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

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TitlePredictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting
AuthorsLamb, JR2
Zhang, C2
Xie, T2
Wang, K2
Zhang, B2
Hao, K2
Chudin, E2
Fraser, HB2
Millstein, J2
Ferguson, M2
Suver, C2
Ivanovska, I2
Scott, M4
Philippar, U4
Bansal, D4
Zhang, Z2
Burchard, J2
Smith, R2
Greenawalt, D2
Cleary, M4
Derry, J2
Loboda, A4
Watters, J4
Poon, RTP1
Fan, ST1
Yeung, C1
Lee, NPY1
Guinney, J3
Molony, C2
Emilsson, V2
BuserDoepner, C4
Zhu, J2
Friend, S4
Mao, M2
Shaw, PM4
Dai, H2
Luk, JM1
Schadt, EE2
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
CitationPlos One, 2011, v. 6 n. 7 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0020090
AbstractBackground: 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. © 2011 Lamb et al.
ISSN1932-6203
2011 Impact Factor: 4.092
2011 SCImago Journal Rankings: 0.519
DOIhttp://dx.doi.org/10.1371/journal.pone.0020090
PubMed Central IDPMC3130029
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorLamb, JR
dc.contributor.authorZhang, C
dc.contributor.authorXie, T
dc.contributor.authorWang, K
dc.contributor.authorZhang, B
dc.contributor.authorHao, K
dc.contributor.authorChudin, E
dc.contributor.authorFraser, HB
dc.contributor.authorMillstein, J
dc.contributor.authorFerguson, M
dc.contributor.authorSuver, C
dc.contributor.authorIvanovska, I
dc.contributor.authorScott, M
dc.contributor.authorPhilippar, U
dc.contributor.authorBansal, D
dc.contributor.authorZhang, Z
dc.contributor.authorBurchard, J
dc.contributor.authorSmith, R
dc.contributor.authorGreenawalt, D
dc.contributor.authorCleary, M
dc.contributor.authorDerry, J
dc.contributor.authorLoboda, A
dc.contributor.authorWatters, J
dc.contributor.authorPoon, RTP
dc.contributor.authorFan, ST
dc.contributor.authorYeung, C
dc.contributor.authorLee, NPY
dc.contributor.authorGuinney, J
dc.contributor.authorMolony, C
dc.contributor.authorEmilsson, V
dc.contributor.authorBuserDoepner, C
dc.contributor.authorZhu, J
dc.contributor.authorFriend, S
dc.contributor.authorMao, M
dc.contributor.authorShaw, PM
dc.contributor.authorDai, H
dc.contributor.authorLuk, JM
dc.contributor.authorSchadt, EE
dc.date.accessioned2011-09-23T05:55:04Z
dc.date.available2011-09-23T05:55:04Z
dc.date.issued2011
dc.description.abstractBackground: 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. © 2011 Lamb et al.
dc.description.naturepublished_or_final_version
dc.identifier.citationPlos One, 2011, v. 6 n. 7 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0020090
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0020090
dc.identifier.epagee20090
dc.identifier.hkuros192464
dc.identifier.isiWOS:000292512000005
Funding AgencyGrant Number
Merck Co
Funding Information:

This work was entirely funded by Merck & Co and its wholly owned subsidiary Rosetta Inpharmatics, Inc. Many of the authors were or are Merck employees. The manuscript was reviewed by Merck and approved for release into the public domain without alteration. Other than this Rosetta Inpharmatics and Merck had no role in study design, data collection and analysis, or preparation of the manuscript.

dc.identifier.issn1932-6203
2011 Impact Factor: 4.092
2011 SCImago Journal Rankings: 0.519
dc.identifier.issue7
dc.identifier.pmcidPMC3130029
dc.identifier.pmid21750698
dc.identifier.scopuseid_2-s2.0-79960000200
dc.identifier.spagee20090
dc.identifier.urihttp://hdl.handle.net/10722/139743
dc.identifier.volume6
dc.languageeng
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
dc.publisher.placeUnited States
dc.relation.ispartofPLoS ONE
dc.relation.referencesReferences in Scopus
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
dc.subject.meshCarcinoma, Hepatocellular - genetics
dc.subject.meshDNA Copy Number Variations
dc.subject.meshGene Expression Profiling
dc.subject.meshLiver - metabolism - pathology
dc.subject.meshLiver Neoplasms - genetics
dc.titlePredictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong
  2. Rosetta Inpharmatics LLC
  3. Fred Hutchinson Cancer Research Center
  4. Merck & Co.