Predictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting

John R. Lamb, Chunsheng Zhang, Tao Xie, Kai Wang, Bin Zhang, Ke Hao, Eugene Chudin, Hunter B. Fraser, Joshua Millstein, Mark Ferguson, Christine Suver, Irena Ivanovska, Martin Scott, Ulrike Philippar, Dimple Bansal, Zhan Zhang, Julja Burchard, Ryan Smith, Danielle Greenawalt, Michele ClearyJonathan Derry, Andrey Loboda, James Watters, Ronnie T.P. Poon, Sheung T. Fan, Chun Yeung, Nikki P.Y. Lee, Justin Guinney, Cliona Molony, Valur Emilsson, Carolyn Buser-Doepner, Jun Zhu, Stephen Friend, Mao Mao, Peter M. Shaw, Hongyue Dai, John M. Luk, Eric E. Schadt

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59 Scopus citations

Abstract

Background: 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.

Original languageEnglish
Article numbere20090
JournalPLoS ONE
Volume6
Issue number7
DOIs
StatePublished - 2011
Externally publishedYes

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