lastname: Hoffe
authors.forename: David
authors.initials: D
authors.lastname: Shibata
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001005:Anus Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D019175:DNA Methylation; D018450:Disease Progression; D057890:Epigenomics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage
chemical_list: D016685:Mitomycin; D002945:Cisplatin; D005472:Fluorouracil