APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q

Christian N. Arnold, Ajay Goel, Donna Niedzwiecki, Jeannette M. Dowell, Linda Wasserman, Carolyn Compton, Robert J. Mayer, Monica M. Bertagnolli, C. Richard Boland

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Abstract

Introduction: Germ-line mutations of the APC gene are associated with familial adenomatous polyposis, and somatic mutations occur frequently in sporadic colorectal cancer. However, to abrogate APC function, both alleles must be inactivated. Recently, it has been demonstrated that epigenetic modification of the APC promoter influences APC silencing. Here we examined the influence of APC methylation on APC expression in tumors with and without LOH at the APC locus. Material and Methods: 137 sporadic colorectal cancer specimens were investigated for LOH at the 5q locus. The methylation status of the APC promoter was determined by methylation-specific PCR. APC expression was performed by immunohistochemistry. Results: expression was reduced or lost in 110 of 137 (80%) tumors and LOH at 5q was found in 13 of 132 (10%) tumors. There was no difference in 5q LOH between tumors with or without intact APC expression. Vice versa, there was no difference in the APC expression in tumors with 5q LOH. Aberrant APC promoter methylation was detected in 33 of 118 (28%) tumors investigated. Of the tumors with 5q LOH for which methylation data were available, 4 of 11 (36%) were methylated versus 28 of 105 (27%) of those without LOH. No difference in methylation was observed in tumors without 5q LOH and normal APC expression and those without 5q LOH and reduced or missing APC expression. Importantly, none of the tumors with 5q LOH and normal APC staining were aberrantly methylated, whereas 50% of the cancers with LOH at 5q and reduced or absent staining were hypermethylated. Conclusions: This report suggests that tumors with 5q LOH and reduced APC expression are more frequently hypermethylated at the APC promoter compared to those tumors with 5q LOH and normal APC expression. The association among APC promoter methylation status, 5q LOH, and reduced or lost APC expression suggests that de novo methylation plays an important role as a "second hit" in silencing APC expression in colorectal neoplasia.

Original languageEnglish (US)
Pages (from-to)960-964
Number of pages5
JournalCancer Biology and Therapy
Volume3
Issue number10
StatePublished - Oct 2004
Externally publishedYes

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Loss of Heterozygosity
Colorectal Neoplasms
Methylation
Neoplasms
Staining and Labeling
APC Genes
Adenomatous Polyposis Coli
Germ-Line Mutation
Epigenomics
Immunohistochemistry
Alleles

Keywords

  • Adenomatous polyposis coli (APC)
  • Colorectal cancer (CRC)
  • Immunohistochemistry (IHC)
  • Loss of heterozygosity (LOH)

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Arnold, C. N., Goel, A., Niedzwiecki, D., Dowell, J. M., Wasserman, L., Compton, C., ... Boland, C. R. (2004). APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q. Cancer Biology and Therapy, 3(10), 960-964.

APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q. / Arnold, Christian N.; Goel, Ajay; Niedzwiecki, Donna; Dowell, Jeannette M.; Wasserman, Linda; Compton, Carolyn; Mayer, Robert J.; Bertagnolli, Monica M.; Boland, C. Richard.

In: Cancer Biology and Therapy, Vol. 3, No. 10, 10.2004, p. 960-964.

Research output: Contribution to journalArticle

Arnold, CN, Goel, A, Niedzwiecki, D, Dowell, JM, Wasserman, L, Compton, C, Mayer, RJ, Bertagnolli, MM & Boland, CR 2004, 'APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q', Cancer Biology and Therapy, vol. 3, no. 10, pp. 960-964.
Arnold, Christian N. ; Goel, Ajay ; Niedzwiecki, Donna ; Dowell, Jeannette M. ; Wasserman, Linda ; Compton, Carolyn ; Mayer, Robert J. ; Bertagnolli, Monica M. ; Boland, C. Richard. / APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q. In: Cancer Biology and Therapy. 2004 ; Vol. 3, No. 10. pp. 960-964.
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title = "APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q",
abstract = "Introduction: Germ-line mutations of the APC gene are associated with familial adenomatous polyposis, and somatic mutations occur frequently in sporadic colorectal cancer. However, to abrogate APC function, both alleles must be inactivated. Recently, it has been demonstrated that epigenetic modification of the APC promoter influences APC silencing. Here we examined the influence of APC methylation on APC expression in tumors with and without LOH at the APC locus. Material and Methods: 137 sporadic colorectal cancer specimens were investigated for LOH at the 5q locus. The methylation status of the APC promoter was determined by methylation-specific PCR. APC expression was performed by immunohistochemistry. Results: expression was reduced or lost in 110 of 137 (80{\%}) tumors and LOH at 5q was found in 13 of 132 (10{\%}) tumors. There was no difference in 5q LOH between tumors with or without intact APC expression. Vice versa, there was no difference in the APC expression in tumors with 5q LOH. Aberrant APC promoter methylation was detected in 33 of 118 (28{\%}) tumors investigated. Of the tumors with 5q LOH for which methylation data were available, 4 of 11 (36{\%}) were methylated versus 28 of 105 (27{\%}) of those without LOH. No difference in methylation was observed in tumors without 5q LOH and normal APC expression and those without 5q LOH and reduced or missing APC expression. Importantly, none of the tumors with 5q LOH and normal APC staining were aberrantly methylated, whereas 50{\%} of the cancers with LOH at 5q and reduced or absent staining were hypermethylated. Conclusions: This report suggests that tumors with 5q LOH and reduced APC expression are more frequently hypermethylated at the APC promoter compared to those tumors with 5q LOH and normal APC expression. The association among APC promoter methylation status, 5q LOH, and reduced or lost APC expression suggests that de novo methylation plays an important role as a {"}second hit{"} in silencing APC expression in colorectal neoplasia.",
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T1 - APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q

AU - Arnold, Christian N.

AU - Goel, Ajay

AU - Niedzwiecki, Donna

AU - Dowell, Jeannette M.

AU - Wasserman, Linda

AU - Compton, Carolyn

AU - Mayer, Robert J.

AU - Bertagnolli, Monica M.

AU - Boland, C. Richard

PY - 2004/10

Y1 - 2004/10

N2 - Introduction: Germ-line mutations of the APC gene are associated with familial adenomatous polyposis, and somatic mutations occur frequently in sporadic colorectal cancer. However, to abrogate APC function, both alleles must be inactivated. Recently, it has been demonstrated that epigenetic modification of the APC promoter influences APC silencing. Here we examined the influence of APC methylation on APC expression in tumors with and without LOH at the APC locus. Material and Methods: 137 sporadic colorectal cancer specimens were investigated for LOH at the 5q locus. The methylation status of the APC promoter was determined by methylation-specific PCR. APC expression was performed by immunohistochemistry. Results: expression was reduced or lost in 110 of 137 (80%) tumors and LOH at 5q was found in 13 of 132 (10%) tumors. There was no difference in 5q LOH between tumors with or without intact APC expression. Vice versa, there was no difference in the APC expression in tumors with 5q LOH. Aberrant APC promoter methylation was detected in 33 of 118 (28%) tumors investigated. Of the tumors with 5q LOH for which methylation data were available, 4 of 11 (36%) were methylated versus 28 of 105 (27%) of those without LOH. No difference in methylation was observed in tumors without 5q LOH and normal APC expression and those without 5q LOH and reduced or missing APC expression. Importantly, none of the tumors with 5q LOH and normal APC staining were aberrantly methylated, whereas 50% of the cancers with LOH at 5q and reduced or absent staining were hypermethylated. Conclusions: This report suggests that tumors with 5q LOH and reduced APC expression are more frequently hypermethylated at the APC promoter compared to those tumors with 5q LOH and normal APC expression. The association among APC promoter methylation status, 5q LOH, and reduced or lost APC expression suggests that de novo methylation plays an important role as a "second hit" in silencing APC expression in colorectal neoplasia.

AB - Introduction: Germ-line mutations of the APC gene are associated with familial adenomatous polyposis, and somatic mutations occur frequently in sporadic colorectal cancer. However, to abrogate APC function, both alleles must be inactivated. Recently, it has been demonstrated that epigenetic modification of the APC promoter influences APC silencing. Here we examined the influence of APC methylation on APC expression in tumors with and without LOH at the APC locus. Material and Methods: 137 sporadic colorectal cancer specimens were investigated for LOH at the 5q locus. The methylation status of the APC promoter was determined by methylation-specific PCR. APC expression was performed by immunohistochemistry. Results: expression was reduced or lost in 110 of 137 (80%) tumors and LOH at 5q was found in 13 of 132 (10%) tumors. There was no difference in 5q LOH between tumors with or without intact APC expression. Vice versa, there was no difference in the APC expression in tumors with 5q LOH. Aberrant APC promoter methylation was detected in 33 of 118 (28%) tumors investigated. Of the tumors with 5q LOH for which methylation data were available, 4 of 11 (36%) were methylated versus 28 of 105 (27%) of those without LOH. No difference in methylation was observed in tumors without 5q LOH and normal APC expression and those without 5q LOH and reduced or missing APC expression. Importantly, none of the tumors with 5q LOH and normal APC staining were aberrantly methylated, whereas 50% of the cancers with LOH at 5q and reduced or absent staining were hypermethylated. Conclusions: This report suggests that tumors with 5q LOH and reduced APC expression are more frequently hypermethylated at the APC promoter compared to those tumors with 5q LOH and normal APC expression. The association among APC promoter methylation status, 5q LOH, and reduced or lost APC expression suggests that de novo methylation plays an important role as a "second hit" in silencing APC expression in colorectal neoplasia.

KW - Adenomatous polyposis coli (APC)

KW - Colorectal cancer (CRC)

KW - Immunohistochemistry (IHC)

KW - Loss of heterozygosity (LOH)

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