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BRAF Mutation Triggers Series of Cellular Transformations Leading to Colon Cancer

By BiotechDaily International staff writers
Posted on 23 Jul 2013
Cancer researchers have found that the activity of the protein encoded by the mutant BRAFV600E gene triggers a series of transformations (hyperplasia to adenoma to carcinoma) that convert normal cells in the colon into a precancerous and ultimately fully cancerous state.

The BRAF (v-Raf murine sarcoma viral oncogene homolog B1) gene encodes the protein serine/threonine-protein kinase B-Raf. About half of melanomas express the BRAFV600E mutation (at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). Inhibitors of B-Raf such as vemurafenib have been approved for the treatment of metastatic melanoma since August 2011. In addition to melanoma, this mutation has been widely observed in papillary thyroid carcinoma and colorectal cancer.

An international team of investigators performed genetic and functional analyses in mice that revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. They reported in the July 8, 2013, issue of the journal Cancer Cell that BRAFV600E expression was sufficient for hyperplasia induction, but later stage intensified MAPK (mitogen-activated protein kinase)-signaling was required to drive both tumor progression and activation of intrinsic tumor suppression.

"Understanding the genetic makeup of different colorectal cancer subtypes will guide therapeutic decision making in the future," said senior author Dr. Allan Bradley, head of the mouse genomics team at the Wellcome Trust Sanger Institute (Hinxton, United Kingdom). "Our ability to engineer specific genetic alterations in mice allows us to study the function of cancer genes and to model specific cancer subtypes at an organismal level. Such mouse models are also invaluable for testing anticancer drugs before using them in clinical trials.”

"Our approach encapsulates the aim of cancer genomics: to discover changes to DNA responsible for cancer development and pinpoint the "Achilles heels" of cancer in order to identify new treatments," said first author Dr. Roland Rad, professor of translational oncology at the Technical University of Munich (Germany). "Our studies in mice revealed how genes cooperate to cause a specific subset of colon cancers. We identified main players, the order in which they occur during tumor progression, and the molecular processes how they turn relatively benign cell growth into threatening cancers. Such processes are targets for new treatments."

Related Links:

Wellcome Trust Sanger Institute
Technical University of Munich


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Image: Endoscopic image of a bowel section known as the sigmoid colon afflicted with ulcerative colitis. The internal surface of the colon is blotchy and broken in places (Photo courtesy of Wikimedia Commons).

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