A BRAF Story | Colorectal, Thyroid CA and Melanoma September 6, 2007Posted by ramunas in cancer genetics, colon cancer, colorectal cancer, genetic testing, hereditary cancer, HNPCC, sporadic cancer.
For the first time I’ve read about BRAF oncogene in a poster presented during one of the European Society of Human Genetics conference, probably in Amsterdam, Holland. It appeared that a single amino acid substitution (p.V600E), a hotspot point mutation, is an useful marker to exclude HNPCC (hereditary non-polyposis colorectal cancer). Interestinlgy, this somatic mutation of BRAF gene, which belongs to the RAF family of protein kinases from the RAS/RAF/MAPK pathway, is more than 90% present in sporadic colorectal cancers with methylated hMLH1 gene. Therefore, if you have access to a tumor DNA after simple PCR test you can exclude or suspect hereditary form of this cancer. The detection of a positive BRAF-V600E mutation in a colorectal cancer suggests a sporadic origin of the disease and the absence of germline alterations of MLH1, MSH2 and also of MSH6. These findings have a potential impact in the genetic testing for HNPCC diagnostics and suggest a potential use of BRAF as exclusion criteria for HNPCC or as a molecular marker of sporadic cancer (via).
Obviously, the confirmation should be done by testing for germline mutations mismatch repair (MMR) genes (mostly MLH1, MSH2, MSH6). Also, immunohistochemistry may point you which protein is missing. The Bethesda guidelines , original (1997) and revised (2003), are designed to select cases for analysis of microsatelite instability (MSI) features of tumor, but testing for BRAF mutation can yield additional and faster information.
Conventional strategy for genetic testing of affected individuals from families with suspected hereditary non-polyposis colorectal cancer (source):
Screening of mismatch repair (MMR) genes can be avoided in cases positive for V600E if no other significant evidence, such as fulfilment of the strict Amsterdam criteria, suggests MMR associated HNPCC. In this context, mutation analysis of the BRAF hotspot is a reliable, fast, and low cost strategy which simplifies genetic testing for HNPCC, one article states.
That is a story about colorectal cancer, but it was interesting for me to find out, that the same mutation of BRAF oncogene can be present in thyroid cancer. That may be useful in predicting the level of aggression of thyroid cancer and help guide treatment options and follow-up care, says the new research paper published in the September issue of the “Annals of Surgery”.
Researchers concluded, that BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.
Study author, Kebebew E, explained that identification of the mutation in patients with thyroid cancer could be very useful in a variety of ways. For example, patients with the mutation may be candidates for a more aggressive approach to surgery, such as removing the central lymph node along with the diseased thyroid, to avoid the possibility of metastasis following surgery. BRAF V600E testing could also be useful for deciding between low- or high-dose radioiodine ablation therapy.
Other BRAF mutations are found in melanoma and BRAF possitive tumors may be more sensitive to a new class of drugs – protein MEK inhibitors (such as PD0325901, developed by Pfizer Research and Development).