Measurement of a tumor's overall genomic instability has gathered recent interest over the identification of specific genomic imbalances, as it may provide a more robust measure of tumor aggressiveness. Here we demonstrate the association of tumor genomic instability in the prediction of disease recurrence in patients with clinically localized clear cell renal cell carcinoma (ccRCC). Genomic copy number analysis was performed using SNP-based microarrays on tumors from 103 ccRCC patients. The number of copy number alterations (CNAs) for each tumor was calculated, and a genomic imbalance threshold (GIT) associated with high stage and high-grade disease was determined. Cox proportional hazards regression analyzes were performed to assess the effect of GIT on recurrence-free survival adjusting for known confounders. In the cohort, copy number losses in chromosome arms 3p, 14q, 6q, 9p, and 1p and gains of 5q and 7p/q were common. CNA burden significantly increased with increasing stage (p < .001) and grade (p < .001). The median CNA burden associated with patients presenting with advanced stage (IV) and high-grade (III/IV) tumors was ≥9, defining the GIT. On regression analysis, GIT was a superior predictor of recurrence (Hazard Ratio 4.44 [CI 1.36-14.48], p = .01) independent of stage, with similar results adjusting for grade. These findings were confirmed using an alternative measure of genomic instability, weighted Genomic Integrity Index. Our data support a key role for genomic instability in ccRCC progression. More importantly, we have identified a GIT (≥ 9 CNAs) that is a superior and independent predictor of disease recurrence in high-risk ccRCC patients.

中文翻译：

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总体肿瘤基因组不稳定性：局部透明细胞肾细胞癌患者无复发生存的重要预测指标。

肿瘤整体基因组不稳定性的测量近来引起了人们对特定基因组失衡鉴定的关注，因为它可以为肿瘤的侵袭性提供更可靠的度量。在这里，我们证明了在临床局部透明细胞肾细胞癌（ccRCC）患者的疾病复发预测中，肿瘤基因组不稳定的关联。使用基于SNP的微阵列对103 ccRCC患者的肿瘤进行了基因组拷贝数分析。计算每个肿瘤的拷贝数改变（CNA）的数量，并确定与晚期和高度疾病相关的基因组失衡阈值（GIT）。进行Cox比例风险回归分析以评估GIT对调整已知混杂因素的无复发生存的影响。在同类中 染色体臂3p，14q，6q，9p和1p中的拷贝数丢失是常见的，而5q和7p / q的获得是常见的。CNA负担随着阶段（p <.001）和等级（p <.001）的增加而显着增加。与患有晚期（IV）和高级别（III / IV）肿瘤的患者相关的CNA负担中位数≥9，定义为GIT。在回归分析中，GIT是复发的最佳预测指标（危险比4.44 [CI 1.36-14.48]，p = .01），与阶段无关，对等级进行调整的结果相似。这些发现已使用替代的基因组不稳定性衡量方法（加权基因组完整性指数）得到了证实。我们的数据支持ccRCC进展中基因组不稳定性的关键作用。更重要的是，我们已经确定了GIT（≥9个CNA），它是高危ccRCC患者疾病复发的较好且独立的预测指标。