Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors.
Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors.
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DOI：
10.1002/gcc.20589
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发表时间：
2008-10
影响因子：
3.7
通讯作者：
Antonescu, Cristina R.
中科院分区：
文献类型：
--
作者：
Agaram, Narasimhan P.;Wong, Grace C.;Guo, Tianhua;Maki, Robert G.;Singer, Samuel;DeMatteo, Ronald P.;Besmer, Peter;Antonescu, Cristina R.
BRAF和NRAS通常在癌症中突变，并且代表恶性黑色素瘤中最常见的遗传事件。最近，黑色素瘤的一个子集被证明过表达KIT和港口KIT突变。尽管大多数胃肠道间质瘤（GIST）在KIT或PDGFRA中表现出激活突变，但约10%的病例缺乏这些基因的突变。根据黑色素瘤模型，我们假设BRAF或NRAS突变可能在野生型GIST发病机制中发挥作用。RAS/MEK/ERK通路的改变也可能参与GIST中伊马替尼耐药的发展，特别是在缺乏继发性KIT或PDGFRA突变的肿瘤中。分析了61例患者（包括15例儿童和28例无继发性KIT突变的伊马替尼耐药肿瘤）的未接受过伊马替尼治疗的野生型GIST。进行BRAF（外显子11和15）和NRAS（外显子2和3）中的热点突变的筛查。在61例GIST患者中的3例中鉴定出BRAF外显子15 V600 E，这些患者具有相似的临床特征，为49至55岁的女性，并且肿瘤位于小肠。肿瘤呈强KIT免疫反应性，恶性风险高。在28例缺乏明确耐药机制的伊马替尼耐药GIST中，也发现了一个相同的V600 E BRAF突变。总之，我们在7%缺乏KIT/PDGFRA突变的成人GIST患者中发现了原发性BRAF V600 E突变。BRAF突变的GIST显示出小肠位置的偏好和恶性肿瘤的高风险。继发性V600 E BRAF突变可能代表伊马替尼耐药的另一种机制。针对BRAF的激酶抑制剂可能是该分子GIST亚组的有效治疗选择。
BRAF and NRAS are commonly mutated in cancer and represent the most frequent genetic events in malignant melanoma. More recently, a subset of melanomas was shown to overexpress KIT and harbor KIT mutations. Although most gastrointestinal stromal tumors (GISTs) exhibit activating mutations in either KIT or PDGFRA, about 10% of the cases lack mutations in these genes. It is our hypothesis following the melanoma model that mutations in BRAF or NRAS may play a role in wild-type GIST pathogenesis. Alterations in RAS/MEK/ERK pathway may also be involved in development of imatinib resistance in GIST, particularly in tumors lacking secondary KIT or PDGFRA mutations. Imatinib-naive wild-type GISTs from 61 patients, including 15 children and 28 imatinib-resistant tumors without secondary KIT mutations were analyzed. Screening for hot spots mutations in BRAF (exons 11 and 15) and NRAS (exons 2 and 3) was performed. A BRAF exon 15 V600E was identified in 3 of 61 GIST patients, who shared similar clinical features, being 49- to 55-years-old females and having their tumors located in the small bowel. The tumors were strongly KIT immunoreactive and had a high risk of malignancy. An identical V600E BRAF mutation was also identified in one of 28 imatinib resistant GIST lacking a defined mechanism of drug resistance. In conclusion, we identified a primary BRAF V600E mutations in 7% of adult GIST patients, lacking KIT/PDGFRA mutations. The BRAF-mutated GISTs show predilection for small bowel location and high risk of malignancy. A secondary V600E BRAF mutation could represent an alternative mechanism of imatinib resistance. Kinase inhibitors targeting BRAF may be effective therapeutic options in this molecular GIST subset.
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影响因子：
8.4
作者：
Debiec-Rychter, M;Dumez, H;van Oosterom, AT
通讯作者：
van Oosterom, AT
影响因子：
64.8
作者：
Solit, DB;Garraway, LA;Rosen, N
通讯作者：
Rosen, N
影响因子：
45.3
作者：
Heinrich, MC;Corless, CL;Fletcher, JA
通讯作者：
Fletcher, JA
影响因子：
9
作者：
Kebebew, Electron;Weng, Julie;Griffin, Ann
通讯作者：
Griffin, Ann
影响因子：
3.3
作者：
Willmore-Payne, C;Holden, JA;Layfield, LJ
通讯作者：
Layfield, LJ