title: DCR3 locus is a predictive marker for 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer.
abstract: Adjuvant chemotherapy reduces the incidence of distant metastasis and increases survival of patients with colorectal cancer. However, predictive markers are needed to define subsets of patients with stage II and III disease that may benefit from adjuvant treatment. A secreted member of the TNF receptor superfamily, the decoy receptor 3 (DcR3), was reported to be amplified in colorectal cancer as a negative regulator of Fas-mediated apoptosis. We analyzed DcR3 gene copy number and protein expression in a large series of tumors from a randomized multicenter trial of 5-fluorouracil/mitomycin C (FU/MMC) adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK 40/81), using real-time quantitative PCR and immunohistochemistry on tumor microarrays. Results of gene status and protein expression of DcR3 were correlated with disease-free and overall survival of patients. We observed amplification of the DcR3 gene in 185/294 (63%) and overexpression of the DcR3 protein in 163/223 (73%) of colorectal tumors. Multivariate analysis showed no prognostic effect of DcR3 gene amplification and protein overexpression. However, adjuvant chemotherapy was significantly more beneficial in patients with normal DcR3 gene copy number than in patients with amplification (DFS: HR 2.84, 95% CI 1.16-6.98, p = 0.02; OS: HR 3.15, 95% CI 1.19-8.32, p = 0.02), whereas DcR3 protein overexpression did not influence the effect of adjuvant chemotherapy (DFS: HR 1.02, 95% CI 0.65-1.60, p = 0.95; OS: HR 0.95, 95% CI 0.61-1.49, p = 0.83). We conclude that amplification of the 20q13 locus is a predictive marker for adjuvant chemotherapy in colorectal cancer.
authors.affiliation: Department of Research, University Hospital of Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mild
authors.forename: Felix
authors.initials: F
authors.lastname: Bachmann
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Boulay
authors.forename: Katharina
authors.initials: K
authors.lastname: Glatz
authors.forename: Urban
authors.initials: U
authors.lastname: Laffer
authors.forename: Adam
authors.initials: A
authors.lastname: Lowy
authors.forename: Urs
authors.initials: U
authors.lastname: Metzger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Reuter
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Rochlitz
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis; D014408:Biomarkers, Tumor; D002890:Chromosomes, Human, Pair 20; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human; D005472:Fluorouracil