Article: A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies

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TitleA genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies
AuthorsShames, DS1
Girard, L1
Gao, B1
Sato, M1
Lewis, CM1
Shivapurkar, N1
Jiang, A1
Perou, CM1
Kim, YH1
Pollack, JR1
Fong, KM1
Lam, CL1
Wong, M1
Shyr, Y1
Nanda, R1
Olopade, OI1
Gerald, W1
Euhus, DM1
Shay, JW1
Gazdar, AF1
Minna, JD1
Issue Date2006
PublisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676
CitationPlos Medicine, 2006, v. 3 n. 12, p. 2244-2263 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pmed.0030486
AbstractBackground: Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The "rules" governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. Methods and Findings: In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5′ CpG islands, are induced from undetectable levels by 5-aza-2′-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. Conclusions: By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent targets for early detection screening or therapeutic intervention. © 2006 Shames et al.
ISSN1549-1277
2011 Impact Factor: 16.269
2011 SCImago Journal Rankings: 1.041
DOIhttp://dx.doi.org/10.1371/journal.pmed.0030486
ISI Accession Number IDWOS:000243482500018
PubMed Central IDPMC1716188
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorShames, DS
dc.contributor.authorGirard, L
dc.contributor.authorGao, B
dc.contributor.authorSato, M
dc.contributor.authorLewis, CM
dc.contributor.authorShivapurkar, N
dc.contributor.authorJiang, A
dc.contributor.authorPerou, CM
dc.contributor.authorKim, YH
dc.contributor.authorPollack, JR
dc.contributor.authorFong, KM
dc.contributor.authorLam, CL
dc.contributor.authorWong, M
dc.contributor.authorShyr, Y
dc.contributor.authorNanda, R
dc.contributor.authorOlopade, OI
dc.contributor.authorGerald, W
dc.contributor.authorEuhus, DM
dc.contributor.authorShay, JW
dc.contributor.authorGazdar, AF
dc.contributor.authorMinna, JD
dc.date.accessioned2010-09-06T09:47:57Z
dc.date.available2010-09-06T09:47:57Z
dc.date.issued2006
dc.description.abstractBackground: Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The "rules" governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. Methods and Findings: In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5′ CpG islands, are induced from undetectable levels by 5-aza-2′-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. Conclusions: By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent targets for early detection screening or therapeutic intervention. © 2006 Shames et al.
dc.description.naturepublished_or_final_version
dc.identifier.citationPlos Medicine, 2006, v. 3 n. 12, p. 2244-2263 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pmed.0030486
dc.identifier.citeulike1288583
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pmed.0030486
dc.identifier.epage2263
dc.identifier.hkuros195651
dc.identifier.hkuros134761
dc.identifier.isiWOS:000243482500018
dc.identifier.issn1549-1277
2011 Impact Factor: 16.269
2011 SCImago Journal Rankings: 1.041
dc.identifier.issue12
dc.identifier.openurl
dc.identifier.pmcidPMC1716188
dc.identifier.pmid17194187
dc.identifier.scopuseid_2-s2.0-33845926895
dc.identifier.spage2244
dc.identifier.urihttp://hdl.handle.net/10722/88784
dc.identifier.volume3
dc.languageeng
dc.publisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676
dc.publisher.placeUnited States
dc.relation.ispartofPLoS Medicine
dc.relation.referencesReferences in Scopus
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
dc.subject.meshCarcinoma, Adenosquamous - genetics
dc.subject.meshDNA Methylation
dc.subject.meshGene Expression Profiling - methods
dc.subject.meshLung Neoplasms - genetics
dc.subject.meshPromoter Regions, Genetic - genetics
dc.titleA genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies
dc.typeArticle
Author Affiliations
  1. UT Southwestern Medical School