title: SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer.
abstract: The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer.
authors.affiliation: Department of Research, University Hospital, CH-4031 Basel, Switzerland. jean-louis.boulay@unibas.ch
authors.forename: J L
authors.initials: JL
authors.lastname: Boulay
authors.forename: G
authors.initials: G
authors.lastname: Mild
authors.forename: A
authors.initials: A
authors.lastname: Lowy
authors.forename: J
authors.initials: J
authors.lastname: Reuter
authors.forename: M
authors.initials: M
authors.lastname: Lagrange
authors.forename: L
authors.initials: L
authors.lastname: Terracciano
authors.forename: U
authors.initials: U
authors.lastname: Laffer
authors.forename: R
authors.initials: R
authors.lastname: Herrmann
authors.forename: C
authors.initials: C
authors.lastname: Rochlitz
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015415:Biomarkers; D017024:Chemotherapy, Adjuvant; D002872:Chromosome Deletion; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein; D015996:Survival Rate; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D005472:Fluorouracil