APOBEC proteins as drivers of chromosomal translocations in solid cancers

总结 染色体易位是致癌转化的关键驱动因素，并经常决定肿瘤的发生。 生物学和对癌细胞治疗的反应。DNA双链断裂的发生机制 引发染色体易位的双链断裂（DSB）在血液系统癌症中是众所周知的，但了解甚少 in solid实体tumors肿瘤.在淋巴瘤和白血病中，大多数导致致癌易位的DSB都是在 通过酶如RAG 1/2和AID的活性。这些酶在生理上负责 免疫球蛋白基因的重排，但可以启动易位时，他们异常靶向其他 基因.相反，在RAG 1/2和AID基本不表达的实体瘤中， 启动DSB形成。物理因素，如紫外线或辐射，或DNA结构固有的因素 或复制被认为是负责部分DSB和易位形成，但它们是 不足以解释实体瘤中致癌易位的复发模式。最近，APOBEC 蛋白质与在几种实体癌中发现的特殊突变特征有关，包括肺癌和肺癌。 乳腺癌重要的是，APOBEC依赖性突变特征通常与基因组共定位。 重组，如易位和体细胞拷贝数改变（SCNA）。基于这些 相关的发现和初步的实验，我们的假设是，APOBEC酶可能是 不仅负责体细胞突变，而且还负责固体中染色体易位的形成 肿瘤的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， 鉴定和绘制不同细胞类型中由APOBEC蛋白诱导的复发性易位。我们将应用 这些技术既用于体外测定，也用于易位形成的体内模型。的 证明APOBEC蛋白可以启动易位形成有可能提供一个关键的 这是目前解释癌症中复发性结构畸变所缺少的机制联系。从这个 示范，各种新的研究线将开放，包括潜在的治疗应用，旨在 阻断APOBEC活性以降低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.