Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations.
Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations.
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DOI：
10.1158/0008-5472.can-15-3371
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发表时间：
2016-05-01
期刊：
影响因子：
11.2
通讯作者：
Testa JR
中科院分区：
文献类型：
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作者：
Kadariya Y;Cheung M;Xu J;Pei J;Sementino E;Menges CW;Cai KQ;Rauscher FJ;Klein-Szanto AJ;Testa JR
携带BAP1遗传杂合生殖系突变的个体易患一系列良性和恶性肿瘤类型，包括恶性间皮瘤、黑色素瘤和肾癌。然而，支持BAP 1在癌症中的肿瘤抑制作用的证据仍然相互矛盾。为了通过实验测试BAP1是否具有肿瘤抑制作用，我们在Bap1中具有种系杂合突变的三种不同小鼠模型中监测了自发肿瘤发展，其中包括两种模型，其中敲入突变与人类BAP1癌症综合征家族中报道的突变相同。我们在93只Bap1突变小鼠中的54只（58%）和43只野生型小鼠中的4只（9%）中观察到自发性恶性肿瘤。所有三种Bap1突变模型均表现出高发病率和相似的肿瘤谱，包括卵巢性索间质肿瘤、肺癌和乳腺癌以及梭形细胞肿瘤。值得注意的是，我们还观察到恶性间皮瘤在两个Bap1突变小鼠，但没有在任何野生型动物。我们进一步证实，剩余的野生型Bap1等位基因在自发性卵巢肿瘤和间皮瘤中丢失，导致Bap1表达的丢失。进一步的研究表明，石棉暴露诱导的侵袭性间皮瘤的发病率在两个小鼠模型携带临床相关的Bap1突变与石棉暴露的野生型同窝仔相比，显着增加。总的来说，这些发现提供了遗传学证据，证明Bap1是一个真正的肿瘤抑制基因，并提供了致癌物暴露对增强癌症易感性的贡献的关键见解。
Individuals harboring inherited heterozygous germline mutations in BAP1 are predisposed to a range of benign and malignant tumor types, including malignant mesothelioma, melanoma, and kidney carcinoma. However, evidence to support a tumor suppressive role for BAP1 in cancer remains contradictory. To test experimentally whether BAP1 behaves as a tumor suppressor, we monitored spontaneous tumor development in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families. We observed spontaneous malignant tumors in 54 of 93 Bap1-mutant mice (58%) versus 4 of 43 (9%) wild-type littermates. All three Bap1-mutant models exhibited a high incidence and similar spectrum of neoplasms, including ovarian sex cord stromal tumors, lung and mammary carcinomas, and spindle cell tumors. Notably, we also observed malignant mesotheliomas in two Bap1-mutant mice, but not in any wild-type animals. We further confirmed that the remaining wild-type Bap1 allele was lost in both spontaneous ovarian tumors and mesotheliomas, resulting in the loss of Bap1 expression. Additional studies revealed that asbestos exposure induced a highly significant increase in the incidence of aggressive mesotheliomas in the two mouse models carrying clinically relevant Bap1 mutations compared with asbestos-exposed wild-type littermates. Collectively, these findings provide genetic evidence that Bap1 is a bona fide tumor suppressor gene, and offer key insights into the contribution of carcinogen exposure to enhanced cancer susceptibility.