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Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events
Author(s) -
Serizawa Reza R.,
Ralfkiær Ulrik,
Steven Kenneth,
Lam Gitte W.,
Schmiedel Sven,
Schüz Joachim,
Hansen Alastair B.,
Horn Thomas,
Guldberg Per
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25651
Subject(s) - bladder cancer , neuroblastoma ras viral oncogene homolog , dna methylation , kras , hras , methylation , epigenetics , cancer research , biology , cancer , mutation , pathology , medicine , gene , genetics , gene expression
The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically screened FGFR3 , PIK3CA , TP53 , HRAS , NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC , ARF , DBC1 , INK4A , RARB , RASSF1A , SFRP1 , SFRP2 , SFRP4 , SFRP5 and WIF1 in a prospective series of tumor biopsies ( N = 105) and urine samples ( N = 113) from 118 bladder tumor patients. We also analyzed urine samples from 33 patients with noncancerous urinary lesions. A total of 95 oncogenic mutations and 189 hypermethylation events were detected in the 105 tumor biopsies. The total panel of markers provided a sensitivity of 93%, whereas mutation and methylation markers alone provided sensitivities of 72% and 70%, respectively. In urine samples, the sensitivity was 70% for all markers, 50% for mutation markers and 52% for methylation markers. FGFR3 mutations occurred more frequently in tumors with no methylation events than in tumors with one or more methylation events (78% vs . 33%; p < 0.0001). FGFR3 mutation in combination with three methylation markers ( APC , RASSF1A and SFRP2 ) provided a sensitivity of 90% in tumors and 62% in urine with 100% specificity. These results suggest an inverse correlation between FGFR3 mutations and hypermethylation events, which may be used to improve noninvasive, DNA‐based detection of bladder cancer.