Journal Article

Clonal Architectures and Driver Mutations in Metastatic Melanomas

Kim, Minjung, Wendl, Michael C., Cornelius, Lynn A., Lu, Charles, Miller, Christopher A., Wilson, Richard K., Kanchi, Krishna L., Griffith, Obi, Griffith, Malachi, Mulé, James J., Goetz, Brian, Fields, Ryan C., Sondak, Vernon K., Dees, Nathan D., Ley, Timothy J., Ding, Li, Sung, Hyeran, Linette, Gerald P., McMichael, Joshua F., Fenstermacher, David, Weber, Jeffrey S.

2014

Overview

To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3' base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Base Sequence / Biology and Life Sciences / Cancer / Cell cycle / Chromatin remodeling / DNA Mutational Analysis / Drug resistance / Etiology / Gene sequencing / Genes / Genes, p16 / Genome, Human - genetics / Genomes / GTP Phosphohydrolases - genetics / Humans / Medical research / Medicine / Medicine and Health Sciences / Melanoma / Melanoma - genetics / Membrane Proteins - genetics / Metastases / Metastasis / Mutation / p53 Protein / Patients / Phosphoprotein Phosphatases - genetics / Phylogeny / Proto-Oncogene Proteins B-raf - genetics / PTEN protein / Receptor Protein-Tyrosine Kinases - genetics / Senescence / Sequence Analysis, DNA / Signature analysis / Skin Neoplasms - genetics / Suppressors / Surgery / Tumor Suppressor Proteins - genetics / Tumors