Zheng Ye, Ahmad Kami, Henikoff Steven
bioRxiv. 2025 Apr 1:2025.03.09.642243. doi: 10.1101/2025.03.09.642243.
Aneuploidy is observed as gains or losses of whole chromosomes or chromosome arms and is a common hallmark of cancer. Whereas models for the generation of aneuploidy in cancer invoke mitotic chromosome segregation errors, whole-arm losses might occur simply as a result of centromere breakage. We recently showed that elevated RNA Polymerase II (RNAPII) level over S-phase-dependent histone genes predicts rapid recurrence of human meningioma and is correlated with total whole-arm losses relative to gains. To explain this imbalance in arm losses over gains, we have proposed that histone overexpression at S-phase competes with the histone H3 variant CENP-A, resulting in centromere breaks and whole-arm losses. To test whether centromere breaks alone can drive aneuploidy, we ask whether total whole-arm aneuploids can predict outcome across different cancer types in large RNA and whole-genome sequencing databanks. We find that total whole-arm losses generally predict outcome, suggesting that centromere breakage is a major initiating factor leading to aneuploidy and the resulting changes in the selective landscape that drive most cancers. We also present evidence that centromere breakage alone is sufficient to account for whole-arm losses and gains, contrary to mitotic spindle error models for generation of aneuploidy. Our results suggest that therapeutic intervention targeting histone overexpression has the potential of reducing aneuploidy and slowing cancer progression.
Gain or loss of whole chromosome arms following centromere breaks is frequent in cancer, but whether or not there is a common initiating event is unknown. Here we show that the total number of whole-arm losses predicts patient outcomes across cancer types, suggesting a causal relationship. This general excess of losses over gains is not predicted by mitotic error models of aneuploidy but rather suggests that centromere breaks themselves initiate whole-arm aneuploidies. Insofar as aneuploidy reshapes the selective landscapes that drive most cancers, our results have potential clinical implications.
非整倍体表现为整条染色体或染色体臂的增加或减少，是癌症的一个常见特征。虽然癌症中非整倍体产生的模型涉及有丝分裂染色体分离错误，但整条染色体臂的丢失可能仅仅是着丝粒断裂的结果。我们最近发现，S期依赖性组蛋白基因上RNA聚合酶II（RNAPII）水平升高预示着人类脑膜瘤的快速复发，并且与整条染色体臂丢失相对于增加的总数相关。为了解释这种染色体臂丢失超过增加的不平衡现象，我们提出S期组蛋白过表达与组蛋白H3变体CENP-A竞争，导致着丝粒断裂和整条染色体臂丢失。为了测试仅着丝粒断裂是否能驱动非整倍体，我们询问在大型RNA和全基因组测序数据库中，整条染色体臂非整倍体总数是否能预测不同癌症类型的预后。我们发现整条染色体臂的丢失通常能预测预后，这表明着丝粒断裂是导致非整倍体以及驱动大多数癌症的选择性环境变化的主要起始因素。我们还提供证据表明，仅着丝粒断裂就足以解释整条染色体臂的丢失和增加，这与非整倍体产生的有丝分裂纺锤体错误模型相反。我们的结果表明，针对组蛋白过表达的治疗干预有可能减少非整倍体并减缓癌症进展。
着丝粒断裂后整条染色体臂的增减在癌症中很常见，但是否存在共同的起始事件尚不清楚。在这里我们表明，整条染色体臂丢失的总数能预测不同癌症类型患者的预后，提示存在因果关系。这种丢失超过增加的普遍现象并非非整倍体的有丝分裂错误模型所预测，而是表明着丝粒断裂本身引发了整条染色体臂的非整倍体。鉴于非整倍体重塑了驱动大多数癌症的选择性环境，我们的结果具有潜在的临床意义。
