Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter 1A in breast and lung carcinomas

A. K. Virmani, A. Rathi, U. G. Sathyanarayana, A. Padar, C. X. Huang, H. T. Cunnigham, A. J. Farinas, S. Milchgrub, D. M. Euhus, M. Gilcrease, J. Herman, J. D. Minna, A. F. Gazdar

Research output: Contribution to journalArticle

222 Citations (Scopus)

Abstract

The adenomatous polyposis coli (APC) gene is a tumor suppressor gene associated with both familial and sporadic cancer. Despite high rates of allelic loss in lung and breast cancers, point mutations of the APC gene are infrequent in these cancer types. Aberrant methylation of the APC promoter 1A occurs in some colorectal and gastric malignancies, and we investigated whether the same mechanism occurs in lung and breast cancers. The methylation status of the APC gene promoter 1A was analyzed in 77 breast, 50 small cell (SCLC), and 106 non-small cell (NSCLC) lung cancer tumors and cell lines and in 68 nonmalignant tissues by methylation-specific PCR. Expression of the APC promoter 1A transcript was examined in a subset of cell lines by reverse transcription-PCR, and loss of heterozygosity at the gene locus was analyzed by the use of 12 microsatellite and polymorphic markers. Statistical tests were two-sided. Promoter 1A was methylated in 34 of 77 breast cancer tumors and cell lines (44%), in 56 of 106 NSCLC tumors and cell lines (53%), in 13 of 50 SCLC cell lines (26%), and in 3 of 68 nonmalignant samples (4%). Most cell lines tested contained the unmethylated or methylated form exclusively. In 27 cell lines tested, there was complete concordance between promoter methylation and silencing of its transcript. Demethylation with 5-aza-2′-deoxycytidine treatment restored transcript 1A expression in all eight methylated cell lines tested. Loss of heterozygosity at the APC locus was observed in 85% of SCLCs, 83% of NSCLCs, and 63% of breast cancer cell lines. The frequency of methylation in breast cancers increased with tumor stage and size. In summary, aberrant methylation of the 1A promoter of the APC gene and loss of its specific transcript is frequently present in breast and NSCLC cancers and cell lines and, to a lesser extent, in SCLC cell lines. Our findings may be of biological and clinical importance.

Original languageEnglish (US)
Pages (from-to)1998-2004
Number of pages7
JournalClinical Cancer Research
Volume7
Issue number7
StatePublished - 2001

Fingerprint

APC Genes
Methylation
Breast Neoplasms
Cell Line
Lung
Adenomatous Polyposis Coli
Loss of Heterozygosity
Tumor Cell Line
decitabine
Lung Neoplasms
Neoplasms
Polymerase Chain Reaction
Tumor Suppressor Genes
Point Mutation
Non-Small Cell Lung Carcinoma
Microsatellite Repeats
Reverse Transcription
Stomach
Breast

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Virmani, A. K., Rathi, A., Sathyanarayana, U. G., Padar, A., Huang, C. X., Cunnigham, H. T., ... Gazdar, A. F. (2001). Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter 1A in breast and lung carcinomas. Clinical Cancer Research, 7(7), 1998-2004.

Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter 1A in breast and lung carcinomas. / Virmani, A. K.; Rathi, A.; Sathyanarayana, U. G.; Padar, A.; Huang, C. X.; Cunnigham, H. T.; Farinas, A. J.; Milchgrub, S.; Euhus, D. M.; Gilcrease, M.; Herman, J.; Minna, J. D.; Gazdar, A. F.

In: Clinical Cancer Research, Vol. 7, No. 7, 2001, p. 1998-2004.

Research output: Contribution to journalArticle

Virmani, AK, Rathi, A, Sathyanarayana, UG, Padar, A, Huang, CX, Cunnigham, HT, Farinas, AJ, Milchgrub, S, Euhus, DM, Gilcrease, M, Herman, J, Minna, JD & Gazdar, AF 2001, 'Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter 1A in breast and lung carcinomas', Clinical Cancer Research, vol. 7, no. 7, pp. 1998-2004.
Virmani AK, Rathi A, Sathyanarayana UG, Padar A, Huang CX, Cunnigham HT et al. Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter 1A in breast and lung carcinomas. Clinical Cancer Research. 2001;7(7):1998-2004.
Virmani, A. K. ; Rathi, A. ; Sathyanarayana, U. G. ; Padar, A. ; Huang, C. X. ; Cunnigham, H. T. ; Farinas, A. J. ; Milchgrub, S. ; Euhus, D. M. ; Gilcrease, M. ; Herman, J. ; Minna, J. D. ; Gazdar, A. F. / Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter 1A in breast and lung carcinomas. In: Clinical Cancer Research. 2001 ; Vol. 7, No. 7. pp. 1998-2004.
@article{cb89e9fb01434251aeb050c9bd55a116,
title = "Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter 1A in breast and lung carcinomas",
abstract = "The adenomatous polyposis coli (APC) gene is a tumor suppressor gene associated with both familial and sporadic cancer. Despite high rates of allelic loss in lung and breast cancers, point mutations of the APC gene are infrequent in these cancer types. Aberrant methylation of the APC promoter 1A occurs in some colorectal and gastric malignancies, and we investigated whether the same mechanism occurs in lung and breast cancers. The methylation status of the APC gene promoter 1A was analyzed in 77 breast, 50 small cell (SCLC), and 106 non-small cell (NSCLC) lung cancer tumors and cell lines and in 68 nonmalignant tissues by methylation-specific PCR. Expression of the APC promoter 1A transcript was examined in a subset of cell lines by reverse transcription-PCR, and loss of heterozygosity at the gene locus was analyzed by the use of 12 microsatellite and polymorphic markers. Statistical tests were two-sided. Promoter 1A was methylated in 34 of 77 breast cancer tumors and cell lines (44{\%}), in 56 of 106 NSCLC tumors and cell lines (53{\%}), in 13 of 50 SCLC cell lines (26{\%}), and in 3 of 68 nonmalignant samples (4{\%}). Most cell lines tested contained the unmethylated or methylated form exclusively. In 27 cell lines tested, there was complete concordance between promoter methylation and silencing of its transcript. Demethylation with 5-aza-2′-deoxycytidine treatment restored transcript 1A expression in all eight methylated cell lines tested. Loss of heterozygosity at the APC locus was observed in 85{\%} of SCLCs, 83{\%} of NSCLCs, and 63{\%} of breast cancer cell lines. The frequency of methylation in breast cancers increased with tumor stage and size. In summary, aberrant methylation of the 1A promoter of the APC gene and loss of its specific transcript is frequently present in breast and NSCLC cancers and cell lines and, to a lesser extent, in SCLC cell lines. Our findings may be of biological and clinical importance.",
author = "Virmani, {A. K.} and A. Rathi and Sathyanarayana, {U. G.} and A. Padar and Huang, {C. X.} and Cunnigham, {H. T.} and Farinas, {A. J.} and S. Milchgrub and Euhus, {D. M.} and M. Gilcrease and J. Herman and Minna, {J. D.} and Gazdar, {A. F.}",
year = "2001",
language = "English (US)",
volume = "7",
pages = "1998--2004",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter 1A in breast and lung carcinomas

AU - Virmani, A. K.

AU - Rathi, A.

AU - Sathyanarayana, U. G.

AU - Padar, A.

AU - Huang, C. X.

AU - Cunnigham, H. T.

AU - Farinas, A. J.

AU - Milchgrub, S.

AU - Euhus, D. M.

AU - Gilcrease, M.

AU - Herman, J.

AU - Minna, J. D.

AU - Gazdar, A. F.

PY - 2001

Y1 - 2001

N2 - The adenomatous polyposis coli (APC) gene is a tumor suppressor gene associated with both familial and sporadic cancer. Despite high rates of allelic loss in lung and breast cancers, point mutations of the APC gene are infrequent in these cancer types. Aberrant methylation of the APC promoter 1A occurs in some colorectal and gastric malignancies, and we investigated whether the same mechanism occurs in lung and breast cancers. The methylation status of the APC gene promoter 1A was analyzed in 77 breast, 50 small cell (SCLC), and 106 non-small cell (NSCLC) lung cancer tumors and cell lines and in 68 nonmalignant tissues by methylation-specific PCR. Expression of the APC promoter 1A transcript was examined in a subset of cell lines by reverse transcription-PCR, and loss of heterozygosity at the gene locus was analyzed by the use of 12 microsatellite and polymorphic markers. Statistical tests were two-sided. Promoter 1A was methylated in 34 of 77 breast cancer tumors and cell lines (44%), in 56 of 106 NSCLC tumors and cell lines (53%), in 13 of 50 SCLC cell lines (26%), and in 3 of 68 nonmalignant samples (4%). Most cell lines tested contained the unmethylated or methylated form exclusively. In 27 cell lines tested, there was complete concordance between promoter methylation and silencing of its transcript. Demethylation with 5-aza-2′-deoxycytidine treatment restored transcript 1A expression in all eight methylated cell lines tested. Loss of heterozygosity at the APC locus was observed in 85% of SCLCs, 83% of NSCLCs, and 63% of breast cancer cell lines. The frequency of methylation in breast cancers increased with tumor stage and size. In summary, aberrant methylation of the 1A promoter of the APC gene and loss of its specific transcript is frequently present in breast and NSCLC cancers and cell lines and, to a lesser extent, in SCLC cell lines. Our findings may be of biological and clinical importance.

AB - The adenomatous polyposis coli (APC) gene is a tumor suppressor gene associated with both familial and sporadic cancer. Despite high rates of allelic loss in lung and breast cancers, point mutations of the APC gene are infrequent in these cancer types. Aberrant methylation of the APC promoter 1A occurs in some colorectal and gastric malignancies, and we investigated whether the same mechanism occurs in lung and breast cancers. The methylation status of the APC gene promoter 1A was analyzed in 77 breast, 50 small cell (SCLC), and 106 non-small cell (NSCLC) lung cancer tumors and cell lines and in 68 nonmalignant tissues by methylation-specific PCR. Expression of the APC promoter 1A transcript was examined in a subset of cell lines by reverse transcription-PCR, and loss of heterozygosity at the gene locus was analyzed by the use of 12 microsatellite and polymorphic markers. Statistical tests were two-sided. Promoter 1A was methylated in 34 of 77 breast cancer tumors and cell lines (44%), in 56 of 106 NSCLC tumors and cell lines (53%), in 13 of 50 SCLC cell lines (26%), and in 3 of 68 nonmalignant samples (4%). Most cell lines tested contained the unmethylated or methylated form exclusively. In 27 cell lines tested, there was complete concordance between promoter methylation and silencing of its transcript. Demethylation with 5-aza-2′-deoxycytidine treatment restored transcript 1A expression in all eight methylated cell lines tested. Loss of heterozygosity at the APC locus was observed in 85% of SCLCs, 83% of NSCLCs, and 63% of breast cancer cell lines. The frequency of methylation in breast cancers increased with tumor stage and size. In summary, aberrant methylation of the 1A promoter of the APC gene and loss of its specific transcript is frequently present in breast and NSCLC cancers and cell lines and, to a lesser extent, in SCLC cell lines. Our findings may be of biological and clinical importance.

UR - http://www.scopus.com/inward/record.url?scp=0034772312&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034772312&partnerID=8YFLogxK

M3 - Article

VL - 7

SP - 1998

EP - 2004

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 7

ER -