Somatic activation of KIT in distinct subtypes of melanoma
Somatic activation of KIT in distinct subtypes of melanoma
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DOI：
10.1200/jco.2006.06.2984
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发表时间：
2006-09-10
影响因子：
45.3
通讯作者：
Bastian, Boris C.
中科院分区：
文献类型：
--
作者：
Curtin, John A.;Busam, Klaus;Bastian, Boris C.
目的黏膜、肢端皮肤(足底、手掌和甲床)和慢性日光损伤皮肤上的黑色素瘤在BRAF和NRAS中很少发生突变，而间歇性日晒皮肤上的黑色素瘤中丝裂原活化蛋白(MAP)激酶通路中的基因通常发生突变。我们分析了102例原发黑色素瘤(38例来自黏膜，28例来自肢端皮肤，18例来自皮肤，18例来自皮肤，18例来自皮肤，18例来自皮肤)的DNA拷贝数异常，以寻找BRAF和NRAS突变不常见的黑色素瘤亚型特有的DNA拷贝数异常。结果在7例有扩增的肿瘤中，有3例KIT基因发生突变。对所有102例原发黑色素瘤的检查发现，在慢性日光损伤皮肤上39%的粘膜、36%的肢端和28%的黑色素瘤中，KIT的突变和/或拷贝数增加，但在没有慢性日光损伤的皮肤上的任何(0%)黑色素瘤中没有发现KIT突变和/或拷贝数增加。79%的突变肿瘤和53%的KIT多拷贝肿瘤显示KIT蛋白水平升高。结论KIT是黑色素瘤的重要癌基因。由于我们在黑色素瘤中发现的大多数KIT突变也发生在其他类型的对伊马替尼敏感的癌症中，伊马替尼可能会对全球黑色素瘤负担中的很大一部分立即提供治疗益处。
PurposeMelanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogen-activated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS.Patients and MethodsWe analyzed array comparative genomic hybridization data from 102 primary melanomas (38 from mucosa, 28 from acral skin, and 18 from skin with and 18 from skin without chronic sun-induced damage) for DNA copy number aberrations specific to melanoma subtypes where mutations in BRAF and NRAS are infrequent. A narrow amplification on 4q12 was found, and candidate genes within it were analyzed.ResultsOncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels.ConclusionKIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden.