title: Inferring an Evolutionary Tree of Uveal Melanoma From Genomic Copy Number Aberrations.
abstract: OBJECTIVE
  The purpose of this study is to study the genomic evolution of primary uveal melanoma.
  
  
  METHODS
  Primary uveal melanoma genomic DNA was assayed on the Illumina Human660W-Quad v1.0 DNA Analysis BeadChip. Raw signal intensity data were quantile normalized to estimate copy number aberration with the Genome Alteration Print algorithm. Distance between samples was calculated as the Manhattan distance between the copy number profiles of the tumors. From the distance matrix, a phylogenetic network (evolutionary relationship inference) was estimated using SplitsTree4.
  
  
  RESULTS
  Of the 57 tumors, one (1.8%) was discarded because of a failed assay, and seven (12.3%) were revealed to be mixtures of several cell populations that could not be resolved. Three clades of tumor were identified (A [59.2%], B [32.7%], and C [6.1%]), each following a distinct evolutionary path and each associated with metastatic status (P = 0.01). One tumor (2.0%) did not fit into any clade. From a normal diploid melanocyte, a few tumors (clade C) lose a large portion of chromosome 6q, but do not develop any mutations on 8q. In an alternate path, the vast majority of tumors (clade A and clade B [91.9%]) gain a copy of the telomeric half of 8q. A majority of these tumors (clade A) subsequently lose a copy of chromosome 3, as well as gain the centromeric half of 8q. The other tumors (clade B) gain copies of 6p, as well as regions on 11p and 22q.
  
  
  CONCLUSIONS
  Our data suggest that there is little overlap in the subtypes of uveal melanoma after divergence (identified as clades A and B) and that these distinct subtypes are not likely to crossover or transform from one major clade to another.
authors.affiliation: School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Nakul
authors.initials: N
authors.lastname: Singh
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States.
authors.forename: Arun D
authors.initials: AD
authors.lastname: Singh
authors.affiliation: Biostatistics Department, Harvard School of Public Health, Boston, Massachusetts, United States 4Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Winston
authors.initials: W
authors.lastname: Hide
mesh_terms: D000368:Aged; D056915:DNA Copy Number Variations; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D046228:Microarray Analysis; D008875:Middle Aged; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D014604:Uveal Neoplasms / Q000235:genetics*; D000098943:Uveal Melanoma