1] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK [2] Department of Biomedicine, Research Group Human Genomics, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
Nat Commun. 2015 Mar 19;6:6336. doi: 10.1038/ncomms7336.
Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.
乳头状肾细胞癌（pRCC）是一种重要的肾癌亚型，其病理分类存在问题，临床行为具有高度变异性。在这里，我们对 31 个 pRCC 进行了基因组或外显子组测序，在四个肿瘤中进行了多区域测序。我们确定了 BAP1、SETD2、ARID2 和 Nrf2 通路基因（KEAP1、NHE2L2 和 CUL3）作为可能的驱动基因，此外还有至少 8 个其他可能的驱动基因。然而，只有约 10%的肿瘤在任何一个驱动基因中存在可检测的致病性变化，而且这些突变通常预测存在于癌症亚克隆中。我们特别检测到同一肿瘤的不同亚区域内多个 SETD2 突变的平行进化。相比之下，7、12、16 和 17 号染色体的大片段拷贝数增益通常是 pRCC 进化中的早期、单克隆变化。大片段拷贝数变异作为 pRCC 的主要驱动因素的优势突出了一种不寻常的肿瘤发生模式，这可能对精准医疗方法提出挑战。
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