Thiesen H-J, Steinbeck F, Maruschke M, Koczan D, Ziems B, Hakenberg O W
Institute of Immunology, University of Rostock, Rostock, Germany.
Department of Urology, University of Rostock, Rostock, Germany.
PLoS One. 2017 May 9;12(5):e0176659. doi: 10.1371/journal.pone.0176659. eCollection 2017.
Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs) presented in 48 clear cell renal cell carcinoma (ccRCC) genomes resulted in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25) and 20 G3 (ratio 0.58). Gene losses and gains of 15762 CNA genes were mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs were classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turned out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. The diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes) has been successfully validated on published Swiss data (GSE19949) leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreased with the number of G3 related gene losses plus G3 related gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and predictive value.
肿瘤发生过程被认为是由表观/遗传和基因组改变驱动的，从单点突变到染色体改变，如核苷酸的插入和缺失，直至大的染色体片段的获得和丢失，包括染色体重排产物，如融合基因和蛋白质。对48个透明细胞肾细胞癌（ccRCC）基因组中呈现的拷贝数改变（CNA）进行的总体比较，得出了26个ccRCC福尔曼恶性分级G1（比率1.25）和20个G3（比率0.58）之间基因丢失与基因获得的比率。15762个CNA基因的基因丢失和获得被映射到795个染色体细胞带位点，包括280个KEGG通路。CNA根据其对福尔曼肿瘤分级G1和G3的贡献进行分类。结果表明，基因获得和丢失在ccRCC基因组中是高度结构化的过程，能够在全基因组范围内对ccRCC肿瘤进行亚分类和分层。ccRCC的CNA似乎始于常见的肿瘤相关基因丢失，两侧是指定福尔曼分级G1丢失的CNA和有利于G3级肿瘤的CNA获得。复发性CNA特征的出现意味着存在因果机制，很可能与ccRCC肿瘤的发病机制和疾病转归有关，可区分低级别和高级别恶性肿瘤。最初的201个基因（108个支持G1表型的基因和93个支持G3表型的基因）的诊断质量已在已发表的瑞士数据（GSE19949）上成功验证，从而得到一个由171个CNA基因组成的受限CNA基因集，其中85个基因有利于福尔曼分级G1，86个基因有利于福尔曼分级G3。关于这些基因集，总体生存率随着G3相关基因丢失和G3相关基因获得的数量而降低。所呈现的CNA基因集为从基因导向和通路相关的功能角度理解个体ccRCC肿瘤内部和之间正在进行的拷贝数改变提供了切入点，从而得出具有预后和预测价值的CNA基因。
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