Conservation of immune gene signatures in solid tumors and prognostic implications.
Conservation of immune gene signatures in solid tumors and prognostic implications.
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DOI：
10.1186/s12885-016-2948-z
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发表时间：
2016-11-22
期刊：
影响因子：
3.8
通讯作者：
Miller LD
中科院分区：
文献类型：
--
作者：
Chifman J;Pullikuth A;Chou JW;Bedognetti D;Miller LD
肿瘤浸润白细胞可以限制癌症生长或促进其扩散。全面评估肿瘤免疫浸润功能复杂性的诊断策略可能具有广泛的临床价值。在之前的工作中，我们在乳腺肿瘤中发现了独特的免疫基因特征，这些特征反映了浸润免疫细胞的相对丰度，并与患者的治疗结果表现出显着的相关性。在这里，我们假设与肿瘤类型无关的免疫基因特征可以通过从头发现富含免疫功能并具有在不同解剖部位的实体瘤中保守的内部相关结构的基因簇来识别。我们收集了包含 5,295 个乳腺癌、结肠癌、肺癌、卵巢癌和前列腺癌肿瘤的微阵列表达数据集。使用无监督聚类方法来确定每个数据集中基因簇的数量和组成。通过基因本体富集鉴定的免疫富集基因簇（特征）进行了跨肿瘤的内部相关结构和保守性分析，然后与以下表达谱进行比较：1）来自外周血的流式分选白细胞和2）来自实体癌和血液癌的超过300个癌细胞系。 Cox 回归分析用于识别与临床结果显着相关的特征。我们确定了在所有五种肿瘤类型中保守的九种不同的免疫富集基因特征。这些特征总体上具有中等辨别能力来区分特定的白细胞谱系，并自然地组织成六个离散的组，表明混合谱系。此外，其中七个特征在癌细胞系中表现出最小且不相关的表达，表明这些特征主要源自浸润性免疫细胞。在一种或多种肿瘤类型中，所有九种免疫特征均与患者预后存在统计学显着相关性（p<0.05），其中在乳腺癌和皮肤癌中观察到的显着性最为显着。指示骨髓谱系的几个特征表现出较差的结果关联，这在脑癌和结肠癌中最为明显。这些发现表明，肿瘤浸润免疫细胞可以通过免疫特异性基因表达模式来区分，这些基因表达模式可以量化一系列实体瘤类型中多种免疫浸润的相对丰度。这些免疫参与标志物与多种癌症的患者预后显着相关，这表明它们作为肿瘤行为和免疫反应性的泛癌标志物的临床实用性。本文的在线版本 (doi:10.1186/s12885-016-2948-z) 包含补充材料，可供授权用户使用。
Tumor-infiltrating leukocytes can either limit cancer growth or facilitate its spread. Diagnostic strategies that comprehensively assess the functional complexity of tumor immune infiltrates could have wide-reaching clinical value. In previous work we identified distinct immune gene signatures in breast tumors that reflect the relative abundance of infiltrating immune cells and exhibited significant associations with patient outcomes. Here we hypothesized that immune gene signatures agnostic to tumor type can be identified by de novo discovery of gene clusters enriched for immunological functions and possessing internal correlation structure conserved across solid tumors from different anatomic sites. We assembled microarray expression datasets encompassing 5,295 tumors of the breast, colon, lung, ovarian and prostate. Unsupervised clustering methods were used to determine number and composition of gene clusters within each dataset. Immune-enriched gene clusters (signatures) identified by gene ontology enrichment were analyzed for internal correlation structure and conservation across tumors then compared against expression profiles of: 1) flow-sorted leukocytes from peripheral blood and 2) >300 cancer cell lines from solid and hematologic cancers. Cox regression analysis was used to identify signatures with significant associations with clinical outcome. We identified nine distinct immune-enriched gene signatures conserved across all five tumor types. The signatures differentiated specific leukocyte lineages with moderate discernment overall, and naturally organized into six discrete groups indicative of admixed lineages. Moreover, seven of the signatures exhibit minimal and uncorrelated expression in cancer cell lines, suggesting that these signatures derive predominantly from infiltrating immune cells. All nine immune signatures achieved statistically significant associations with patient prognosis (p<0.05) in one or more tumor types with greatest significance observed in breast and skin cancers. Several signatures indicative of myeloid lineages exhibited poor outcome associations that were most apparent in brain and colon cancers. These findings suggest that tumor infiltrating immune cells can be differentiated by immune-specific gene expression patterns that quantify the relative abundance of multiple immune infiltrates across a range of solid tumor types. That these markers of immune involvement are significantly associated with patient prognosis in diverse cancers suggests their clinical utility as pan-cancer markers of tumor behavior and immune responsiveness. The online version of this article (doi:10.1186/s12885-016-2948-z) contains supplementary material, which is available to authorized users.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
45.3
作者：
Adams, Sylvia;Gray, Robert J.;Badve, Sunil S.
通讯作者：
Badve, Sunil S.
影响因子：
4.4
作者：
Deffrennes, V;Vedrenne, J;Alcaïde-Loridan, C
通讯作者：
Alcaïde-Loridan, C
影响因子：
3.9
作者：
Brady, MS;Eckels, DD;Lee, JS
通讯作者：
Lee, JS
影响因子：
10.1
作者：
Doucette T;Rao G;Rao A;Shen L;Aldape K;Wei J;Dziurzynski K;Gilbert M;Heimberger AB
通讯作者：
Heimberger AB