title: Identification of a DNA methylation signature to predict disease-free survival in locally advanced rectal cancer.
abstract: In locally advanced rectal cancer a preoperative predictive biomarker is necessary to adjust treatment specifically for those patients expected to suffer relapse. We applied whole genome methylation CpG island array analyses to an initial set of patients (n=11) to identify differentially methylated regions (DMRs) that separate a good from a bad prognosis group. Using a quantitative high-resolution approach, candidate DMRs were first validated in a set of 61 patients (test set) and then confirmed DMRs were further validated in additional independent patient cohorts (n=71, n=42). We identified twenty highly discriminative DMRs and validated them in the test set using the MassARRAY technique. Ten DMRs could be confirmed which allowed separation into prognosis groups (p=0.0207, HR=4.09). The classifier was validated in two additional cohorts (n=71, p=0.0345, HR=3.57 and n=42, p=0.0113, HR=3.78). Interestingly, six of the ten DMRs represented regions close to the transcriptional start sites of genes which are also marked by the Polycomb Repressor Complex component EZH2. In conclusion we present a classifier comprising 10 DMRs which predicts patient prognosis with a high degree of accuracy. These data may now help to discriminate between patients that may respond better to standard treatments from those that may require alternative modalities.
authors.affiliation: Department of General and Visceral Surgery, University Medical Center Goettingen, Goettingen, Germany. Both authors contributed equally.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany. Both authors contributed equally.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leha
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. Dept. of Medicine, Div. Hematology/Oncology, University of Freiburg Medical Center, Freiburg, Germany (present address).
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.affiliation: Department of Pathology, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kitz
authors.affiliation: Department of General and Visceral Surgery, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Grade
authors.affiliation: Department of Radiation Oncology, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Hendrik A
authors.initials: HA
authors.lastname: Wolff
authors.affiliation: Department of General and Visceral Surgery, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Jo
authors.affiliation: Radiotherapy Department, Cyclotron Biomédical, Centre Antoine-Lacassagne Nice, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Doyen
authors.affiliation: Radiotherapy Department, Cyclotron Biomédical, Centre Antoine-Lacassagne Nice, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gérard
authors.affiliation: Department of General and Visceral Surgery, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Beißbarth
authors.affiliation: Department of General and Visceral Surgery, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ghadimi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D016002:Discriminant Analysis; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005820:Genetic Testing / Q000379:methods*; D055106:Genome-Wide Association Study; D005858:Germany; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D057285:Precision Medicine; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012004:Rectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015203:Reproducibility of Results; D012307:Risk Factors; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor