title: The mitochondrial and autosomal mutation landscapes of prostate cancer.
abstract: BACKGROUND
  Prostate cancer (PCa) is the most common cancer in men. PCa is strongly age associated; low death rates in surveillance cohorts call into question the widespread use of surgery, which leads to overtreatment and a reduction in quality of life. There is a great need to increase the understanding of tumor characteristics in the context of disease progression.
  
  
  OBJECTIVE
  To perform the first multigenome investigation of PCa through analysis of both autosomal and mitochondrial DNA, and to integrate exome sequencing data, and RNA sequencing and copy-number alteration (CNA) data to investigate how various different tumor characteristics, commonly analyzed separately, are interconnected.
  
  
  METHODS
  Exome sequencing was applied to 64 tumor samples from 55 PCa patients with varying stage and grade. Integrated analysis was performed on a core set of 50 tumors from which exome sequencing, CNA, and RNA sequencing data were available.
  
  
  METHODS
  Genes, mutated at a significantly higher rate relative to a genomic background, were identified. In addition, mitochondrial and autosomal mutation rates were correlated to CNAs and proliferation, assessed as a cell cycle gene expression signature.
  
  
  CONCLUSIONS
  Genes not previously reported to be significantly mutated in PCa, such as cell division cycle 27 homolog (Saccharomyces cerevisiae) (CDC27), myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3), lysine (K)-specific demethylase 6A (KDM6A), and kinesin family member 5A (KIF5A) were identified. The mutation rate in the mitochondrial genome was 55 times higher than that of the autosomes. Multilevel analysis demonstrated a tight correlation between high reactive-oxygen exposure, chromosomal damage, high proliferation, and in parallel, a transition from multiclonal indolent primary PCa to monoclonal aggressive disease. As we only performed targeted sequence analysis; copy-number neutral rearrangements recently described for PCa were not accounted for.
  
  
  CONCLUSIONS
  The mitochondrial genome displays an elevated mutation rate compared to the autosomal chromosomes. By integrated analysis, we demonstrated that different tumor characteristics are interconnected, providing an increased understanding of PCa etiology.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.forename: Daniel
authors.initials: D
authors.lastname: Klevebring
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.forename: Mårten
authors.initials: M
authors.lastname: Neiman
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wikström
authors.forename: Peter
authors.initials: P
authors.lastname: Wiklund
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
mesh_terms: D000368:Aged; D059472:Exome / Q000235:genetics*; D020869:Gene Expression Profiling; D050259:Genes, Mitochondrial / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics*