title: DNA methylation array analyses identified breast cancer-associated HYAL2 methylation in peripheral blood.
abstract: Breast cancer (BC) is the leading cause of cancer-related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC-associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome-wide methylation screening and identified a BC-associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p = 2.61 × 10(-9) adjusted for cell-type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p < 0.0001; second validation round with 189 BC case and 189 controls: p < 0.0001). In addition to cg27091787, the decreased methylation of a 650-bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p-value of 0.006. To note, the BC-associated decreased HYAL2 methylation was replicated in the T-cell fraction (p = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early-stage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) = 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC = 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood-based marker for the detection of early BC.
authors.affiliation: Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany; Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Rongxi
authors.initials: R
authors.lastname: Yang
authors.forename: Katrin
authors.initials: K
authors.lastname: Pfütze
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Frederik
authors.initials: F
authors.lastname: Marme
authors.forename: Bin
authors.initials: B
authors.lastname: Qu
authors.forename: Katarina
authors.initials: K
authors.lastname: Cuk
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.forename: Markus
authors.initials: M
authors.lastname: Hoth
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Rita
authors.initials: R
authors.lastname: Schmutzler
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000097:blood / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D058851:GPI-Linked Proteins / Q000097:blood / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C473096:Hyal2 protein, human; D006821:Hyaluronoglucosaminidase
keywords: HYAL2; breast cancer; early detection; marker; methylation