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

David S. Shames, Luc Girard, Boning Gao, Mitsuo Sato, Cheryl M. Lewis, Narayan Shivapurkar, Aixiang Jiang, Charles M. Perou, Young H. Kim, Jonathan R. Pollack, Kwun M. Fong, Chi Leung Lam, Maria Wong, Yu Shyr, Rita Nanda, Olufunmilayo I. Olopade, William Gerald, David M. Euhus, Jerry W. Shay, Adi F. Gazdar & 1 others John D. Minna

Research output: Contribution to journalArticle

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Abstract

Background: 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.

Original languageEnglish (US)
Pages (from-to)2244-2263
Number of pages20
JournalPLoS Medicine
Volume3
Issue number12
DOIs
StatePublished - Dec 2006

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Methylation
Lung Neoplasms
Genes
Genome
Tumors
Neoplasms
Cells
decitabine
Tissue
Breast Neoplasms
Colonic Neoplasms
Prostatic Neoplasms
CpG Islands
Lung
Penetrance
Loss of Heterozygosity
Genetic Promoter Regions
Gene expression
DNA Methylation
Genetic Markers

ASJC Scopus subject areas

  • Medicine(all)

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A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies. / Shames, David S.; Girard, Luc; Gao, Boning; Sato, Mitsuo; Lewis, Cheryl M.; Shivapurkar, Narayan; Jiang, Aixiang; Perou, Charles M.; Kim, Young H.; Pollack, Jonathan R.; Fong, Kwun M.; Lam, Chi Leung; Wong, Maria; Shyr, Yu; Nanda, Rita; Olopade, Olufunmilayo I.; Gerald, William; Euhus, David M.; Shay, Jerry W.; Gazdar, Adi F.; Minna, John D.

In: PLoS Medicine, Vol. 3, No. 12, 12.2006, p. 2244-2263.

Research output: Contribution to journalArticle

Shames, DS, Girard, L, Gao, B, Sato, M, Lewis, CM, Shivapurkar, N, Jiang, A, Perou, CM, Kim, YH, Pollack, JR, Fong, KM, Lam, CL, Wong, M, Shyr, Y, Nanda, R, Olopade, OI, Gerald, W, Euhus, DM, Shay, JW, Gazdar, AF & Minna, JD 2006, 'A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies', PLoS Medicine, vol. 3, no. 12, pp. 2244-2263. https://doi.org/10.1371/journal.pmed.0030486
Shames, David S. ; Girard, Luc ; Gao, Boning ; Sato, Mitsuo ; Lewis, Cheryl M. ; Shivapurkar, Narayan ; Jiang, Aixiang ; Perou, Charles M. ; Kim, Young H. ; Pollack, Jonathan R. ; Fong, Kwun M. ; Lam, Chi Leung ; Wong, Maria ; Shyr, Yu ; Nanda, Rita ; Olopade, Olufunmilayo I. ; Gerald, William ; Euhus, David M. ; Shay, Jerry W. ; Gazdar, Adi F. ; Minna, John D. / A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies. In: PLoS Medicine. 2006 ; Vol. 3, No. 12. pp. 2244-2263.
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abstract = "Background: 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.",
author = "Shames, {David S.} and Luc Girard and Boning Gao and Mitsuo Sato and Lewis, {Cheryl M.} and Narayan Shivapurkar and Aixiang Jiang and Perou, {Charles M.} and Kim, {Young H.} and Pollack, {Jonathan R.} and Fong, {Kwun M.} and Lam, {Chi Leung} and Maria Wong and Yu Shyr and Rita Nanda and Olopade, {Olufunmilayo I.} and William Gerald and Euhus, {David M.} and Shay, {Jerry W.} and Gazdar, {Adi F.} and Minna, {John D.}",
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T1 - A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies

AU - Shames, David S.

AU - Girard, Luc

AU - Gao, Boning

AU - Sato, Mitsuo

AU - Lewis, Cheryl M.

AU - Shivapurkar, Narayan

AU - Jiang, Aixiang

AU - Perou, Charles M.

AU - Kim, Young H.

AU - Pollack, Jonathan R.

AU - Fong, Kwun M.

AU - Lam, Chi Leung

AU - Wong, Maria

AU - Shyr, Yu

AU - Nanda, Rita

AU - Olopade, Olufunmilayo I.

AU - Gerald, William

AU - Euhus, David M.

AU - Shay, Jerry W.

AU - Gazdar, Adi F.

AU - Minna, John D.

PY - 2006/12

Y1 - 2006/12

N2 - Background: 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.

AB - Background: 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.

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