Open AccessDeregulation of PAX 2 expression in renal cell tumours: mechanisms and potential use in differential diagnosis
Author(s) -
Patrício Patrícia,
RamalhoCarvalho João,
CostaPinheiro Pedro,
Almeida Mafalda,
BarrosSilva João Diogo,
Vieira Joana,
Dias Paula Cristina,
Lobo Francisco,
Oliveira Jorge,
Teixeira Manuel R.,
Henrique Rui,
Jeronimo Carmen
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12090
Subject(s) - biology , chromophobe cell , oncocytoma , methylation , dna methylation , monosomy , cancer research , epigenetics , microbiology and biotechnology , immunohistochemistry , pathology , kidney , clear cell , chromosome , gene expression , karyotype , genetics , gene , medicine , immunology
Expression of PAX 2 (Paired‐box 2) is suppressed through promoter methylation at the later stages of embryonic development, but eventually reactivated during carcinogenesis. Pax‐2 is commonly expressed in the most prevalent renal cell tumour ( RCT ) subtypes—clear cell RCC (cc RCC ), papillary RCC ( pRCC ) and oncocytoma—but not in chromophobe RCC (chr RCC ), which frequently displays chromosome 10 loss (to which PAX 2 is mapped). Herein, we assessed the epigenetic and/or genetic alterations affecting PAX 2 expression in RCT s and evaluated its potential as biomarker. We tested 120 RCT s (30 of each main subtype) and four normal kidney tissues. Pax‐2 expression was assessed by immunohistochemistry and PAX 2 mRNA expression levels were determined by quantitative RT ‐ PCR . PAX 2 promoter methylation status was assessed by methylation‐specific PCR and bisulfite sequencing. Chromosome 10 and PAX 2 copy number alterations were determined by FISH . Pax‐2 immunoexpression was significantly lower in chr RCC compared to other RCT subtypes. Using a 10% immunoexpression cut‐off, Pax‐2 immunoreactivity discriminated chr RCC from oncocytoma with 67% sensitivity and 90% specificity. PAX 2 mRNA expression was significantly lower in chr RCC , compared to cc RCC , pRCC and oncocytoma, and transcript levels correlated with immunoexpression. Whereas no promoter methylation was found in RCT s or normal kidney, 69% of chr RCC displayed chromosome 10 monosomy, correlating with Pax‐2 immunoexpression. We concluded that Pax‐2 expression might be used as an ancillary tool to discriminate chr RCC from oncocytomas with overlapping morphological features. The biological rationale lies on the causal relation between Pax‐2 expression and chromosome 10 monosomy, but not PAX 2 promoter methylation, in chr RCC .