Understanding the driver mutations of canine lymphoma: towards new biomarkers and repositioning human therapies

癌症是狗过早死亡的头号原因，淋巴瘤是最常见的犬类癌症。与我们目前对人类肿瘤发生中发生的遗传变化的了解相比，我们对犬癌症（包括淋巴瘤）发展中出现的突变知之甚少。在过去的十年中，基于肿瘤的基因组成，已经合理地开发了新一代治疗人类癌症的癌症药物。对犬淋巴瘤的进一步了解可能使这种最初为应用于人类癌症而开发的“靶向”癌症疗法也被“重新定位”以应用于兽医癌症。使用新的DNA测序技术，我将搜索犬癌症的DNA，从淋巴瘤开始，寻找负责将正常细胞转化为淋巴瘤癌细胞的遗传变化（突变）。重点将放在与人类淋巴瘤相关基因具有共同功能的基因（直系同源物）上。我还将寻找可能与癌症表型相关的剂量变化（“基因表达”）。这种分析可以揭示新的疾病亚型和预后生物标志物，使我们能够更好地预测哪些动物肿瘤对当前的治疗方案反应良好。分析这些类型的数据需要复杂的计算方法，统称为“生物信息学”。新的生物信息学技术将在这里开发，以促进从狗的肿瘤DNA序列的分析。我还将开发新的分子方法，在体液中非侵入性地搜索本研究中确定的体细胞突变。例如，将开发用于检测狗血浆中肿瘤特异性突变的测定法，以用作“生物标志物”。这项工作最终可能使我们能够更准确地诊断淋巴瘤，并且比目前使用的检查侵入性更小。这里使用的方法最终可以推广到狗和猫的兽医癌症。

Cancer is the number one cause of premature death in dogs and lymphoma is the most common of the canine cancers. Compared to our current knowledge of the genetic changes that occur in human oncogenesis we know little about the mutations that arise in the development of canine cancers including lymphoma. Over the past decade a new generation generation of cancer drugs for treating human cancers have been rationally developed based on the genetic makeup of tumours. An improved understanding of canine lymphoma may allow such "targeted" cancer therapies, originally developed for application to human cancers, to also be "repositioned" for application to veterinary cancers. Using new DNA sequencing technologies, I will search the DNA from canine cancers, beginning with lymphomas, for genetic changes (mutations) that are responsible for converting normal cells to lymphoma cancer cells. Focus will be placed on the genes with shared functions (orthologues) to human lymphoma-related genes. I will also search for dosage changes ("gene expression") likely to be associated with the cancer phenotype. Such analyses can reveal new disease subtypes and prognostic biomarkers that allow us to better predict which animals tumours will respond well to current treatment regimens. Analyzing these types of data requires sophisticated computational approaches collectively referred to as "bioinformatics". New bioinformatics techniques will be developed here to facilitate the analysis of tumour DNA sequence from dogs. I will also develop new molecular approaches to non-invasively search in bodily fluids for the somatic mutations identified in this study. For example, assays will be developed to detect the tumour-specific mutations in the blood plasma of dogs for use as "biomarkers". This work may eventually allow us to diagnose lymphomas more accurately and with less invasive tests than those currently being used. The methods used here can ultimately be generalized to veterinary cancers in both dogs and cats.