Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma-猫眼课题宝

DOI：

10.21203/rs.3.rs-3675752/v1

发表时间：

2023-12

期刊：

Research Square

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

R. Houlston;R. Culliford;Sam Lawrence;Charlie Mills;Z. Tippu;D. Chubb;A. Cornish;Lisa Browining;B. Kinnersley;R. Bentham;Amit Sud;H. Pallikonda;A. Frangou;Andreas J. Gruber;K. Litchfield;D. Wedge;James Larkin;S. Turajlic

透明细胞肾细胞癌（ccRCC）是最常见的肾癌形式，但缺乏对其基因组景观的全面描述。我们报告了778名ccRCC患者的全基因组测序，这些患者参加了100，000个基因组计划，提供了迄今为止最详细的体细胞突变景观。我们确定了新的驱动基因，并强调了表观遗传调控在ccRCC中的主要作用，突出了额外的生物学途径，延长了药物再利用的机会。基因组特征鉴定出临床结果不同的患者;较高数量的结构拷贝数改变与较差的预后相关，而VHL突变与较好的预后独立相关。较高的T细胞浸润与较好的结果相关，并且遗传预测的免疫逃避并不常见，这两项观察结果支持免疫治疗的基本原理。这些发现应该为ccRCC患者的个性化监测和治疗策略提供信息。

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing the most detailed somatic mutational landscape to date. We identify new driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for drug repurposing. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The twin observations that higher T-cell infiltration is associated with better outcome and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.

Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma

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