title: Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1.
abstract: Surgical excision of colorectal cancer at early clinical stages is highly effective, but 20-30% of patients relapse. Therefore, it is of clinical relevance to identify patients at high risk for recurrence, who would benefit from adjuvant chemotherapy. The objective of this study was to identify prognostic and/or predictive methylation markers in stage II colorectal cancer patients. Therefore, we selected six gene promoters (FZD9, PCDH10 (protocadherin 10), SFRP2, SPARC (secreted protein acidic and rich in cysteine), UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), and WIF1) for methylation analysis in formalin-fixed, paraffin-embedded primary tumor samples of colorectal cancer patients (n=143) who were enrolled in a prospective randomized phase III trial of the Austrian Breast and Colorectal cancer Study Group. Patients were randomized to adjuvant chemotherapy with 5-fluorouracil and leucovorin or surveillance only. Survival analyses revealed that combined evaluation of three promoters (PCDH10, SPARC, and UCHL1) showed differential effects with regard to disease-free survival and overall survival in the two treatment groups (significance level 0.007). In the chemotherapy arm, a statistically insignificant trend for patients without methylation toward longer survival was observed (P=0.069 for disease-free survival and P=0.139 for overall survival). Contrary, patients in the surveillance arm without methylation in their gene promoters had shorter disease-free survival and overall survival (P=0.031 for disease-free survival and P=0.003 for overall survival), indicating a prognostic effect of methylation in this group (test for interaction, P=0.006 for disease-free survival and P=0.018 for overall survival). These results indicate that promoter methylation status of PCDH10, SPARC, and UCHL1 may be used both as prognostic and predictive molecular marker for colorectal cancer patients and, therefore, may facilitate treatment decisions for stage II colorectal cancer.
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Ellen
authors.initials: E
authors.lastname: Heitzer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Artl
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Margit
authors.initials: M
authors.lastname: Resel
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Graf
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Weißenbacher
authors.affiliation: Institute of Pathology, General Hospital Graz West, Graz, Austria.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lax
authors.affiliation: Department of Surgery, Comprehensive Cancer Center, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
authors.affiliation: Department of Pathology, Comprehensive Cancer Center, Vienna, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Third Medical Department, Paracelsus Private Medical University, Salzburg, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.affiliation: Department of Pathology, Paracelsus Private Medical University, Salzburg, Austria.
authors.forename: Otto
authors.initials: O
authors.lastname: Dietze
authors.affiliation: Department of Surgery, Hospital Oberpullendorf, Oberpullendorf, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Hofbauer
authors.affiliation: Department of Pathology, Hospital Oberwart, Oberwart, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Böhm
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Höfler
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Hellmut
authors.initials: H
authors.lastname: Samonigg
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Schaberl-Moser
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Marija
authors.initials: M
authors.lastname: Balic
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Nadia
authors.initials: N
authors.lastname: Dandachi
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015820:Cadherins / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015676:Osteonectin / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D000091363:Protocadherins; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D057832:Watchful Waiting
chemical_list: D015820:Cadherins; D015676:Osteonectin; C438603:PCDH10 protein, human; D000091363:Protocadherins; C577241:SPARC protein, human; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase; D002955:Leucovorin; D005472:Fluorouracil