Which molecular and genetic findings are characteristic of clear cell renal cell carcinoma (CCRCC)?

Updated: Mar 11, 2019
  • Author: Ronald J Cohen, MB, BCh, PhD, FRCPA, FFPATH; Chief Editor: Liang Cheng, MD  more...
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Studies in patients with VHL disease established the importance of genetic alterations involving chromosome 3p in the development of CCRCC, while subsequent research has shown that chromosome 3 or 3p is lost in 80-98% of sporadic CCRCCs. [89, 90, 91]

Inactivation or loss of the VHL gene results in the absence of a functional VHL protein, which under normoxic conditions usually targets the alpha subunit of the transcription factor hypoxia-inducible factor (HIF) for degradation. Loss of functional VHL protein therefore leads to accumulation of HIF and activation of its hypoxia-inducible target genes under normoxic rather than hypoxic conditions. HIF target genes include the vascular endothelial growth factor gene VEGF, which may explain the prolific angiogenesis associated with CCRCC. [13]

Although alterations at 3p are believed to be the initiating genetic event, recent work suggests that CCRCC can subsequently progress along at least 2 distinct genetic pathways. [91] The most common pathway (80% of CCRCC) mainly involves losses of entire chromosomes and partial losses through unbalanced translocations, resulting in a hypodiploid karyotype. In this pathway, loss of 3p often occurs together with gain of 5q via a translocation between chromosomes 3 and 5. Gain of 5q is seen in 40-70% of cases, and this tends to be followed by losses of chromosomes 14 or 14q (40-60%), 8 or 8p (20-30%), 9 or 9p (15-25%), and 6 or 6p (15-25%). Furthermore, as a result of the HIF1A gene residing on chromosome 14, loss of 14q has been associated with differential expression of HIF1α and subsequent prognostic phenotypes. [92, 93]

A less common pathway followed in 18% of CCRCCs mainly involves gains of entire chromosomes resulting in a hyperdiploid karyotype. Common gains involve chromosomes 7 (18-30%), 16 (11%), 20 (10%), 12 (10-15%), and 2 (9-14%). This second pathway is similar to the genetic events seen in papillary RCC, except that most (67%) papillary RCCs also show gain of chromosome 17.

Progression of CCRCC can eventually involve reduplication of the entire genome to give a polyploid karyotype, followed by further losses or gains of genetic material. [89, 90, 91] Complex polyploid karyotypes are particularly common in tumors with sarcomatoid differentiation. [94, 95]

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