Herculean efforts by the Wellcome Sanger Institute, the National Cancer Institute, and the National Human Genome Research Institute to sequence thousands of tumors representing all major cancer types have yielded more than 700 genes that contribute to neoplastic growth when mutated, amplified, or deleted. While some of these genes (now included in the COSMIC Cancer Gene Census) encode proteins previously identified in hypothesis-driven experiments (oncogenic transcription factors, protein kinases, etc.), additional classes of cancer drivers have emerged, perhaps none more surprisingly than RNA-binding proteins (RBPs). Over 40 RBPs responsible for virtually all aspects of RNA metabolism, from synthesis to degradation, are recurrently mutated in cancer, and just over a dozen are considered major cancer drivers. This Review investigates whether and how their RNA-binding activities pertain to their oncogenic functions. Focusing on several well-characterized steps in RNA metabolism, we demonstrate that for virtually all cancer-driving RBPs, RNA processing activities are either abolished (the loss-of-function phenotype) or carried out with low fidelity (the LoFi phenotype). Conceptually, this suggests that in normal cells, RBPs act as gatekeepers maintaining proper RNA metabolism and the “balanced” proteome. From the practical standpoint, at least some LoFi phenotypes create therapeutic vulnerabilities, which are beginning to be exploited in the clinic.

Wellcome Sanger 研究所、国家癌症研究所和国家人类基因组研究所对代表所有主要癌症类型的数千个肿瘤进行测序的巨大努力已经产生了 700 多个在突变、扩增或删除时有助于肿瘤生长的基因。虽然其中一些基因（现在包括在 COSMIC 癌症基因普查中）编码先前在假设驱动的实验中发现的蛋白质（致癌转录因子、蛋白激酶等），但已经出现了其他类别的癌症驱动因素，也许最令人惊讶的是 RNA结合蛋白（RBP）。超过 40 种 RBP 几乎负责 RNA 代谢的所有方面，从合成到降解，在癌症中反复发生突变，只有十几种被认为是主要的癌症驱动因素。本综述调查了它们的 RNA 结合活性是否以及如何与其致癌功能相关。专注于 RNA 代谢中几个特征明确的步骤，我们证明，对于几乎所有癌症驱动的 RBP，RNA 加工活动要么被取消（功能丧失表型），要么以低保真度（LoFi 表型）进行。从概念上讲，这表明在正常细胞中，RBP 充当守门人，维持适当的 RNA 代谢和“平衡”蛋白质组。从实际的角度来看，至少一些 LoFi 表型会产生治疗漏洞，这些漏洞已开始在临床中得到利用。RNA 加工活动要么被取消（功能丧失表型），要么以低保真度（LoFi 表型）进行。从概念上讲，这表明在正常细胞中，RBP 充当守门人，维持适当的 RNA 代谢和“平衡”蛋白质组。从实际的角度来看，至少一些 LoFi 表型会产生治疗漏洞，这些漏洞已开始在临床中得到利用。RNA 加工活动要么被取消（功能丧失表型），要么以低保真度（LoFi 表型）进行。从概念上讲，这表明在正常细胞中，RBP 充当守门人，维持适当的 RNA 代谢和“平衡”蛋白质组。从实际的角度来看，至少一些 LoFi 表型会产生治疗漏洞，这些漏洞已开始在临床中得到利用。