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J Mol Diagn. 2014 Sep;16(5):564-572. doi: 10.1016/j.jmoldx.2014.04.007. Epub 2014 Jul 3.

Molecular classification of non-muscle-invasive bladder cancer (pTa low-grade, pT1 low-grade, and pT1 high-grade subgroups) using methylation of tumor-suppressor genes.

Author information

1
Bladder Cancer Group, Proteomics Unit, CIC bioGUNE, Derio, Spain; Department of Urology, Central Hospital of Asturias, Oviedo, Spain.
2
Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain.
3
Department of Urology, Central Hospital of Asturias, Oviedo, Spain.
4
Department of Pathology, Central Hospital of Asturias, Oviedo, Spain.
5
Bladder Cancer Group, Proteomics Unit, CIC bioGUNE, Derio, Spain; Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain. Electronic address: mscarbayo@cicbiogune.es.

Abstract

The role of epigenetics in distinguishing pathological and clinical subgroups in bladder cancer is not fully characterized. We evaluated whether methylation of tumor-suppressor genes (TSGs) would classify non-muscle-invasive (NMI) bladder cancer subgroups and predict outcome. A retrospective design included the following paraffin-embedded primary NMI tumor types (n = 251): pTa low grade (LG) (n = 79), pT1LG (n = 81), and pT1 high grade (HG) (n = 91). Methylation of 25 TSGs was measured using methylation-specific, multiplex, ligation-dependent probe amplification. The TSGs most frequently methylated in the overall series were STK11 (96.8%), MGMT2 (64.5%), RARB (63.0%), and GATA5 (63.0%). TSG methylation correlated to clinicopathological variables in each subgroup and in the overall NMI series. Methylation of RARB, CD44, PAX5A, GSTP1, IGSF4 (CADM1), PYCARD, CDH13, TP53, and GATA5 classified pTa versus pT1 tumors whereas RARB, CD44, GSTP1, IGSF4, CHFR, PYCARD, TP53, STK11, and GATA5 distinguished LG versus HG tumors. Multivariate analyses indicated that PAX5A, WT1, and BRCA1 methylation independently predicted recurrence in pTaLG, PAX6, ATM, CHFR, and RB1 in pT1LG disease; PYCARD, in pT1HG disease; and PAX5A and RB1, in the overall series. Methylation of TSGs provided a molecular classification of NMI disease according to clinicopathological factors. Furthermore, TSG methylation predicted recurrence in NMI subgroups.

PMID:
24998186
DOI:
10.1016/j.jmoldx.2014.04.007
[Indexed for MEDLINE]

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