Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
Cancer Res. 2011 May 15;71(10):3447-52. doi: 10.1158/0008-5472.CAN-10-3667. Epub 2011 Jan 26.
Chromosomal instability (CIN) is associated with poor prognosis in human cancer. However, in certain animal tumor models elevated CIN negatively impacts upon organism fitness, and is poorly tolerated by cancer cells. To better understand this seemingly contradictory relationship between CIN and cancer cell biological fitness and its relationship with clinical outcome, we applied the CIN70 expression signature, which correlates with DNA-based measures of structural chromosomal complexity and numerical CIN in vivo, to gene expression profiles of 2,125 breast tumors from 13 published cohorts. Tumors with extreme CIN, defined as the highest quartile CIN70 score, were predominantly of the estrogen receptor negative (ER(-)), basal-like phenotype and displayed the highest chromosomal structural complexity and chromosomal numerical instability. We found that the extreme CIN/ER(-) tumors were associated with improved prognosis relative to tumors with intermediate CIN70 scores in the third quartile. We also observed this paradoxical relationship between CIN and prognosis in ovarian, gastric, and non-small cell lung cancer, with poorest outcome in tumors with intermediate, rather than extreme, CIN70 scores. These results suggest a nonmonotonic relationship between gene signature expression and HR for survival outcome, which may explain the difficulties encountered in the identification of prognostic expression signatures in ER(-) breast cancer. Furthermore, the data are consistent with the intolerance of excessive CIN in carcinomas and provide a plausible strategy to define distinct prognostic patient cohorts with ER(-) breast cancer. Inclusion of a surrogate measurement of CIN may improve cancer risk stratification and future therapeutic approaches.
染色体不稳定性（CIN）与人类癌症的预后不良有关。然而，在某些动物肿瘤模型中，升高的 CIN 对机体适应性产生负面影响，并且癌细胞难以耐受。为了更好地理解 CIN 与癌细胞生物学适应性之间这种看似矛盾的关系及其与临床结果的关系，我们应用了 CIN70 表达特征，该特征与体内基于 DNA 的结构染色体复杂性和数值 CIN 的测量相关联，对来自 13 个已发表队列的 2125 个乳腺癌肿瘤的基因表达谱进行了分析。极端 CIN（定义为最高四分位 CIN70 评分）的肿瘤主要是雌激素受体阴性（ER(-)）、基底样表型，并且表现出最高的染色体结构复杂性和染色体数值不稳定性。我们发现，与具有中等 CIN70 评分的肿瘤相比，极端 CIN/ER(-)肿瘤与改善的预后相关。我们还观察到 CIN 和预后之间在卵巢癌、胃癌和非小细胞肺癌中存在这种矛盾的关系，在具有中等而非极端 CIN70 评分的肿瘤中，结果最差。这些结果表明基因特征表达与生存结果的 HR 之间存在非单调关系，这可能解释了在 ER(-)乳腺癌中识别预后表达特征所遇到的困难。此外，这些数据与癌中过度 CIN 的不耐受性一致，并为定义具有 ER(-)乳腺癌的不同预后患者队列提供了一种合理的策略。包含 CIN 的替代测量可能会改善癌症风险分层和未来的治疗方法。
