Rapisuwon Suthee, Parks Kellie, Al-Refaie Waddah, Atkins Michael B
aDivision of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center bMelanoma Disease Group, Medstar-Georgetown Cancer Network, Washington, District of Columbia cDivision of Surgical Oncology, Medstar-Georgetown University Hospital, USA.
Melanoma Res. 2014 Oct;24(5):509-11. doi: 10.1097/CMR.0000000000000102.
Primary mucosal melanomas represent ∼1.3% of all cases of melanoma diagnosed in the USA. The sinonasal location is the most common primary site. Mutations in the KIT gene occur in 10-22% of mucosal melanomas. Tumor response to imatinib mesylate has been reported in about half of the patients with tumors harboring KIT mutations. Responses are almost exclusively restricted to tumors with mutations in KIT exon 9 or 11. We report a case of a patient with a sinonasal mucosal melanoma with a novel exon 8 mutation (C443S) who had marked initial response to imatinib. Somatic exon 8 KIT mutations have not been previously reported in mucosal melanoma or in other human solid tumors; however, such mutations have been reported in canine and feline mast cell tumors. Protein transcripts from exon 8 play an important role in the structural and functional integrity of the extracellular domain of KIT. In preclinical studies, a mutation in exon 8 led to autophosphorylation, independent of KIT ligand, and constitutive activation of the tyrosine kinase. This biology may explain the successful application of imatinib in animals with tumors harboring exon 8 KIT mutations and in our patient with mucosal melanoma. This report expands the population of patients with melanoma who might benefit from imatinib to those with somatic exon 8 KIT mutations. Such mutations should be looked for in patients with mucosal melanoma.
原发性黏膜黑色素瘤约占美国诊断出的所有黑色素瘤病例的1.3%。鼻窦部位是最常见的原发部位。KIT基因的突变发生在10%至22%的黏膜黑色素瘤中。据报道，大约一半携带KIT基因突变的肿瘤患者对甲磺酸伊马替尼有肿瘤反应。反应几乎完全局限于KIT外显子9或11发生突变的肿瘤。我们报告了一例鼻窦黏膜黑色素瘤患者，该患者有一个新的外显子8突变（C443S），对伊马替尼有明显的初始反应。此前尚未在黏膜黑色素瘤或其他人类实体瘤中报道过体细胞外显子8 KIT突变；然而，在犬类和猫类肥大细胞肿瘤中已报道过此类突变。外显子8的蛋白质转录本在KIT细胞外结构域的结构和功能完整性中起重要作用。在临床前研究中，外显子8的突变导致了自磷酸化，独立于KIT配体，并导致酪氨酸激酶的组成性激活。这种生物学特性可能解释了伊马替尼在携带外显子8 KIT突变的肿瘤动物以及我们的黏膜黑色素瘤患者中的成功应用。本报告将可能从伊马替尼中获益的黑色素瘤患者群体扩大到了具有体细胞外显子8 KIT突变的患者。对于黏膜黑色素瘤患者应寻找此类突变。
