Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma.
Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma.
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DOI：
10.1097/md.0000000000002491
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发表时间：
2016-01
期刊：
影响因子：
1.6
通讯作者：
Gill AJ
中科院分区：
文献类型：
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作者：
Andrici J;Goeppert B;Sioson L;Clarkson A;Renner M;Stenzinger A;Tayao M;Watson N;Farzin M;Toon CW;Smith RC;Mittal A;Samra JS;Hugh TJ;Chou A;Lawlor RT;Weichert W;Schirmacher P;Sperandio N;Ruzzenente A;Scarpa A;Gill AJ
BRCA 1相关蛋白1（BAP 1）是一种去泛素化酶，作为肿瘤抑制基因发挥作用。在包括肝内胆管癌（ICC）在内的一系列肿瘤类型中已报告了双重打击BAP 1失活，有时与种系突变相关。我们在3个不同国家的3个机构对211例接受根治性手术切除的ICC患者进行了BAP 1的免疫组化。诊断时的中位年龄为65岁（范围，36.5-86岁），108例（51%）为男性。在55个ICC（26%）中出现BAP 1阴性染色（定义为在非肿瘤细胞中存在阳性内部对照时完全不存在核染色）。BAP 1缺失预测中位生存期有明显改善趋势，为40.80个月（95% CI，28.14-53.46）vs 24.87个月（95% CI，18.73-31.01），P = 0.059）。 在包括年龄、性别、BAP 1状态、肿瘤分期、肿瘤分级、淋巴管浸润和肿瘤大小的多变量模型中，女性性别与生存期延长相关（风险比[HR] 0.54; 95%CI，0.34-0.85），而晚期肿瘤分期和淋巴管浸润（HR 1.89; 95%CI，1.09-3.28）与生存期缩短相关。在多变量分析中，高级别肿瘤与BAP 1丢失相关（比值比[OR] 3.32; 95%CI，1.29-8.55），而淋巴管浸润与BAP 1丢失呈负相关（OR 0.36; 95%CI，0.13-0.99）。总之，我们观察到ICC预后改善的趋势与BAP 1表达缺失相关，BAP 1缺失与较高的组织学分级和无淋巴浸润相关。女性与生存率提高相关，而晚期肿瘤分期和淋巴管浸润与生存率降低相关。
BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that functions as a tumor suppressor gene. Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation. We performed immunohistochemistry for BAP1 on a well-characterized cohort of 211 ICC patients undergoing surgical resection with curative intent at 3 institutions based in 3 different countries. The median age at diagnosis was 65 years (range, 36.5–86) and 108 (51%) were men. Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in nonneoplastic cells) occurred in 55 ICCs (26%). BAP1 loss predicted a strong trend toward improved median survival of 40.80 months (95% CI, 28.14–53.46) versus 24.87 months (95% CI, 18.73–31.01), P = 0.059). In a multivariate model including age, sex, BAP1 status, tumor stage, tumor grade, lymphovascular invasion, and tumor size, female sex was associated with improved survival (hazard ratio [HR] 0.54; 95% CI, 0.34–0.85), while advanced tumor stage and lymphovascular invasion (HR 1.89; 95% CI, 1.09–3.28) correlated with decreased survival. In a multivariate analysis, high grade tumors were associated with BAP1 loss (odds ratio [OR] 3.32; 95% CI, 1.29–8.55), while lymphatic invasion was inversely associated with BAP1 loss (OR 0.36; 95% CI, 0.13–0.99). In conclusion, we observed a trend toward improved prognosis in ICC associated with absent expression of BAP1 and an association of BAP1 loss with higher histological grade and absent lymphatic invasion. Female sex was associated with improved survival while advanced tumor stage and lymphatic invasion were associated with decreased survival.