**Part 1**

**Translational** 

**1** 

*Brazil* 

**Molecular Pathogenesis** 

Israel Gomy and Wilson Araújo Silva Jr.

*Genetics Department, Ribeirão Preto,* 

*University of São Paulo, Medical School of Ribeirão Preto,* 

**of Renal Cell Carcinoma: A Review** 

Renal cell carcinomas (RCC) represent almost 90% of all kidney cancers and in about 2% of cases there is a family history of RCC (McLaughlin et al, 1984). Despite their rare incidences, Mendelian hereditary syndromes with RCC have provided important insights into the molecular pathogenesis of this tumor. The cloning of susceptibility genes that are involved in familial predisposition has offered entry points into the signaling pathways that are deregulated in sporadic RCC. Sporadic RCC are extremely heterogeneous and are classified into many histolological subtypes. The most frequent form is clear cell or conventional RCC, accounting for approximately 75% of all cases, whereas the most common non-clear cell tumor is papillary RCC (12% of cases), which is subdivided into types 1 and 2. Other subtypes include chromophobe and oncocytomas, each of them occurring in 4% of patients, collectingduct (<1%) and rare forms or yet to be classified (< 2%). The correlation between histopathological features and genetic alterations in RCC has been introduced in 1997 with the Heidelberg classification (Kovacs et al, 1997). More recently, expression profiles through microarrays have been done for many of the kidney tumor subtypes and provide the evidence that their expression patterns reflect their histological classifications and demonstrate that

various renal tumor subtypes are genetically distinct entities (Higgins et al, 2003).

germline mutations in the *BHD* tumor suppressor gene.

Generally, there is a good correlation between the genetic causes of familial RCC and their histopathological features as exemplified by the commonest form of hereditary RCC, von Hippel-Lindau (VHL) disease, which invariably presents a clear cell type. Moreover, germline mutations in the *MET* proto-oncogene cause type 1 papillary RCC, whereas type 2 is correlated with germline mutations in the fumarate hidratase gene, which cause hereditary leiomyomatosis. Birt-Hogg-Dubè syndrome is also characterized by susceptibility to RCC but with a mixed chromophobe-oncocytoma histopathology, and is associated with

All the genes identified so far, which are involved in the molecular pathogenesis of hereditary and sporadic RCC comprise a diverse set of complex biochemical and cell metabolism pathways, such as iron, energy, nutrient and oxygen-sensing (Linehan et al., 2010a). A plenty of biochemical and molecular studies of the numerous signalling pathways

**1. Introduction** 
