Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Academic Urology Group, Department of Surgery, Addenbrooke's Hospitals NHS Foundation Trust, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK.
Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK; Renal and Skin Units, The Royal Marsden National Health Service (NHS) Foundation Trust, London SW3 6JJ, UK.
Cell. 2018 Apr 19;173(3):611-623.e17. doi: 10.1016/j.cell.2018.02.020. Epub 2018 Apr 12.
Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.
透明细胞肾细胞癌（ccRCC）的特征是几乎普遍丧失 3 号染色体的短臂，从而删除了几个肿瘤抑制基因。我们分析了来自 33 名透明细胞肾细胞癌患者的 95 份活检样本的全基因组。我们在 TERT 的 5'UTR 中发现了热点突变，这些突变靶向与端粒延长相关的 MYC-MAX-MAD1 抑制剂。最常见的结构异常同时导致 3p 缺失和 5q 获得（36%的患者），通常通过染色体重排。这种事件发生在儿童或青少年时期，通常作为启动事件，在肿瘤最近的共同祖先出现之前，早至几年，晚至几十年。类似的基因组变化驱动遗传性 ccRCC。对遗传性和散发性癌症之间年龄发病差异的建模表明，能够引发散发性肿瘤的 3p 缺失细胞数量不超过几百个。ccRCC 的早期发展遵循明确的进化轨迹，为早期干预提供了机会。
