Supervisors info:
Ανδρέας Χ. Λάζαρης, Καθηγητής, Ιατρική, ΕΚΠΑ
Νικόλαος Γούτας, Αναπληρωτής Καθηγητής, Ιατρική, ΕΚΠΑ
Ειρήνη Θυμαρά, Επίκουρη Καθηγήτρια, Ιατρική, ΕΚΠΑ
Summary:
Renal cell carcinoma (RCC) is a heterogenous groups of cancers of the renal parenchyma and accounts for >90% of cancers of the kidney. RCC represents more than ten histopathological subtypes. RCC major subtypes (>5%) include clear cell RCC (~75%), papillary RCC(~15%) and chromophobe RCC(~5%). The remaining subtypes are rare including, medullary RCC, collecting duct RCC, translocation RCC, and unclassified.
The classification of the subtypes has been repeatedly revised in the last two decades, due to advances in the histological and molecular characterization.
From a molecular and genetic point of view, ccRCC is the best –studied subtype.
ccRCCs evolve through genetic and epigenetic alterations. In ccRCC, the VHL tumour suppressor gene is the most frequently mutated gene and its loss through genetic (point mutations and 3p25 loss) and/or epigenetic (promoter methylation) mechanisms constitutes the earliest, truncal oncogenic driving event. Loss of VHL leads to aberrant accumulation of HIF proteins, which in turn results in uncontrolled activation of HIF target genes that regulate angiogenesis, glycolysis and apoptosis.
Large genomic studies have revealed mutations in the genes PBRM1, SETD2 and BAP1, which encode chromatin and histone regulating proteins. These genes are located at 3p21 and function as tumour suppressors.
MTOR mutations in ccRCC are generally missense and functionally activating, which could explain the reason mTOR pathway inhibitors are effective.
As inactivation of VHL is the founding event of ccRCC, its mutation status has no effect on clinical outcome, whereas mutations involved in disease progression such as PBRM1, SETD2 and BAP1 as well as KDM5C (which is also involved in chromatin modification) were shown to associate with aggressive clinical features.
Intertumor and intratumor heterogeneity is possibly a reason for treatment failure and development of resistance. The genetic profile of a renal tumor differs spatially within a tumor as well among patients. Genomic nutations can change temporally with resistant subclones becoming dominant over time.
Common driver events such as SETD2, PBRM1, MTOR, PIK3CA, PTEN and KDM5C mutations are present heterogeneously within the primary tumour and metastatic sites.
Dinstinct molecular subtypes of ccRCC according to the mutation status of PBRM1, BAP1, and KDM5C could have potential biomarkers value for patients with metastatic ccRCC treated with target therapy.
Papillary cell RCC is subdivided into type1 (p1RCC) and type2(p2RCC) based on histological characteristics. Sporadic p1RCC is associated with MET gene alterations, while sporadic p2RCC is characterized by CDKN2A silencing, SETD2 mutations, NF2 mutations, CUL3 mutations, TERT promoter mutations, increased expression of the NRF2-antioxidant pathway and gains of chromosomes 7,12, 16, and 17.
The chromophobe RCC display pathognomonic loss of chromosomes 1,2,6,10,13,17 and 21. Whole genome sequencing have demonstrated mutations of TP53 and PTEN and oxidative phosphorylation defects.
Keywords:
Renal cell carcinoma, Histologic subtypes, Pathways of carcinogenesis, Genomic classification
