title: Global DNA methylation is altered by neoadjuvant chemoradiotherapy in rectal cancer and may predict response to treatment - A pilot study.
abstract: OBJECTIVE
  In rectal cancer, not all tumours display a response to neoadjuvant treatment. An accurate predictor of response does not exist to guide patient-specific treatment. DNA methylation is a distinctive molecular pathway in colorectal carcinogenesis. Whether DNA methylation is altered by neoadjuvant treatment and a potential response predictor is unknown. We aimed to determine whether DNA methylation is altered by neoadjuvant chemoradiotherapy (CRT) and to determine its role in predicting response to treatment.
  
  
  METHODS
  Fifty-three (n = 53) patients with locally advanced rectal cancers treated with neoadjuvant CRT followed by surgery were identified from the pathology databases of 2 tertiary referral centres over a 4-year period. Immunohistochemical staining of treatment specimens was carried out using the 5-Methylcytidine (Eurogentec, Seraing, Belgium) antibody. Quantitative analysis of staining was performed using an automated image analysis platform. The modified tumour regression grading system was used to assess tumour response to neoadjuvant therapy.
  
  
  RESULTS
  Seven (13%) patients showed complete pathological response while 46 (87%) patients were partial responders to neoadjuvant treatment. In 38 (72%) patients, significant reduction in methylation was observed in post-treatment resection specimens compared to pre-treatment specimens (171.5 vs 152.7, p = 0.01); in 15 (28%) patients, methylation was increased. Pre-treatment methylation correlated significantly with tumour regression (p < 0.001), T-stage (p = 0.005), and was able to predict complete and partial pathological responders (p = 0.01).
  
  
  CONCLUSIONS
  Neoadjuvant CRT appears to alter the rectal cancer epigenome. The significant correlation between pre-treatment DNA methylation with tumour response suggests a potential role for methylation as a biomarker of response.
authors.affiliation: Department of Surgical Research, Connolly Hospital & RCSI, Blanchardstown, Dublin, Ireland. Electronic address: julianst@yahoo.com.
authors.forename: J S
authors.initials: JS
authors.lastname: Tsang
authors.affiliation: Department of Surgical Research, Connolly Hospital & RCSI, Blanchardstown, Dublin, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Vencken
authors.affiliation: Department of Pathology, UCD, Dublin, Ireland.
authors.forename: O
authors.initials: O
authors.lastname: Sharaf
authors.affiliation: Department of Pathology, Beaumont Hospital & RCSI, Dublin, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Leen
authors.affiliation: Department of Pathology, Beaumont Hospital & RCSI, Dublin, Ireland.
authors.forename: E W
authors.initials: EW
authors.lastname: Kay
authors.affiliation: Department of Surgery, Beaumont Hospital, Dublin, Ireland.
authors.forename: D A
authors.initials: DA
authors.lastname: McNamara
authors.affiliation: Department of Surgery, Beaumont Hospital, Dublin, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Deasy
authors.affiliation: Department of Surgical Research, Connolly Hospital & RCSI, Blanchardstown, Dublin, Ireland.
authors.forename: E D
authors.initials: ED
authors.lastname: Mulligan
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059186:Chemoradiotherapy, Adjuvant; D015331:Cohort Studies; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010865:Pilot Projects; D011379:Prognosis; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012189:Retrospective Studies; D016896:Treatment Outcome
keywords: DNA methylation; Neoadjuvant treatment; Rectal cancer