In the first stage of a genome-wide screen, the authors have focused on pathways that are known to be deregulated in cancer.
BRAF
is involved in the RAS–RAF–MEK–ERK pathway — RAS is mutated in ∼15% of human cancers — so was a prime candidate for analysis. The gene was sequenced from genomic DNA that was isolated from 15 cancer cell lines, three of which — one melanoma and two non-small-cell lung cancers — were shown to contain single-base-pair substitutions. An extensive screen of 530 cancer cell lines followed this initial result, and revealed that 43, from a range of cancer types, contained a mutation in BRAF. Mutations were found exclusively in exons 11 and 15, and analysis of just these two exons from 378 primary cancers or short-term cultures confirmed that BRAF was frequently mutated in human cancer.
Although BRAF is mutated in a range of cancer types, it is most frequently mutated in melanoma: 59% of the melanoma cancer cell lines and 66% of the melanoma primary cancers investigated contained a mutation. Interestingly, the mutations are not linked to the principal cause of melanoma — ultraviolet (UV)-light irradiation — as the mutations are distinct from the C→T transitions that occur following UV-light-induced thymine dimer formation. Instead, the specificity for melanoma seems to be related to melanocyte biology, as α-melanocyte-stimulating hormone initiates a proliferative signal that operates through the BRAF–ERK kinase cascade.
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