Paradoxical relationship between chromosomal instability and survival outcome in cancer.
Paradoxical relationship between chromosomal instability and survival outcome in cancer.
复制标题
DOI：
10.1158/0008-5472.can-10-3667
复制
发表时间：
2011-05-15
期刊：
影响因子：
11.2
通讯作者：
Swanton C
中科院分区：
文献类型：
--
作者：
Birkbak NJ;Eklund AC;Li Q;McClelland SE;Endesfelder D;Tan P;Tan IB;Richardson AL;Szallasi Z;Swanton C
染色体不稳定性（CIN）与人类癌症的不良预后有关。然而，在某些动物肿瘤模型中，升高的CIN对生物体健康产生负面影响，并且癌细胞耐受性差。为了更好地理解CIN和癌细胞生物学适应性之间看似矛盾的关系及其与临床结果的关系，我们将CIN 70表达特征（与体内基于DNA的结构染色体复杂性和数值染色体不稳定性的测量相关）应用于来自13个已发表队列的2125个乳腺肿瘤的基因表达谱。极端CIN（定义为最高四分位数CIN 70评分）肿瘤主要为雌激素受体（ER）阴性、基底样表型，并显示最高的染色体结构复杂性和染色体数量不稳定性。我们发现，相对于在第三四分位数中具有中等CIN 70评分的肿瘤，极端CIN/ER阴性肿瘤与预后改善相关。我们还观察到CIN与卵巢癌、胃癌和非小细胞肺癌预后之间的矛盾关系，CIN 70评分中等而非极端的肿瘤预后最差。这些结果表明基因签名表达和生存结果的风险比之间存在非单调关系，这可能解释了在ER阴性乳腺癌中识别预后表达签名时遇到的困难。此外，这些数据与癌症中过度CIN的不耐受性一致，并提供了一种合理的策略来定义ER阴性乳腺癌的不同预后患者队列。纳入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。
Chromosomal instability (CIN) is associated with poor prognosis in human cancer. However, in certain animal tumour 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 chromosomal instability in vivo, to gene expression profiles of 2125 breast tumours from 13 published cohorts. Tumours with extreme CIN, defined as the highest quartile CIN70 score, were predominantly of the estrogen receptor (ER) negative, basal-like phenotype and displayed the highest chromosomal structural complexity and chromosomal numerical instability. We found that the extreme CIN/ER-negative tumours were associated with improved prognosis relative to tumours 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 tumours with intermediate, rather than extreme, CIN70 scores. These results suggest a non-monotonic relationship between gene signature expression and hazard ratio for survival outcome, which may explain the difficulties encountered in the identification of prognostic expression signatures in ER negative 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-negative breast cancer. Inclusion of a surrogate measurement of CIN may improve cancer risk stratification and future therapeutic approaches.