Purchase this article with an account.
Nakul Singh, Arun D Singh, Winston Hide; Inferring an evolutionary tree of uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5308.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Lack of repeated access to pathologic samples over time in a given patient limits study of tumor evolution. Herein, we apply tools developed within the field of evolutionary biology for the study of evolution of species to the genomes of primary uveal melanoma.
Primary uveal melanoma genomic DNA was assayed on the Illumina Human660WQuad v1.0 DNA Analysis Bead Chip. Raw signal intensity data were quantile normalized, which were then used 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 the SplitsTree package. Each copy number segment was tested for an association with tumor clade by means of a Fisher’s exact test, using a Benjamini-Hochberg corrected p value of 0.05.
Of the 57 tumors, 1(1.7%) was discarded because of a failed assay, and 8 (13.8%) revealed to be mixtures of several cell populations that could not be resolved by the GAP algorithm. Three clades of tumor, each following a distinct evolutionary path, were identified. The clades contained 29 (59.2%), 16 (32.7%), and 3 (6.1%) samples each, and were labeled Clade A, B and C, respectively. These clades were associated with metastatic status (p value 0.04 by Fisher’s exact test). From a normal diploid melanocyte, a few tumors (Clade C) lose a large portion of chromosome 6q. A few tumors within this group subsequently lose almost all of chromosome arm 1p. Clade C tumors do not develop any mutations on 8q. In an alternate path, the vast majority of tumors (Clade A and Clade B) gain a copy of the telomeric half of 8q. A majority of these tumors (Clade A) then subsequently lose a copy of chromosome 3, as well as the rest of 8q. The other tumors (Clade B) gain copies of 6p, as well as regions on 11p and 22q.
Applying an evolutionary framework to uveal melanoma genome reveals that there are distinct subtypes of uveal melanoma, and these subtypes resemble each other at the beginning of their development, but diverge soon thereafter. Our data also suggests that there is little overlap in the subtypes of uveal melanoma after divergence that are not likely to crossover or transform from one major clade to another major clade.
This PDF is available to Subscribers Only