Kidney cancer is not a single disease; it is made up of a number of different types of cancer, with different histologic types and different clinical courses and caused by alteration of a different gene. From Linehan et al.(3)
The VHL gene is the gene for the inherited form of clear cell renal carcinoma associated with VHL and for common form of sporadic, noninherited clear cell renal carcinoma. Patients with VHL are at risk for bilateral, multifocal (A and B) RCC that is clear cell type (C). Reduced from ×40. VHL gene mutation is detected in germline of affected individuals in VHL kindreds (D). From Linehan et al.(3)
HPRC is a hereditary cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal, type 1 papillary renal carcinoma (21)
. (A) CT of abdomen reveals multiple bilateral solid renal tumors. (B) Representative kidney demonstrates multiple, discrete tumor nodules of varying size. (C) Type 1 papillary histology characteristic of HPRC tumors (×200). (D) Pedigree of HPRC family 160 showing autosomal dominant pattern of inheritance. Closed symbols indicate affected individuals; open symbols indicate unaffected individuals. HPRC is caused by germ-line mutation of the c-Met gene (24)
. From Linehan et al. (3)
Birt Hogg Dubé-associated kidney cancers. Birt Hogg Dubé is a hereditary cancer syndrome in which affected individuals are at risk for the development of chromophobe and oncocytic renal carcinoma and oncocytoma (28, 55)
. Individuals affected with BHD are at risk for bilateral, multifocal renal tumors (left). BHD associated renal tumors may be chromophobe renal carcinoma (upper right), hybrid-oncocytic neoplasms (center right) or oncocytoma (lower right). Individuals affected with BHD are characterized by BHD gene germline mutation. Reduced from ×20 (upper and center right) and ×40 (lower right). From Linehan et al.(3)
HLRCC is a hereditary cancer syndrome (56)
in which affected individuals are at risk for the development of an aggressive form of type 2 papillary renal carcinoma. HLRCC is characterized by germ-line mutation of the Krebs cycle enzyme, FH (33, 34)
. A shows an abdominal image of a young man affected with HLRCC with a large left-sided kidney mass that was found to by type 2 papillary RCC (B).
An alternate approach to molecular therapeutics is by disrupting the interaction between the chaperone protein, Hsp90, and client proteins, such as HIF1-α (A). Isaacs et al.(52)
have shown that treatment of VHL−/− RCC cells with 17-allylamino-17-desmethoxygeldanamycin, a small molecule geldanamycin analog inhibitor of HSP90, is associated with oxygen-independent degradation of HIF1-α (B and C). Efforts are under way to evaluate this approach in neoplasms in which c-Met and c-Kit are critical to tumorigenesis.