title: High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer.
abstract: BACKGROUND
  Cancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes.
  
  
  METHODS
  Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases.
  
  
  RESULTS
  In total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR <0.1). MACROD2 was affected in 41% of CRC samples and another 169 genes showed breakpoints in >3% of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis.
  
  
  CONCLUSIONS
  We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Evert
authors.initials: E
authors.lastname: van den Broek
authors.affiliation: Department of Computer Science, VU University, Amsterdam, The Netherlands.
authors.forename: Maurits J J
authors.initials: MJ
authors.lastname: Dijkstra
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.
authors.forename: Josien C
authors.initials: JC
authors.lastname: Haan
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Joleen J H
authors.initials: JJ
authors.lastname: Traets
authors.affiliation: Department of Epidemiology & 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, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.affiliation: Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
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 Computer Science, VU University, Amsterdam, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Abeln
authors.affiliation: Department of Pathology, VU University Medical Center, 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.
authors.forename: Remond J A
authors.initials: RJ
authors.lastname: Fijneman
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D019457:Chromosome Breakage; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D055106:Genome-Wide Association Study; D006801:Humans; D015337:Multicenter Studies as Topic; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic
chemical_list: D014408:Biomarkers, Tumor