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

TitlePredictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting
Authors
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2011, v. 6 n. 7 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/139743
ISSN
2014 Impact Factor: 3.234
2014 SCImago Journal Rankings: 1.300
PubMed Central ID
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorLamb, JRen_HK
dc.contributor.authorZhang, Cen_HK
dc.contributor.authorXie, Ten_HK
dc.contributor.authorWang, Ken_HK
dc.contributor.authorZhang, Ben_HK
dc.contributor.authorHao, Ken_HK
dc.contributor.authorChudin, Een_HK
dc.contributor.authorFraser, HBen_HK
dc.contributor.authorMillstein, Jen_HK
dc.contributor.authorFerguson, Men_HK
dc.contributor.authorSuver, Cen_HK
dc.contributor.authorIvanovska, Ien_HK
dc.contributor.authorScott, Men_HK
dc.contributor.authorPhilippar, Uen_HK
dc.contributor.authorBansal, Den_HK
dc.contributor.authorZhang, Zen_HK
dc.contributor.authorBurchard, Jen_HK
dc.contributor.authorSmith, Ren_HK
dc.contributor.authorGreenawalt, Den_HK
dc.contributor.authorCleary, Men_HK
dc.contributor.authorDerry, Jen_HK
dc.contributor.authorLoboda, Aen_HK
dc.contributor.authorWatters, Jen_HK
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorFan, STen_HK
dc.contributor.authorYeung, Cen_HK
dc.contributor.authorLee, NPYen_HK
dc.contributor.authorGuinney, Jen_HK
dc.contributor.authorMolony, Cen_HK
dc.contributor.authorEmilsson, Ven_HK
dc.contributor.authorBuserDoepner, Cen_HK
dc.contributor.authorZhu, Jen_HK
dc.contributor.authorFriend, Sen_HK
dc.contributor.authorMao, Men_HK
dc.contributor.authorShaw, PMen_HK
dc.contributor.authorDai, Hen_HK
dc.contributor.authorLuk, JMen_HK
dc.contributor.authorSchadt, EEen_HK
dc.date.accessioned2011-09-23T05:55:04Z-
dc.date.available2011-09-23T05:55:04Z-
dc.date.issued2011en_HK
dc.identifier.citationPlos One, 2011, v. 6 n. 7en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139743-
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.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS ONEen_HK
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 limitingen_HK
dc.typeArticleen_HK
dc.identifier.emailPoon, RTP: poontp@hkucc.hku.hken_HK
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.emailLee, NPY: nikkilee@hku.hken_HK
dc.identifier.emailLuk, JM: jmluk@hkucc.hku.hken_HK
dc.identifier.authorityPoon, RTP=rp00446en_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.identifier.authorityLee, NPY=rp00263en_HK
dc.identifier.authorityLuk, JM=rp00349en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0020090en_HK
dc.identifier.pmid21750698-
dc.identifier.pmcidPMC3130029-
dc.identifier.scopuseid_2-s2.0-79960000200en_HK
dc.identifier.hkuros192464en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79960000200&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume6en_HK
dc.identifier.issue7en_HK
dc.identifier.spagee20090en_US
dc.identifier.epagee20090en_US
dc.identifier.isiWOS:000292512000005-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLamb, JR=7201524642en_HK
dc.identifier.scopusauthoridZhang, C=9747304800en_HK
dc.identifier.scopusauthoridXie, T=35286182300en_HK
dc.identifier.scopusauthoridWang, K=35286098800en_HK
dc.identifier.scopusauthoridZhang, B=35427050800en_HK
dc.identifier.scopusauthoridHao, K=34770116300en_HK
dc.identifier.scopusauthoridChudin, E=6603175835en_HK
dc.identifier.scopusauthoridFraser, HB=7201872161en_HK
dc.identifier.scopusauthoridMillstein, J=24367129900en_HK
dc.identifier.scopusauthoridFerguson, M=35208305500en_HK
dc.identifier.scopusauthoridSuver, C=24367502200en_HK
dc.identifier.scopusauthoridIvanovska, I=6507113691en_HK
dc.identifier.scopusauthoridScott, M=7403481621en_HK
dc.identifier.scopusauthoridPhilippar, U=6506975144en_HK
dc.identifier.scopusauthoridBansal, D=46061812500en_HK
dc.identifier.scopusauthoridZhang, Z=54792458900en_HK
dc.identifier.scopusauthoridBurchard, J=35586927300en_HK
dc.identifier.scopusauthoridSmith, R=36629469300en_HK
dc.identifier.scopusauthoridGreenawalt, D=12143427800en_HK
dc.identifier.scopusauthoridCleary, M=7202006129en_HK
dc.identifier.scopusauthoridDerry, J=36939895600en_HK
dc.identifier.scopusauthoridLoboda, A=25122992300en_HK
dc.identifier.scopusauthoridWatters, J=7102055993en_HK
dc.identifier.scopusauthoridPoon, RTP=7103097223en_HK
dc.identifier.scopusauthoridFan, ST=7402678224en_HK
dc.identifier.scopusauthoridYeung, C=26531966700en_HK
dc.identifier.scopusauthoridLee, NPY=7402722690en_HK
dc.identifier.scopusauthoridGuinney, J=14324594600en_HK
dc.identifier.scopusauthoridMolony, C=23987362300en_HK
dc.identifier.scopusauthoridEmilsson, V=6701439213en_HK
dc.identifier.scopusauthoridBuserDoepner, C=6507890254en_HK
dc.identifier.scopusauthoridZhu, J=35286163000en_HK
dc.identifier.scopusauthoridFriend, S=7007092262en_HK
dc.identifier.scopusauthoridMao, M=7102960472en_HK
dc.identifier.scopusauthoridShaw, PM=7401651642en_HK
dc.identifier.scopusauthoridDai, H=7402206916en_HK
dc.identifier.scopusauthoridLuk, JM=7006777791en_HK
dc.identifier.scopusauthoridSchadt, EE=6701604029en_HK

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