The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer
The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer
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DOI：
10.1158/1055-9965.epi-18-1359
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发表时间：
2020-02-01
影响因子：
3.8
通讯作者：
Culhane, Aedin C.
中科院分区：
文献类型：
--
作者：
Schwede, Matthew;Waldron, Levi;Culhane, Aedin C.
背景资料：最近为改善高级别浆液性卵巢癌（女性癌症死亡的主要原因）的结局所做的努力主要集中在识别分子亚型和预后基因特征上，但现有亚型的交叉研究稳健性较差。我们测试的贡献发表的卵巢癌的分子亚型和预后的基因significants.Methods：肿瘤和间质的基因签名的细胞混合物开发使用配对的显微组织从两个独立的研究。基质基因进行了研究，在两个分子亚型分类和61个已发表的基因签名。在2，527例卵巢肿瘤（16项研究）中评估了基质混合物基因签名的预后性能。通过混合成对的显微切割卵巢肿瘤和间质的基因表达谱进行了增加间质细胞比例的计算模拟。结果：最近描述的卵巢癌分子亚型与细胞混合物密切相关。在基质细胞百分比增加的模拟中，肿瘤被分类为不同的分子亚型。基质基因在大块肿瘤中的表达与总生存率相关（风险比，1.17; 95%置信区间，1.11-1.23），在一个数据集中，基质增加与解剖取样位置相关。五个已发表的预后基因签名不再预后的多变量模型，调整为stromal content.Conclusions：细胞混合物影响卵巢癌的分子亚型和基因签名来自散装组织的解释和再现。阐明间质在肿瘤微环境和预后中的作用是重要的。影响：可能需要单细胞分析来细化高级别浆液性卵巢癌的分子亚型。
Background: Recent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures.Methods: Gene signatures of tumor and stroma were developed using paired microdissected tissue from two independent studies. Stromal genes were investigated in two molecular subtype classifications and 61 published gene signatures. Prognostic performance of gene signatures of stromal admixture was evaluated in 2,527 ovarian tumors (16 studies). Computational simulations of increasing stromal cell proportion were performed by mixing geneexpression profiles of paired microdissected ovarian tumor and stroma.Results: Recently described ovarian cancer molecular subtypes are strongly associated with the cell admixture. Tumors were classified as different molecular subtypes in simulations where the percentage of stromal cells increased. Stromal gene expression in bulk tumors was associated with overall survival (hazard ratio, 1.17; 95% confidence interval, 1.11-1.23), and in one data set, increased stroma was associated with anatomic sampling location. Five published prognostic gene signatures were no longer prognostic in a multivariate model that adjusted for stromal content.Conclusions: Cell admixture affects the interpretation and reproduction of ovarian cancer molecular subtypes and gene signatures derived from bulk tissue. Elucidating the role of stroma in the tumor microenvironment and in prognosis is important.Impact: Single-cell analyses may be required to refine the molecular subtypes of high-grade serous ovarian cancer.