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Human Molecular Genetics, 2001, Vol. 10, No. 26 3001-3007
© 2001 Oxford University Press

DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis

Manel Esteller1,2, Mario F. Fraga2,11, Mingzhou Guo1, Jesus Garcia-Foncillas4, Ingrid Hedenfalk7,13, Andrew K. Godwin5, Joerg Trojan6, Catherine Vaurs-Barrière8, Yves-Jean Bignon8, Susan Ramus15, Javier Benitez3, Trinidad Caldes10, Yoshimitsu Akiyama1,9, Yusuhito Yuasa9, Virpi Launonen14, Maria Jesus Canal11, Roberto Rodriguez11, Gabriel Capella12, Miguel Angel Peinado12, Ake Borg13, Lauri A. Aaltonen14, Bruce A. Ponder15, Stephen B. Baylin1 and James G. Herman1,+

1The Johns Hopkins Oncology Center, Baltimore, MD, USA, 2Cancer Epigenetics Laboratory and 3Human Genetics Laboratory, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain, 4Laboratory of Biotechnology and Genomics, Clinica Universitaria Pamplona, University of Navarra, Spain, 5Molecular Genetics Laboratory, Fox Chase Cancer Center, Philadelphia, PA, USA, 6Department of Internal Medicine, Johan Wolfgang Goethe University, Frankfurt, Germany, 7Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA, 8Laboratoire d’Oncologie Moleculaire, Centre Jean Perrin, Clermont-Ferrand, France, 9Department of Molecular Oncology, Tokyo Medical and Dental University School of Medicine, Tokyo, Japan, 10Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain, 11Department of Biochemistry, School of Biology, Oviedo, Spain, 12Institut de Recerca Oncologica and Institut Catala d’Oncologia, Barcelona, Catalonia, Spain, 13Department of Oncology, University of Lund, Lund, Sweden, 14Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland and 15Cambridge Institute for Medical Research, Addenbrookes Hospital, Cambridge, UK

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, p16INK4a, p14ARF, MGMT, GSTP1 and RARß2) 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.

+ To whom correspondence should be addressed at: The Johns Hopkins Oncology Center, Room 543, 1650 Orleans Street, Baltimore, MD 21231, USA. Tel: +1 410 955 8506; Fax: +1 410 614 9884; Email: hermanji@jhmi.edu


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