DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis

Manel Esteller; Mario F. Fraga; Mingzhou Guo; Jesus Garcia-Foncillas; Ingrid Hedenfalk; Andrew K. Godwin; Joerg Trojan; Catherine Vaurs-Barrière; Yves Jean Bignon; Susan Ramus; Javier Benitez; Trinidad Caldes; Yoshimitsu Akiyama; Yusuhito Yuasa; Virpi Launonen; Maria Jesus Canal; Roberto Rodriguez; Gabriel Capella; Miguel Angel Peinado; Ake Borg; Lauri A. Aaltonen; Bruce A. Ponder; Stephen B. Baylin; James G. Herman

doi:10.1093/hmg/10.26.3001

DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis

Manel Esteller, Mario F. Fraga, Mingzhou Guo, Jesus Garcia-Foncillas, Ingrid Hedenfalk, Andrew K. Godwin, Joerg Trojan, Catherine Vaurs-Barrière, Yves Jean Bignon, Susan Ramus, Javier Benitez, Trinidad Caldes, Yoshimitsu Akiyama, Yusuhito Yuasa, Virpi Launonen, Maria Jesus Canal, Roberto Rodriguez, Gabriel Capella, Miguel Angel Peinado, Ake BorgLauri A. Aaltonen, Bruce A. Ponder, Stephen B. Baylin, James G. Herman

School of Medicine

Research output: Contribution to journal › Article › peer-review

370 Scopus citations

Abstract

Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p 16^INK4a, p14^ARF, MGMT, GSTP1 and RARβ2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n= 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second 'hit', associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers 'mimic' the DNA methylation patterns present in the sporadic tumors.

Original language	English (US)
Pages (from-to)	3001-3007
Number of pages	7
Journal	Human molecular genetics
Volume	10
Issue number	26
DOIs	https://doi.org/10.1093/hmg/10.26.3001
State	Published - Dec 15 2001

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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Esteller, M., Fraga, M. F., Guo, M., Garcia-Foncillas, J., Hedenfalk, I., Godwin, A. K., Trojan, J., Vaurs-Barrière, C., Bignon, Y. J., Ramus, S., Benitez, J., Caldes, T., Akiyama, Y., Yuasa, Y., Launonen, V., Canal, M. J., Rodriguez, R., Capella, G., Peinado, M. A., ... Herman, J. G. (2001). DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Human molecular genetics, 10(26), 3001-3007. https://doi.org/10.1093/hmg/10.26.3001

Esteller, M, Fraga, MF, Guo, M, Garcia-Foncillas, J, Hedenfalk, I, Godwin, AK, Trojan, J, Vaurs-Barrière, C, Bignon, YJ, Ramus, S, Benitez, J, Caldes, T, Akiyama, Y, Yuasa, Y, Launonen, V, Canal, MJ, Rodriguez, R, Capella, G, Peinado, MA, Borg, A, Aaltonen, LA, Ponder, BA, Baylin, SB & Herman, JG 2001, 'DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis', Human molecular genetics, vol. 10, no. 26, pp. 3001-3007. https://doi.org/10.1093/hmg/10.26.3001

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title = "DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis",

abstract = "Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p 16INK4a, p14ARF, MGMT, GSTP1 and RARβ2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n= 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second 'hit', associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers 'mimic' the DNA methylation patterns present in the sporadic tumors.",

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T1 - DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis

AU - Esteller, Manel

AU - Fraga, Mario F.

AU - Guo, Mingzhou

AU - Garcia-Foncillas, Jesus

AU - Hedenfalk, Ingrid

AU - Godwin, Andrew K.

AU - Trojan, Joerg

AU - Vaurs-Barrière, Catherine

AU - Bignon, Yves Jean

AU - Ramus, Susan

AU - Benitez, Javier

AU - Caldes, Trinidad

AU - Akiyama, Yoshimitsu

AU - Yuasa, Yusuhito

AU - Launonen, Virpi

AU - Canal, Maria Jesus

AU - Rodriguez, Roberto

AU - Capella, Gabriel

AU - Peinado, Miguel Angel

AU - Borg, Ake

AU - Aaltonen, Lauri A.

AU - Ponder, Bruce A.

AU - Baylin, Stephen B.

AU - Herman, James G.

PY - 2001/12/15

Y1 - 2001/12/15

N2 - Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p 16INK4a, p14ARF, MGMT, GSTP1 and RARβ2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n= 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second 'hit', associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers 'mimic' the DNA methylation patterns present in the sporadic tumors.

AB - Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p 16INK4a, p14ARF, MGMT, GSTP1 and RARβ2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n= 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second 'hit', associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers 'mimic' the DNA methylation patterns present in the sporadic tumors.

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DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis

Abstract

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