Chromosomal instability selects gene copy-number variants encoding core regulators of proliferation in ER+ breast cancer.
Chromosomal instability selects gene copy-number variants encoding core regulators of proliferation in ER+ breast cancer.
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DOI：
10.1158/0008-5472.can-13-2664
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发表时间：
2014-09-01
期刊：
影响因子：
11.2
通讯作者：
Kschischo M
中科院分区：
文献类型：
--
作者：
Endesfelder D;Burrell R;Kanu N;McGranahan N;Howell M;Parker PJ;Downward J;Swanton C;Kschischo M
染色体不稳定(CIN)与包括乳腺癌在内的上皮性恶性肿瘤预后不良有关。有证据表明，雌激素受体阳性(ER+)乳腺癌的预后标志定义为CIN和高增殖潜力的肿瘤。有趣的是，CIN在低等真核细胞和人类细胞中的诱导是上下文相关的，通常会导致增殖劣势，但在强大的选择压力下会带来适应性优势。我们假设CIN通过产生不同的DNA拷贝数事件来加速基因组进化，这些事件可能在疾病发展过程中被选择。为了支持这一假设，我们发现了在CIN相关癌症基因组中选择核心增殖调节因子基因扩增的证据。核心调控因子TPX2和UBE2C的稳定DNA拷贝数扩增与参与增殖的基因模块的表达有关。在ER+乳腺癌的预后标志性基因集中，模块基因被丰富，提供了CIN和预后标志性表达之间的逻辑联系。我们的研究结果为破译肿瘤内异质性对关键癌症表型的影响提供了一个框架，并提示CIN为选择驱动肿瘤增殖的拷贝数改变提供了一个允许的图景。
Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context-dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesised that CIN permits accelerated genomic evolution through the generation of diverse DNA copy number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER+ breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy number alterations which drive cancer proliferation.