Clinicopathological characteristics associated with BRAF^K601E and BRAF^L597 mutations in melanoma

Abstract

BRAF mutations at codons L597 and K601 occur uncommonly in melanoma. Clinical and pathological associations of these mutations were investigated in a cohort of 1119 patients with known BRAF mutation status. A BRAF mutation was identified in 435 patients; Mutations at L597 and the K601E mutation were seen in 3.4 and 3.2% of these, respectively. K601E melanomas tended to occur in male patients, a median age of 58 yr, were generally found on the trunk (64%) and uncommonly associated with chronically sun-damaged (CSD) skin. BRAF L597 melanomas occurred in older patients (median 66 yr), but were associated with CSD skin (extremities or head and neck location - 73.3%, P = 0.001). Twenty-three percent of patients with V600E- and 43% of patients with K601E-mutant melanomas presented with nodal disease at diagnosis compared to just 14% of patients with BRAF wild-type tumors (P = 0.001 and 0.006, respectively). Overall, these mutations represent a significant minority of BRAF mutations, but have distinct clinicopathological phenotypes and clinical behaviors.

Targeted Therapy in Advanced Melanoma With Rare BRAF Mutations

“…34 L597P has not been functionally or clinically validated, but is considered likely oncogenic as a result of its vicinity to L597Q/R/S. [35][36][37] Ectopic expression of L597Q/R/S has shown elevated phospho-MEK and -ERK, and tumor regression was shown for L597S and L597Q in vitro and in vivo when treated with MEKi. 24,35 This finding was clinically supported in two case reports in patients with L597R-and L597S-mutated melanoma.…”

Feasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations

“…Several additional mutations were identified in some of the tumors, as listed in Table 1. CBRC013 contained both GNAQ[R183Q] and NRAS[Q61H] mutations, CBRC058 contained an unusual BRAF[VK600_601>E] mutation (42), and CBRC026 contained a FGFR2[N653D] mutation. CBRC029 and CBRC056 did not contain any other hotspot mutations.…”

Treating malignant melanoma when a rare BRAF V600M mutation is present: case report and literature review

“…The clinical trials, however, support this correlation in cases with V600E and V600K mutations, which are the more prevalent mutations (more than 95%), and cannot address the issue of benefit (or lack of) with the more rare mutations, such as V600M or V600D. The V600M BRAF mutation is present in less than 1% of melanoma cases [4] and it consists of a substitution at position 600 in the BRAF gene, from a valine (V) to a methionine (M).…”

“…Although curable in its early stages, advanced/metastatic melanoma carries a very bad prognosis; the efforts to combat metastatic malignant melanoma through systemic therapy have all but stagnated up until relatively recently, with the description of the MAPK pathway as a therapeutic target [1] and the discovery of BRAF inhibition through tyrosine-kinase inhibiting drugs. Mutations in the BRAF gene seem to be present in around 40-50% of the cutaneous melanomas [2,3,4] and have been clinically proven to correlate with an increased benefit in terms of response rate and overall survival, compared to classical chemotherapy, from treatment with BRAF-inhibiting drugs, such as vemurafenib or dabrafenib [5,6]. The clinical trials, however, support this correlation in cases with V600E and V600K mutations, which are the more prevalent mutations (more than 95%), and cannot address the issue of benefit (or lack of) with the more rare mutations, such as V600M or V600D.…”