BRAF pV600E Mutation Testing in Malignant Melanoma
BRAF is a serine/threonine protein kinase, activating the MAP kinase/ERK-signalling pathway.
About 50% of melanomas harbour activating BRAF mutations (80-90% of these are the V600E mutation).
Vemurafenib has been demonstrated to be effective in inhibiting melanomas carrying both the V600E and the rarer V600K mutation.
NICE recommends Vemurafenib as a possible treatment for unresectable or metastatic melanoma with the BRAF V600 mutation.
Molecular testing in Melanoma covering NRAS codons 12, 13 , 59 and 61 together with BRAF V600 covering cDNA positions c.1798, c.1799 and c.1800 which account for >95% of all BRAF mutations (Catalogue of Somatic Mutations In Cancer: cancer.sanger.ac.uk/cancergenome/projects/cosmic/).
C-KIT Testing in Melanoma
KIT mutations are mutually exclusive with those of BRAF and NRAS. KIT mutations constitutively activating RTK signalling, typically point mutations, have been identified in 14% and 18% of acral lentiginous and mucosal melanoma’s respectively (Woodman and Davies et al, 2010). Overall, the frequency of KIT mutations is therefore relatively low (3%).These occur most frequently in KIT exons 9, 11, 13 and 17, with the missense mutation c.1727T>C p.(Leu576Pro) in exon 11 being the most prevalent (Rother and Jones, 2009).
Dysregulation of RTK signalling renders malignant cells responsive to tyrosine kinase inhibitor’s (TKI’s), and phase II clinical trials report sensitivity of melanoma’s harbouring KIT mutations to a variety of clinically available TKI’s including imatinib, and sorafenib (Hodi et al, 2008; Rother and Jones, 2009; Carvajal et al, 2011). However, as these treatments are not currently NICE approved, testing of KIT in melanoma is by specific clinical request only. Nevertheless, accurately identifying exon 9, 11, 13 and 17 KIT mutations in specific malignant melanoma cases, currently by Sanger sequencing, is a useful guide in providing information that can guide patient therapy.