Whole-exome sequencing brings to light a novel oncogene, a tumor-suppressor gene, and new melanoma pathways.
The ability to decode the human genome through sequencing has provided new insights into all diseases, cancer in particular. On the assumption that the driving influences on melanoma biology result from changes in the coding region (i.e., segments of the genome that yield proteins), investigators performed whole-exome sequencing to assess all acquired (i.e., somatic) mutations in the DNA of 14 matched normal tissue and metastatic tumor specimens. By definition, these mutations occur in tumor but not in matched normal tissue (e.g., blood) from the same patient.
To identify new oncogenes, the researchers looked for recurrence. In well-known oncogenes, such as BRAF and NRAS, repeat mutations of certain amino acids occur; these changes most effectively drive tumor formation. In addition to the expected repeat BRAF mutations, the researchers found a recurrent alteration in the TRRAP gene in 7 of the 14 specimens. Transfection with the mutated form of TRRAP transformed NIH-3T3 cells in the manner of other oncogenes, and suppression of TRRAP led to cell death; the TRRAP Ser722Phe mutation is likely a newly identified oncogenic variant in melanoma.
In addition to recurrence of the same mutation, some genes were more frequently mutated than expected. Among these was GRIN2A, found to be mutated in 34 of 135 samples (25.2%). Several nonsense alterations were scattered along the length of GRIN2A, a pattern consistent with GRIN2A being a novel tumor suppressor in melanoma.
Comment: This herculean effort identified a novel oncogene (TRRAP) and a new tumor-suppressor gene (GRIN2A). Their mechanisms of action are unknown. TRRAP is a part of a multiprotein complex with a role in the transcriptional activity of cancer genes p53, c-Myc and E2F1. GRIN2A encodes a glutamate-receptor member of the class of ionotropic glutamate receptors; prior reports in the mouse literature suggest a role for glutamate receptors in melanoma pathogenesis. Particularly exciting is that this whole-exome approach identified several brand-new pathways in melanoma. These discoveries could produce new therapeutic approaches that might enhance the effectiveness of anti-BRAF drugs.
— Hensin Tsao, MD, PhD
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