DNA methylation profiling in breast cancer discordant identical twins identifies DOK7 as novel epigenetic biomarker

Using whole blood from 15 twin pairs discordant for breast cancer and high-resolution (450K) DNA methylation analysis, we identified 403 differentially methylated CpG sites including known and novel potential breast cancer genes. Confirming the results in an independent validation cohort of 21 twin pairs determined the docking protein DOK7 as a candidate for blood-based cancer diagnosis. DNA hypermethylation of the promoter region was also seen in primary breast cancer tissues and cancer cell lines. Hypermethylation of DOK7 occurs years before tumor diagnosis, suggesting a role as a powerful epigenetic blood-based biomarker as well as providing insights into breast cancer pathogenesis.

[1]  Michael Jones,et al.  Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. , 2012, Cancer research.

[2]  Robin M. Murray,et al.  Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population , 2012, PLoS genetics.

[3]  Zachary D. Smith,et al.  A unique regulatory phase of DNA methylation in the early mammalian embryo , 2012, Nature.

[4]  Brian J. Stevenson,et al.  Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. , 2012, Genome research.

[5]  Thomas Lengauer,et al.  A DNA methylation fingerprint of 1628 human samples. , 2011, Genome research.

[6]  P. Laird,et al.  Genome-Scale Screen for DNA Methylation-Based Detection Markers for Ovarian Cancer , 2011, PloS one.

[7]  Seok-Jun Kim,et al.  Development of microRNA-145 for therapeutic application in breast cancer. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[8]  S. Rafii,et al.  Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. , 2011, Molecular cell.

[9]  K. Gunderson,et al.  High density DNA methylation array with single CpG site resolution. , 2011, Genomics.

[10]  W. Richard McCombie,et al.  Sperm Methylation Profiles Reveal Features of Epigenetic Inheritance and Evolution in Primates , 2011, Cell.

[11]  A. Feinberg,et al.  Increased methylation variation in epigenetic domains across cancer types , 2011, Nature Genetics.

[12]  M. Esteller,et al.  Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome , 2011, Epigenetics.

[13]  M. Esteller,et al.  CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer , 2011, Epigenetics.

[14]  R. Stewart,et al.  Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells , 2011, Nature.

[15]  Tim D. Spector,et al.  A twin approach to unraveling epigenetics , 2011, Trends in genetics : TIG.

[16]  Joseph K. Pickrell,et al.  DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines , 2011, Genome Biology.

[17]  Thomas A. Down,et al.  Identification of Type 1 Diabetes–Associated DNA Methylation Variable Positions That Precede Disease Diagnosis , 2010, PLoS genetics.

[18]  J. Herman,et al.  BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Phillip A. Sharp,et al.  Emerging Roles for Natural MicroRNA Sponges , 2010, Current Biology.

[20]  S. Hubbard,et al.  The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. , 2010, Molecular cell.

[21]  Gary D. Bader,et al.  The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function , 2010, Nucleic Acids Res..

[22]  Z. Szallasi,et al.  Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Fatima Al-Shahrour,et al.  Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. , 2010, Genome research.

[24]  Y. Mo,et al.  MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. , 2010, Cancer research.

[25]  Peter A. Jones,et al.  Epigenetics in cancer. , 2010, Carcinogenesis.

[26]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[27]  Martin J Aryee,et al.  Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts , 2009, Nature Genetics.

[28]  Pornpimol Charoentong,et al.  ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks , 2009, Bioinform..

[29]  A. Feinberg,et al.  Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores , 2008, Nature Genetics.

[30]  James D. Brenton,et al.  Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer , 2008, Human molecular genetics.

[31]  J. McPherson,et al.  Massively parallel bisulphite pyrosequencing reveals the molecular complexity of breast cancer-associated cytosine-methylation patterns obtained from tissue and serum DNA. , 2007, Genome research.

[32]  W. Willett,et al.  A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer , 2007, Nature Genetics.

[33]  M. Esteller.  Cancer epigenomics: DNA methylomes and histone-modification maps , 2007, Nature Reviews Genetics.

[34]  J. Jónasson,et al.  Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer , 2006, Breast Cancer Research.

[35]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[36]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[37]  J. Herman,et al.  Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. , 2000, Journal of the National Cancer Institute.

[38]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[39]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .