Familial renal cancer: molecular genetics and surgical management

Abstract

Familial renal cancer (FRC) is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and Birt-Hogg-Dubé (BHD) are rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer.

Figures

Figure 1

Histopathology of the most common malignant renal neoplasms. (a) Clear cell; (b) papillary type 1; (c) papillary type 2; and (d) chromophobe. (From Linehan et al. [10], with permission.)

Figure 2

The VHL complex targets HIF-1α and HIF-2α for ubiquitin-mediated degradation. In clear cell RCC, an alteration in the VHL gene in the α or β domain disrupts HIF degradation. HIF overaccumulates leading to increased transcription of downstream genes. (a) VHL alteration; (b) VHL/HIF pathway molecular targeting; and (c) VHL/HIF downstream molecular targeting. (From Linehan and Zbar [23], with permission.)

Figure 3

Alterations in the intracellular tyrosine kinase domain of the MET proto-oncogene are found in patients with HPRC. These mutations result in the activation of the MET pathway. (From Linehan et al. [10], with permission.)

Figure 4

In a normoxic environment, HIF is hydroxylated by HPH allowing the VHL complex to initiate ubiquitin-mediated breakdown in the proteosome. In HLRCC, FH alteration results in a buildup of fumarate. Fumarate competitively inhibits HPH allowing a rise in HIF levels and subsequent transcription of downstream genes. (From Pfaffenroth and Linehan [59], with permission.)

Figure 5

FLCN pathway. (a) FLCN is the gene associated with BHD. Normal FCLN protein complexes with FNIP1, FNIP2, and AMPK. This complex is phosphorylated by a rapamycin-sensitive kinase (mTORC1). (b) When FLCN is altered, it fails to complex and allows activation of AKT, mTORC1, and mTORC2. (From Hasumi et al. [69], with permission.)