Editors' ChoiceCancer

Hidden in Plain Sight

See allHide authors and affiliations

Science Translational Medicine  16 Jun 2010:
Vol. 2, Issue 36, pp. 36ec97
DOI: 10.1126/scitranslmed.3001357

The Philadelphia chromosome was the first described chromosomal translocation in cancer because it was easily visible by means of karyotype analysis of metaphase spreads in all cases of chronic myelogenous leukemia. Other examples of translocations in cancer—such as TMPRSS2:ERG, which is present in over 50% of prostate cancer—proved more challenging to identify through conventional methods. Whole-genome analysis based on massively parallel sequencing of small DNA fragments does not identify translocations because the chromosome of origin of the fragments is not known but rather inferred from their sequence. A recent method that was specifically developed to identify translocations in the genome is referred to as paired-end sequencing. One of the genes involved in translocations that were recently discovered with this method is BRAF, which is the main downstream signaling component in the Ras pathway.

Palanisamy and colleagues now report previously undiscovered translocations involving not only BRAF but also a related protein, CRAF (RAF1). By screening hundreds of human tumor samples, they identified the translocations involving BRAF or CRAF in 2 and 1% of prostate cancers, respectively. In addition, 1 to 2% of gastric cancer samples harbored translocations involving BRAF, and rare cases of melanoma demonstrated BRAF or CRAF rearrangements. The translocation partners for the RAF genes are diverse and in some cases remain unknown. One example of the fusion protein found in prostate cancer, SLC45A3-BRAF, results in increased proliferation when expressed in prostate epithelial cells, accompanied by activation of signaling downstream of RAF; this is reversed with RAF or MEK inhibitors.

Thus, even though BRAF and CRAF translocations are rare, they may define a subset of tumors that are driven by the Ras-RAF-MEK pathway and therefore are sensitive to RAF inhibition, providing yet another glimpse into the future of cancer therapy dominated by personalized approaches.

N. Palanisamy et al., Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat. Med. 6 June 2010 (10.1038/nm.2166). [Abstract]

Navigate This Article