Melanoma has become the poster cancer for genomic research. The identification of a driver mutation in the BRAF gene found in approximately 40% of metastatic melanoma patients and the subsequent approval last year of the targeted BRAF inhibitor, vemurafenib, has resulted in a surge of both clinical and laboratory research.
Treatment decisions for metastatic melanoma are now largely driven by whether a patient’s tumor harbors the BRAF V600E mutation. Furthermore, researchers have been actively analyzing the mechanisms of resistance to BRAF inhibitors, attempting to identify the next-generation therapies and novel combination treatments to stop further cancer progression.
A study published yesterday in Nature is taking a leap forward with the analysis of the genome of melanoma from 25 metastatic melanoma patients. The goal of this type of research is to identify important driver mutations to develop new targeted therapies—and combination therapies—as well as to understand the mechanisms of cancer progression.
Thanks to a thorough whole-genome sequencing analysis, Michael F. Berger, the Broad Institute of Harvard and the Massachusetts Institute of Technology, and colleagues have identified a new gene—PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)—mutated with an estimated frequency of mutation of 14% in the patients analyzed. Based on the mutational significance of the PREX2 gene, the authors conclude that mutations in PREX2 appear to be highly susceptible to positive selection pressure in the development of melanoma.
PREX2 both negatively regulates and directly interacts with the PTEN tumor suppressor protein. PTEN is part of the phosphatidylinositol 3-kinase (PI3K) pathway that is mutated in various cancers. PREX2 has been previously implicated in breast cancer. But not much else is known about the function of PREX2.
The Sequencing Results
Twenty-three somatic base-pair mutations and a frameshift mutation were detected among the tumor samples analyzed. Nine somatic rearrangements occurred in proximity to the PREX2 gene in the melanoma genomes—one of the tumor samples had both a complex rearrangement and amplification of the PREX2 gene. The authors emphasize that this finding may hint that “sites of complex rearrangements” in melanoma may denote genes that have functional importance for the development of this tumor type. Additionally, 4 of the 25 samples had nonsense, truncation mutations within the PREX2 gene.
The BRAF V600E mutation was present in 64% (16 of 25) of the tumors and NRAS was mutated in 36% (9 of 25) of tumors independent of a mutation in the BRAF gene. The analysis identified an average of 97 rearrangements per each melanoma tumor—the number of rearrangements spanned from 6 to 420. The authors highlight that the number of both intrachromosomal and interchromosomal rearrangements varied widely among the melanoma genomes.
The researchers went on to validate the functional relevance of PREX2 mutations in mutagenesis—ectopic expression of several mutant forms of PREX2 found in the patient tumor samples was shown to accelerate tumor formation in human melanocytes in a mouse model.
The role of PREX2 still needs to be analyzed and larger melanoma patient cohorts are likely needed to validate the prevalence of PREX2 mutations among patients. Still, the authors hypothesize that mutations in the gene give PREX2 oncogenic activity. Specifically, mutations in PREX2 may be a new category of cancer genes distinct from tumor suppressors or oncogenes according to Berger et al. Overexpression of these cancer genes could promote tumor growth and development through dominant negative effects or more subtle effects, state the authors.
1. Berger MF, Hodis E, Heffernan TP, et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012 May 9. [Epub ahead of print]