title: SFRP1 CpG island methylation locus is associated with renal cell cancer susceptibility and disease recurrence.
abstract: Loss of the secreted Fzd-related protein 1 (SFRP1) and concurrent alteration of the SFRP1/WNT pathway are frequently observed in human cancers such as in renal cell cancer (RCC). Whether methylation of a SFRP1 CpG island locus in normal human solid tissues is associated with increased tissue specific cancer risk has not been determined to date. Here we measure the cancer risk attributable to SFRP1 DNA methylation in renal tissue. Pyrosequencing of bisulfite treated DNA was used for a case-control study including 120 normal-appearing renal tissues of autopsy specimens and 72 normal-appearing tissues obtained from tumor adjacent areas, and a cross sectional study of 96 RCCs. Association of methylation with demographic risk factor age, clinicopathological parameters and course of patients was investigated. We show significant hypermethylation of a SFRP1 CpG island locus in normal-appearing renal tissues from RCC patients compared with normal-appearing autopsy kidney tissues. Inter quartile analysis revealed a 6-, 13- and 11-fold increased cancer risk for the second, third and fourth quartiles of methylation in the age matched subgroup of tissues (p = 0.001, p = 1.3E-6, p = 6.9E-6). Methylation in autopsy tissues increased with age and methylation in tumors was an independent predictor of recurrence free survival. SFRP1 DNA methylation, accumulates with age in normal-appearing kidney tissues and is associated with increased renal cancer risk, suggesting this CGI sub region as an epigenetic susceptibility locus for RCC. Our data underline the need to further analyze the tissue specific risks conferred by methylated loci for the development of human cancers.
authors.affiliation: Department of Urology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Faranaz
authors.initials: F
authors.lastname: Atschekzei
authors.forename: Jörg
authors.initials: J
authors.lastname: Hennenlotter
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jänisch
authors.forename: Annika
authors.initials: A
authors.lastname: Großhennig
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Tränkenschuh
authors.forename: Sandra
authors.initials: S
authors.lastname: Waalkes
authors.forename: Inga
authors.initials: I
authors.lastname: Peters
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Axel S
authors.initials: AS
authors.lastname: Merseburger
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.forename: Markus A
authors.initials: MA
authors.lastname: Kuczyk
authors.forename: Jürgen
authors.initials: J
authors.lastname: Serth
mesh_terms: D001344:Autopsy; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015992:Body Mass Index; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D018899:CpG Islands; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D056426:Genetic Loci; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D012307:Risk Factors; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D014408:Biomarkers, Tumor; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins