Monday, April 28, 2014

The discovery of BRAF mutation in melanoma is shown to be extraordinarily important

by Ellie Pringle

After reading the articles about DNA sequencing and the cancer genome and because for my project topic my partner and I are focusing on how a mutated BRAF gene is a cause of melanoma, I decided I wanted to learn more about how sequencing and the discovery of the relationship between the mutated BRAF gene and melanoma has changed cancer treatments today.  To do this I chose to start by focusing on the initial discovery of the mutated BRAF gene in cancers.
As we read in the article by MacConaill and Garraway, one of the first discoveries made after the implementation of large-scale DNA sequencing was that of a mutation in BRAF.  BRAF codes for a serine/threonine kinase oncogene that transmits signals downstream of RAS in the MAP kinase cascade to transduce regulatory signals from Ras to MEK1/2.  This sequence eventually codes for cell growth.  In this post I am going to discuss the first discoveries of the BRAF gene in Melanoma.
It was discovered in 2002 that BRAF somatic missense mutatations occurred in 66% of malignant melanomas.  BRAF mutations were also found in other cancers that tended to have RAS mutations as well, like colorectal cancer and some types of ovarian cancers, but the mutation was overwhelmingly found more in melanoma cases.

Figure 1: This figure shows the difference in genome sequence of normal DNA sequences and cancer stricken DNA sequences. 

  There were three single-base mutations detected, two of them were found in exon 15 and one was found in exon 11.  The most frequent mutation occurred in a specific region of the B-raf protein at V599E.  This mutation was studied further and it was found that it had elevated basal kinase activity compared with wild-type BRAF.  This suggests that the mutated BRAF gene mimics the stimulation of multiple growth factors to encourage transformation and autonomous growth.
Figure 2: This is a picture that shows the MAPK kinase and the position that the B-raf protein has in it.  It also shows why targeting the ERK inhibitor would potentially stop growth, which is where one of the first ideas for drug treatment of melanoma stemmed from.

         The BRAF mutations found in malignant melanoma were not related to the effects of ultraviolet light, which is traditionally the most commonly known environmental factor leading to melanoma.  The difference between melanoma caused by a mutation in BRAF is different from that of melanomas found from sunlight exposure in that the T to A change at nucleotide 1796, which is found in 92% of BRAF mutations in melanoma, differs from the CC to TT or C to T changes that are associated with exposure to ultraviolet light. 
The discovery of the BRAF mutation in melanoma cancers has prompted many new drug treatment therapies.  Before this discovery there were very few ways to treat melanoma past extraction of the area affected.  Melanoma that had metastasized to distant sites that was not caught early enough for extraction had only a 6% 5-year survival rate.  This is an early example of how genome sequencing can be used to determine specialized treatments for patients.  It was an extremely important discovery both because of its prospect for helping with melanoma treatment and because of the potential it showed for the positive affects that the cancer genome project could have. This New York Times article was published shortly after the discovery and shows the excitement that ensued from it.
 In upcoming posts I will discuss new drug treatment therapies that focus on the BRAF gene.  One of the very first treatments that was thought to help in the treatment of melanoma was the use of ERK1/2 inhibitor U0126 that caused decreases in proliferation of melanoma cell lines that had BRAF mutations.


Davies, Helen. et al. "Mutations of the BRAF gene in human cancer". Nature Publishing Group, 2002. Print.

Maldonado, Janet L. et al. "Determinants of BRAF Mutations in Primary Melanomas". Journal of the National Cancer Institute, 2003. Print.

Pollock, Pamela M. and Paul S. Meltzer. "A genome-based strategy uncovers frequent BRAF mutations in melanoma". Cancer Cell, 2002. Print.