de la Rosa Jorge, Weber Julia, Friedrich Mathias Josef, Li Yilong, Rad Lena, Ponstingl Hannes, Liang Qi, de Quirós Sandra Bernaldo, Noorani Imran, Metzakopian Emmanouil, Strong Alexander, Li Meng Amy, Astudillo Aurora, Fernández-García María Teresa, Fernández-García María Soledad, Hoffman Gary J, Fuente Rocío, Vassiliou George S, Rad Roland, López-Otín Carlos, Bradley Allan, Cadiñanos Juan
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain.
Nat Genet. 2017 May;49(5):730-741. doi: 10.1038/ng.3817. Epub 2017 Mar 20.
The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.
通过癌症基因组测序鉴定出的大量基因改变需要采用互补方法来解释其意义和相互作用。在此，我们在小鼠中开发了一种新型的全身插入诱变筛选方法，该方法旨在发现与Pten协同作用的肿瘤抑制因子。为实现这一目标，我们将单拷贝失活的睡美人转座子的转座与同一基因组内的Pten破坏相结合。对278个转座诱导的前列腺、乳腺和皮肤肿瘤的分析检测到了参与癌症的已知基因和候选基因的组织特异性和共享数据集。我们验证了ZBTB20、CELF2、PARD3、AKAP13和WAC，这些基因是我们在多种癌症类型的筛选中鉴定出来的，它们是前列腺癌中的新肿瘤抑制基因。我们证明了它们与PTEN在体外预防侵袭方面的协同作用，并证实了它们的临床相关性。对Wac在体内的进一步表征显示，在Pten缺陷的背景下，该基因（编码一种自噬调节因子）存在必需的单倍剂量不足。我们的研究在不同癌症类型中鉴定出了复杂的与PTEN协同作用的肿瘤抑制网络，具有潜在的临床意义。
