title: Genomic profiling of stage II and III colon cancers reveals APC mutations to be associated with survival in stage III colon cancer patients.
abstract: Tumor profiling of DNA alterations, i.e. gene point mutations, somatic copy number aberrations (CNAs) and structural variants (SVs), improves insight into the molecular pathology of cancer and clinical outcome. Here, associations between genomic aberrations and disease recurrence in stage II and III colon cancers were investigated. A series of 114 stage II and III microsatellite stable colon cancer samples were analyzed by high-resolution array-comparative genomic hybridization (array-CGH) to detect CNAs and CNA-associated chromosomal breakpoints (SVs). For 60 of these samples mutation status of APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS was determined using targeted massive parallel sequencing. Loss of chromosome 18q12.1-18q12.2 occurred more frequently in tumors that relapsed than in relapse-free tumors (p < 0.001; FDR = 0.13). In total, 267 genes were recurrently affected by SVs (FDR < 0.1). CNAs and SVs were not associated with disease-free survival (DFS). Mutations in APC and TP53 were associated with increased CNAs. APC mutations were associated with poor prognosis in (5-fluorouracil treated) stage III colon cancers (p = 0.005; HR = 4.1), an effect that was further enhanced by mutations in MAPK pathway (KRAS, NRAS, BRAF) genes. We conclude that among multiple genomic alterations in CRC, strongest associations with clinical outcome were observed for common mutations in APC.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Evert
authors.initials: E
authors.lastname: van den Broek
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Daoud
authors.initials: D
authors.lastname: Sie
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Tijssen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mongera
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.|Department of Mathematics, VU University, Amsterdam, The Netherlands.
authors.forename: Mark A
authors.initials: MA
authors.lastname: van de Wiel
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Surgery, VU University, Amsterdam, The Netherlands.
authors.forename: Eric J Th
authors.initials: EJ
authors.lastname: Belt
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Surgery, VU University, Amsterdam, The Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: den Uil
authors.affiliation: Department of Pathology, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Bril
authors.affiliation: Department of Surgery, VU University, Amsterdam, The Netherlands.
authors.forename: Hein B A C
authors.initials: HB
authors.lastname: Stockmann
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Remond J A
authors.initials: RJ
authors.lastname: Fijneman
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D002887:Chromosomes, Human, Pair 18; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D056915:DNA Copy Number Variations; D016158:Genes, p53; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D012008:Recurrence
chemical_list: D025601:Adenomatous Polyposis Coli Protein
keywords: APC; colon cancer; copy number aberrations; disease recurrence; structural variants