Kaji Tatsuya, Yamasaki Osamu, Takata Minoru, Otsuka Masaki, Hamada Toshihisa, Morizane Shin, Asagoe Kenji, Yanai Hiroyuki, Hirai Yoji, Umemura Hiroshi, Iwatsuki Keiji
Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan; Melanoma Center, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan; Okada Orthopedics and Dermatology Clinic, 39-1 Kamigori, Hyogo, 678-1225, Japan.
J Dermatol Sci. 2017 Jan;85(1):51-57. doi: 10.1016/j.jdermsci.2016.10.006. Epub 2016 Oct 13.
BACKGROUND: Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy. OBJECTIVES: We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations. METHODS: Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared. RESULTS: Of 77 tissue samples, BRAF V600E was detected in 21 samples (27%), CDK4 R24C in 7, EPHB6 G404S in 6, BRAF V600K in 2, NEK10 E379K in 2, and CDK4 R24H, NRAS Q61K, NRAS Q61R, KRAS G12A, KIT L576P, KIT V559A, ERBB4 E452K, and PDGFRA E996K in one sample each. No driver mutations related to the MAPK cascade including RAS and BRAF were detected in the chronically sun-damaged (CSD) group of melanoma. Dual or triple driver mutations were found in four of 40 (10%) samples from the primary melanomas, and three of 37 (8%) of the metastatic melanomas. Fourteen of 26 (54%) samples of non-CSD melanoma, and 3 of 6 (50%) melanomas of unknown primary origin had the BRAF V600E mutation. Mutations in membrane-bound receptors including KIT, ERBB4 and EPHB6 were detected in 8 of 77 (10%) samples. Of 17 pairs of primary and metastatic melanomas from the same patient, the primary mutation pattern was changed to a novel one in three cases, and only one of the plural mutations in the primary melanoma was found in the metastatic lesions in two cases. CONCLUSIONS: BRAF V600E is a predominant mutation in non-CSD melanoma and melanomas of unknown primary origin. Mutational heterogeneity may exist in the primary melanoma (intra-tumor heterogeneity), and between the primary and metastatic lesions (inter-tumor heterogeneity).
背景：寻找黑色素瘤中的驱动突变对于理解黑色素瘤的发生、发展及对治疗的反应至关重要。 目的：我们旨在研究日本原发性和转移性黑色素瘤（包括原发灶不明的病例）中驱动突变的频率和模式，并探讨其与临床病理表现的关系。 方法：采用Sequenom MelaCarta MassARRAY技术对60例黑色素瘤患者的77个样本进行20个癌基因的70个驱动突变筛查，并比较原发性和转移性黑色素瘤的检测结果。 结果：在77个组织样本中，21个样本（27%）检测到BRAF V600E突变，7个样本检测到CDK4 R24C突变，6个样本检测到EPHB6 G404S突变，2个样本检测到BRAF V600K突变，2个样本检测到NEK10 E379K突变，各有1个样本检测到CDK4 R24H、NRAS Q61K、NRAS Q61R、KRAS G12A、KIT L576P、KIT V559A、ERBB4 E452K和PDGFRA E996K突变。在慢性日光损伤（CSD）黑色素瘤组中未检测到与RAS和BRAF等MAPK级联相关的驱动突变。在40例原发性黑色素瘤样本中有4例（10%）、37例转移性黑色素瘤样本中有3例（8%）检测到双重或三重驱动突变。26例非CSD黑色素瘤样本中有14例（54%）、6例原发灶不明的黑色素瘤样本中有3例（50%）检测到BRAF V600E突变。77个样本中有8个（10%）检测到包括KIT、ERBB4和EPHB6在内的膜结合受体突变。在17对来自同一患者的原发性和转移性黑色素瘤中，有3例原发性突变模式转变为新的模式，2例中仅在转移性病灶中发现原发性黑色素瘤多个突变中的1个。 结论：BRAF V600E是非CSD黑色素瘤和原发灶不明黑色素瘤中的主要突变。原发性黑色素瘤（肿瘤内异质性）以及原发性和转移性病灶之间（肿瘤间异质性）可能存在突变异质性。
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