BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma
BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma
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DOI：
10.1038/modpathol.2013.206
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发表时间：
2014-07-01
期刊：
影响因子：
7.5
通讯作者：
Capper, David
中科院分区：
文献类型：
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作者：
Goeppert, Benjamin;Frauenschuh, Lena;Capper, David
BRAF突变已成为转移性黑素瘤的重要预测生物标志物。其他类型的癌症也可能受益于BRAF突变靶向治疗。在胆道癌中，报告的BRAF突变率存在很大争议，胆囊腺癌的突变率为0 - 33%，胆管癌的突变率为0 - 22%。我们在这里分析了一个大的队列的胆道癌（n=377），包括159肝内胆管癌，149肝外胆管癌，69胆囊腺癌的BRAF V600 E突变的组织微阵列，使用高灵敏度的免疫组化筛选方法实施BRAF V600 E蛋白特异性抗体VE 1。所有VE 1阳性病例以及42例VE 1阴性病例通过桑格测序进行额外分析。总共仅检测到5例VE 1阳性病例（5/377; 1%）。所有病例均通过直接测序证实BRAFV 600 E突变。所有5例突变病例均为肝内胆管癌（5/159; 3%）。肝外胆管癌和胆囊腺癌均无VE 1阳性表达。除了BRAF V600 E突变对肝内胆管癌的亚型限制和女性优势（4名女性，1名男性）外，未检测到与临床病理学数据和患者结局的显著相关性。总之，我们证明BRAF V600 E突变在胆道癌中是一种罕见的事件，仅占所有亚型的1%，并且仅限于肝内胆管癌。此外，我们证明了VE 1免疫组化是一种可行的方法，可以常规筛查胆道癌患者的BRAF V600 E突变，从而有助于检测可能受益于BRAF突变靶向治疗的罕见患者。
BRAF mutations have emerged as an important predictive biomarker for metastasized melanoma. Other types of cancer may also benefit from BRAF mutation-targeted therapies. In biliary tract cancer, reported BRAF mutation rates are highly controversial, ranging from 0 to 33% in adenocarcinoma of the gallbladder and 0 to 22% in cholangiocarcinoma. We here analyzed tissue microarrays of a large cohort of biliary tract cancer (n=377) including 159 intrahepatic cholangiocarcinomas, 149 extrahepatic cholangiocarcinomas, and 69 adenocarcinomas of the gallbladder for BRAF V600E mutation using a highly sensitive immunohistochemical screening approach implementing the BRAF V600E protein-specific antibody VE1. All VE1-positive cases as well as 42 VE1-negative cases were additionally analyzed by Sanger sequencing. In total, only 5 VE1-positive cases were detected (5/377; 1%). BRAFV600E mutation was confirmed by direct sequencing in all cases. All 5 mutated cases were intrahepatic cholangiocarcinomas (5/159; 3%). None of the extrahepatic cholangiocarcinomas and adenocarcinomas of the gallbladder were VE1 positive. Apart from the subtype restriction of BRAF V600E mutation to intrahepatic cholangiocarcinoma and a female predominance (4 female, 1 male), no significant correlation with clinicopathological data and patient outcome was detected. In conclusion, we demonstrate that BRAF V600E mutation is a rare event in biliary tract cancer, accounting for only 1% of all subtypes, and is restricted to intrahepatia cholangiocarcinoma. In addition, we demonstrate that VE1 immunohistochemistry is a feasible approach to routinely screen for BRAF V600E mutation in biliary tract cancer patients, thereby facilitating the detection of rare patients who may benefit from BRAF mutation-targeted therapies.