APOBEC proteins as drivers of chromosomal translocations in solid cancers

摘要 染色体易位是致癌转化的关键驱动因素，并经常决定 癌细胞的生物学和治疗反应。产生DNA双链断裂的机制 引起染色体易位的双链断裂(DSB)在血液病癌症中广为人知，但知之甚少 在实体瘤中。在淋巴瘤和白血病中，大多数导致致癌易位的DSB都是产生的 由RAG1/2和AID等酶的活性决定。这些酶在生理上对 免疫球蛋白基因的重排，但当它们以其他基因为靶点时，会引发易位 基因。相反，在RAG1/2和AID基本上不表达的实体肿瘤中，哪些因素尚不清楚 启动DSB队形。物理因素，如紫外线或辐射，或DNA结构固有的因素 或复制被认为是部分DSB和易位形成的原因，但它们是 不足以解释实体肿瘤中致癌易位的复发模式。最近，APOBEC 蛋白质与几种实体癌症中发现的特殊突变特征有关，包括肺癌和 乳腺癌。重要的是，依赖于APOBEC的突变特征通常与基因组共定位 重排，如易位和体细胞拷贝数改变(SCNA)。基于这些 相关发现和初步实验，我们的假设是APOBEC酶可能是 不仅对体细胞突变负责，而且对固体中染色体易位的形成负责 肿瘤。我们将通过应用我们在实验室开发的创新测序技术来验证这一假设 识别和定位APOBEC蛋白在不同细胞类型中诱导的反复易位。我们会申请 这些技术既包括体外试验，也包括体内易位形成模型。这个 APOBEC蛋白可以启动易位形成的证明有可能提供一个关键 机制上的联系，目前尚不能解释癌症中反复出现的结构异常。由此 演示，各种新的研究路线将开通，包括旨在 阻断APOBEC活性以减少癌症中的基因组不稳定性。

Summary Chromosomal translocations are key drivers of oncogenic transformation and frequently determine the biology and response to therapy of cancer cells. The mechanisms that generate the DNA double strand breaks (DSBs) that initiate chromosomal translocations are well known in hematologic cancers but poorly understood in solid tumors. In lymphoma and leukemia, most DSBs that lead to an oncogenic translocation are generated by the activity of enzymes such as RAG1/2 and AID. These enzymes are physiologically responsible for the rearrangements of the immunoglobulin genes, but can initiate a translocation when they aberrantly target other genes. In contrast, in solid tumors where RAG1/2 and AID are largely not expressed, it is unclear what factors initiate DSB formation. Physical factors, such as UV light or irradiation, or factors intrinsic to the DNA structure or replication are thought to be responsible for part of the DSB and translocation formation, but they are insufficient to explain the recurrent patterns of oncogenic translocations in solid tumors. Recently, the APOBEC proteins have been linked to peculiar mutational signatures found in several solid cancers, including lung and breast cancers. Importantly, the APOBEC-dependent mutational signatures typically co-localize with genomic rearrangements such as translocations and somatic copy number alterations (SCNAs). Based on these correlative findings and preliminary experiments, our hypothesis is that APOBEC enzymes could be responsible not only for somatic mutations but also for the formation of chromosomal translocation in solid tumors. We will test this hypothesis by applying innovative sequencing techniques we developed in our lab to identify and map recurrent translocations induced by APOBEC proteins in different cell types. We will apply these techniques both in in vitro assays as well as to in vivo models of translocation formation. The demonstration that APOBEC protein can initiate translocation formation has the potential to provide a key mechanistic link that is currently missing to explain recurrent structural aberrations in cancer. From this demonstration, a variety of new research lines will open including potential therapeutic applications aimed at blocking APOBEC activity to reduce genomic instability in cancer.