Rosetta Inpharmatics, LLC, Seattle, Washington, United States of America.
PLoS One. 2011;6(7):e20090. doi: 10.1371/journal.pone.0020090. Epub 2011 Jul 5.
In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear.
METHODOLOGY/PRINCIPAL FINDINGS: Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ∼250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU.
CONCLUSIONS/SIGNIFICANCE: This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types.
在肝细胞癌 (HCC) 中，已在相邻正常 (AN) 和肿瘤 (TU) 组织中发现了与生存相关的基因。这两组预测基因与肿瘤发生和疾病进展的一般过程之间的关系尚不清楚。
方法/主要发现：在这里，我们通过比较约 250 个 AN 和 TU 样本的基因表达、DNA 拷贝数变异和生存情况，研究了 HCC 的肿瘤发生。使用基因-基因相关性元分析程序比较 AN 与 TU 组织，定义参与肿瘤发生的基因。发现参与肿瘤发生的基因在预测 AN 生存的基因 (AN-survival genes) 中富集，表明它们直接参与肿瘤发生过程。此外，在 TU 组织中，AN-survival genes 在肿瘤发生后大多不再具有预测性，这种转变与顺式和反式体细胞 DNA 拷贝数变异 (sCNV) 的影响有关，并且在很大程度上可以解释这种转变。数据与 AN-survival genes 的变异性是肿瘤发生的限速步骤一致，这通过一种促进 HCC 肿瘤发生的治疗得到了证实，该治疗选择性地改变了 AN-survival genes 和 AN 与 TU 之间差异相关的基因。
结论/意义：这表明肿瘤进化过程涉及与肿瘤起源背景相关的限速步骤，这些步骤通常与临床结果相关。此外，改变肿瘤发生可能性的治疗方法可能通过改变 AN-survival genes 来发挥作用，这表明该过程可以被操纵。进一步的 sCNV 解释了肿瘤特异性表达的很大一部分，因此可能是 HCC 甚至许多实体肿瘤类型肿瘤进化的因果驱动因素。
