Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
J Mol Diagn. 2013 Mar;15(2):220-6. doi: 10.1016/j.jmoldx.2012.10.002. Epub 2012 Dec 27.
The US Food and Drug Administration (FDA) approved vemurafenib to treat patients with metastatic melanoma harboring the BRAF c.1799T>A (p.V600E) mutation. However, a subset of melanomas harbor non-p.V600E BRAF mutations, and these data are of potential importance regarding the efficacy of current targeted therapies. To better understand the BRAF mutation profile in melanomas, we retrospectively analyzed data from 1112 primary and metastatic melanomas at our institution. The cohort included nonacral cutaneous (n = 774), acral (n = 111), mucosal (n = 26), uveal (n = 23), leptomeningeal (n = 1), and metastatic melanomas of unknown primary site (n = 177). BRAF mutation hotspot regions in exons 11 and 15 were analyzed by pyrosequencing or with the primer extension MassARRAY system. A total of 499 (44.9%) specimens exhibited BRAF mutations, involving exon 15 [497 (99.6%)] or exon 11 [2 (0.4%)]. p.V600E was detected in 376 (75.4%) cases; the remaining 123 (24.6%) cases exhibited non-p.V600E mutations, of which p.V600K was most frequent [86 (17.2%)]. BRAF mutations were more frequent in nonacral cutaneous (51.4%) than acral melanomas [18 (16.2%)] (P < 0.001); however, there was no significant difference among cutaneous histological subtypes. All mucosal, uveal, and leptomeningeal melanomas were BRAF wild type (WT). The high frequency of non-p.V600E BRAF mutations in melanoma has important implications because the FDA-approved companion diagnostic test for p.V600E detects some but not all non-p.V600E mutations. However, the therapeutic efficacy of vemurafenib is not well established in these lesions.
美国食品和药物管理局（FDA）批准vemurafenib 用于治疗携带 BRAF c.1799T>A（p.V600E）突变的转移性黑色素瘤患者。然而，一部分黑色素瘤携带非 p.V600E BRAF 突变，这些数据对于当前靶向治疗的疗效具有潜在重要性。为了更好地了解黑色素瘤中的 BRAF 突变谱，我们回顾性分析了我院 1112 例原发和转移性黑色素瘤的数据。该队列包括非肢端皮肤黑色素瘤（n = 774）、肢端黑色素瘤（n = 111）、黏膜黑色素瘤（n = 26）、葡萄膜黑色素瘤（n = 23）、软脑膜黑色素瘤（n = 1）和不明原发部位转移性黑色素瘤（n = 177）。通过焦磷酸测序或引物延伸 MassARRAY 系统分析外显子 11 和 15 的 BRAF 突变热点区域。共有 499 例（44.9%）标本显示 BRAF 突变，涉及外显子 15 [497 例（99.6%）]或外显子 11 [2 例（0.4%）]。在 376 例（75.4%）病例中检测到 p.V600E；其余 123 例（24.6%）病例显示非 p.V600E 突变，其中 p.V600K 最为常见[86 例（17.2%）]。非肢端皮肤黑色素瘤的 BRAF 突变率（51.4%）明显高于肢端黑色素瘤[18 例（16.2%）]（P < 0.001）；然而，皮肤组织学亚型之间没有显著差异。所有黏膜、葡萄膜和软脑膜黑色素瘤均为 BRAF 野生型（WT）。黑色素瘤中非 p.V600E BRAF 突变的高频率具有重要意义，因为 FDA 批准的用于检测 p.V600E 的伴随诊断测试可以检测到一些但不是所有的非 p.V600E 突变。然而，vemurafenib 的治疗效果在这些病变中尚未得到很好的证实。
