BRAF V600E and V600K in Melanoma: Clinicopathologic Correlation
Bibianna M Purgina, Tomislav Jelic, Simion I Chiosea. University of Pittsburgh Medical Center, Pittsburgh, PA
Background: The aim of this study was to compare the clinicopathologic correlates of two most common BRAF mutations in melanomas: V600E and V600K.
Design: Patients with melanomas harboring BRAF V600E or V600K mutations were identified among cases consecutively tested for BRAF mutations as part of routine clinical management. Sanger sequencing was performed on formalin-fixed paraffin embedded samples. The type of BRAF mutation, disease-free survival (DFS), and clinicopathologic features were tabulated and analyzed. To characterize BRAF mutant allele specific imbalance (MASI), peak heights of BRAF mutant allele (MA) and wild type allele (WTA) as seen on forward sequencing electropherograms (SE) were compared and categorized in 2 groups: MA>WTA, i.e., MASI, or MA≤WTA. Eight cases of MA>WTA and 3 cases of MA≤WTA were selected for BRAF fluorescence in situ hybridization (FISH) with BRAF/CEP7 dual color probe (Abbott Molecular, Inc., Des Plaines, IL). BRAF /CEP7 ratio ≥ 2 was considered positive for amplification. Polysomy was defined as > 2 chromosome enumeration probe 7 signals in ≥ 40% of cells.
Results: Patients with BRAF V600E (n=64) were on average 17 years younger than patients with BRAF V600K melanomas (n = 18) (47 years versus 64 years of age, p<0.001). MASI was more commonly seen in V600E than in V600K mutations (44/64, 69%, versus 7/18, 39%, p < 0.001). Cases with BRAF MA>WTA on SE showed BRAF amplification (3/8 cases), chromosome 7 polysomy (5/7 cases) and chromosome 7 monosomy (1/8 cases) on FISH. Patients with BRAF V600K melanomas had shorter DFS compared to BRAF V600E melanomas (mean DFS 18.4 months, 95% confidence interval [95 CI] 8.8 – 28 versus 64.8, 95 CI 44 – 85 months, respectively, p < 0.001). Age, gender, BRAF MASI and clinical stage did not correlate with DFS or overall survival.
Conclusions: BRAF V600K was found in 22% of cases in this cohort. BRAF MASI is more common in V600E than in V600K and develops by BRAF amplification, chromosome 7 polysomy and monosomy. Patients with BRAF V600K melanomas present at an older age and have a shorter DFS compared to BRAF V600E melanomas.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 86, Monday Morning