Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor.
Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor.
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DOI：
10.1158/1541-7786.mcr-14-0674-t
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发表时间：
2015-08
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影响因子：
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通讯作者：
Starr TK
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作者：
Dorr C;Janik C;Weg M;Been RA;Bader J;Kang R;Ng B;Foran L;Landman SR;O'Sullivan MG;Steinbach M;Sarver AL;Silverstein KA;Largaespada DA;Starr TK
非小细胞肺癌（nsclc）包含数千个隐藏遗传驱动因素的乘客事件。即使是在NSCLC中高度复发的事件，如PTEN、EGFR、KRAS和ALK的突变，最多也只能在30%的患者中检测到。因此，许多未知的低渗透事件导致了很大一部分肺癌。为了检测NSCLC的低外显率驱动因素，在Pten缺乏背景下，使用睡美人（SB） DNA转座子作为随机突变原在小鼠中进行了前向遗传筛选。SB突变加上Pten缺乏足以在29%的小鼠中产生肺肿瘤。单独的Pten缺乏，没有SB突变，导致11%的小鼠发生肺肿瘤，而对照组小鼠的发生率为~3%。此外，甲状腺癌和其他癌症以及细支气管和肺泡上皮化也在Pten缺乏的小鼠中被发现。对常见转座子插入位点的分析鉴定出76个候选癌症驱动基因。这些基因在人类肺癌中经常失调，并涉及几种信号通路。Cullin3 （Cul3）是一个泛素连接酶复合体的成员，在氧化应激反应途径中发挥作用，在筛选中被发现，有证据表明Cul3具有肿瘤抑制作用。
Non-small cell lung cancers (NSCLCs) harbor thousands of passenger events that hide genetic drivers. Even highly recurrent events in NSCLC, such as mutations in PTEN, EGFR, KRAS, and ALK, are only detected in, at most, 30% of patients. Thus, many unidentified low-penetrant events are causing a significant portion of lung cancers. To detect low-penetrance drivers of NSCLC a forward genetic screen was performed in mice using the Sleeping Beauty (SB) DNA transposon as a random mutagen to generate lung tumors in a Pten deficient background. SB mutations coupled with Pten deficiency were sufficient to produce lung tumors in 29% of mice. Pten deficiency alone, without SB mutations, resulted in lung tumors in 11% of mice, while the rate in control mice was ~3%. In addition, thyroid cancer and other carcinomas as well as the presence of bronchiolar and alveolar epithelialization in mice deficient for Pten were also identified. Analysis of common transposon insertion sites identified 76 candidate cancer driver genes. These genes are frequently dysregulated in human lung cancers and implicate several signaling pathways. Cullin3 (Cul3), a member of an ubiquitin ligase complex that plays a role in the oxidative stress response pathway, was identified in the screen and evidence demonstrates that Cul3 functions as a tumor suppressor.