Ontario Cancer Institute, Toronto, Ontario, Canada.
J Clin Invest. 2010 Sep;120(9):3310-25. doi: 10.1172/JCI42391. Epub 2010 Aug 9.
Some cancers have been stratified into subclasses based on their unique involvement of specific signaling pathways. The mapping of human cancer genomes is revealing a vast number of somatic alterations; however, the identification of clinically relevant molecular tumor subclasses and their respective driver genes presents challenges. This information is key to developing more targeted and personalized cancer therapies. Here, we generate a new mouse model of genomically unstable osteosarcoma (OSA) that phenocopies the human disease. Integrative oncogenomics pinpointed cAMP-dependent protein kinase type I, alpha regulatory subunit (Prkar1a) gene deletions at 11qE1 as a recurrent genetic trait for a molecularly distinct subclass of mouse OSA featuring RANKL overexpression. Using mouse genetics, we established that Prkar1a is a bone tumor suppressor gene capable of directing subclass development and driving RANKL overexpression during OSA tumorigenesis. Finally, we uncovered evidence for a PRKAR1A-low subset of human OSA with distinct clinical behavior. Thus, tumor subclasses develop in mice and can potentially provide information toward the molecular stratification of human cancers.
一些癌症已经根据其独特涉及的特定信号通路被分为亚类。人类癌症基因组图谱揭示了大量的体细胞改变；然而，确定临床上相关的分子肿瘤亚类及其各自的驱动基因具有挑战性。这些信息是开发更有针对性和个性化癌症治疗方法的关键。在这里，我们生成了一种新的基因组不稳定骨肉瘤（OSA）的小鼠模型，其表型与人疾病相似。综合肿瘤基因组学将 cAMP 依赖性蛋白激酶 I 型，α 调节亚基（Prkar1a）基因缺失定位在 11qE1，作为一个分子上不同的小鼠 OSA 亚类的反复出现的遗传特征，其特征是 RANKL 过表达。使用小鼠遗传学，我们确定 Prkar1a 是一种骨肿瘤抑制基因，能够指导亚类的发展，并在 OSA 肿瘤发生过程中驱动 RANKL 过表达。最后，我们发现了人类 OSA 中存在 PRKAR1A-低亚类的证据，其具有不同的临床行为。因此，肿瘤亚类在小鼠中发展，并可能为人类癌症的分子分层提供信息。
