Man's Best Friend for Driver-Passenger Distinction

描述（由申请人提供）：我们在此提出使用新的人-狗自发性癌症比较基因组学和肿瘤学策略来区分由TCGA报道的人结肠直肠癌（CRC）的>7000个扩增/缺失基因的癌症驱动者和乘客。我们发表的原理证明研究表明，自发犬CRC确实与人类CRC具有相似的分子致癌途径。此外，我们还在一项试点研究中成功验证了这种新的人-狗比较策略。对于拟议的项目，我们将首先确定改变基因在约100犬自发性癌是微卫星不稳定性（MSI）阴性，与国家的最先进的下一代测序分析方法。然后，我们将比较我们的研究结果与TCGA报告的驾驶员-乘客歧视。拟议的研究将导致超越TCGA发现的重大进展。它的成功将为解决癌症研究的核心目标提供一种有效的策略，为未来的研究和使用快速积累的大量癌症基因组数据开辟新的途径。这些发现将有助于了解CRC病因，并为这种流行癌症的治疗干预提供有效目标。最后，该项目将大大提高人们对伴侣犬自发性癌症的认识，这是人类癌症研究中一种非常有价值但研究不足和利用不足的资源。

DESCRIPTION (provided by applicant): We propose herein to use a novel human-dog spontaneous cancer comparative genomics and oncology strategy to discriminate cancer drivers from passengers for the >7000 amplified/deleted genes reported by TCGA for human colorectal cancer (CRC). Our published proof-of-principle studies have shown that spontaneous canine CRCs indeed share similar molecular carcinogenesis pathways with their human counterparts. In addition, we have also successfully validated this novel human-dog comparison strategy in a pilot study. For the proposed project, we will first identify altered genes in ~100 canine spontaneous carcinomas that are microsatellite instability (MSI)-negative, with state-of-the-art next generation sequencing analysis approaches. Then, we will compare our findings to those reported by TCGA for driver-passenger discrimination. The proposed study will lead to a significant advancement beyond the TCGA findings. Its success will present an effective strategy to address a central aim of cancer research, opening up novel avenues for future research and for the use of vast amounts of cancer genomic data rapidly accumulated. The findings will contribute to the understanding of CRC etiology and yield effective targets for therapeutic intervention of this prevalent cancer. Finally, the project will significantly raise awareness of spontaneous cancers in companion dogs, an immensely valuable yet greatly understudied and underutilized resource in human cancer research.