Genomic profiling of stage II and III colon cancers reveals APC mutations to be associated with survival in stage III colon cancer patients

// Evert van den Broek 1, 6 , Oscar Krijgsman 1 , Daoud Sie 1 , Marianne Tijssen 1, 6 , Sandra Mongera 1 , Mark A. van de Wiel 2, 3 , Eric J. Th. Belt 1, 4 , Sjoerd H. den Uil 1, 4 , Herman Bril 5 , Hein B.A.C. Stockmann 4 , Bauke Ylstra 1 , Beatriz Carvalho 1, 6 , Gerrit A. Meijer 1, 6 , Remond J.A. Fijneman 1, 6 1 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands 3 Department of Mathematics, VU University, Amsterdam, The Netherlands 4 Department of Surgery, VU University, Amsterdam, The Netherlands 5 Department of Pathology, Spaarne Gasthuis, Haarlem, The Netherlands 6 Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands Correspondence to: Remond J.A. Fijneman, email: R.Fijneman@nki.nl Keywords: colon cancer, copy number aberrations, APC, structural variants, disease recurrence Received: April 06, 2016      Accepted: October 01, 2016      Published: October 06, 2016 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 .