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Introduction
Melanoma is an aggressive cancer with an extremely poor prognosis. In 2015, the number of newly diagnosed cases of melanoma in the United States was 73,870, and the number of deaths was approximately 9,940 (1). In China, the number of newly diagnosed cases of melanoma in 2015 was 8,000, and the number of deaths was approximately 3200 (2).
BRAF is an important serine/threonine kinase in the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a critical role in cell proliferation and apoptosis (3,4). Abnormal expression or activation of BRAF has been found in a variety of tumors (5). In melanoma, BRAF mutations have been detected in 66% of Caucasian patients (6) and 25.5% of non-Caucasian patients (7). Moreover, BRAF p.V600E (1799T>A) is a hotspot mutation that is detected in melanoma, and this mutation can increase BRAF kinase activity by 10–20-fold (8) and accounts for 80–90% of all detected BRAF mutations (7,9). Patients can be treated effectively because the selective inhibitors vemurafenib plus cobimetinib (10) or dabrafenib plus trametinib (11) have been classified as the primary first-line therapy by the National Comprehensive Cancer Network (NCCN) for the treatment of advanced BRAF V600-mutant melanoma. However, the clinical significance of other BRAF mutations, which account for approximately 10 to 20% of cases, is largely unknown.
Recent studies suggest that the effects of BRAF mutations can be divided into kinase-activating (e.g., p.V600E) and kinase-impairing (e.g., p.D594G or G596N) mutations (12). In contrast to BRAF V600E, which causes hyperactivation of downstream kinase pathways, kinase-impairing mutations lead to a reduction in BRAF kinase activity or alternatively activation of silent and wild-type CRAF to elevate MEK activity (13,14).
Because BRAF kinase-impairing mutations are different from kinase-activating (e.g., p.V600E) mutations, we retrospectively collected samples and clinical data from a non-Caucasian patient population and compared the clinical and pathological characteristics as well as clinical outcomes of patients bearing BRAF kinase-activating mutated melanoma with those of patients with BRAF wild-type melanoma. Our goal was to shed light on different therapeutic strategies for treating BRAF-mutated tumors.
Materials and methods
Patients and tissue samples
This study used samples from 1,554 melanoma patients who were hospitalized between July 2012 and July 2015 at Beijing Cancer Hospital and Institute. All samples were analyzed by hematoxylin and eosin (H&E)...