The etiology of renal cell carcinoma is unknown; however, associations between a number of environmental factors and kidney cancer have been established by epidemiological studies (see Risk factors).  Hormonal imbalance has been suggested as a possible after an experiment showed that prolonged administration of estrogen can induce renal carcinomas in the male golden hamster.  Such hormonal factors involve a steroid effect on gene expression of the kidney androgen-regulated protein (KAP) which controls renal tubule epithelial cell levels of several inducible proteins and enzymes.
 
 

    Chemical carcinogens are identified by their ability to act alone to cause malignant tumors after administration to animals (they act as initiators and promoters). The first stage of chemical carcinogenesis results directly from administration of the chemical carcinogen. Initiation is an irreversible, rapid process during which chemical produces permanent changes in DNA of target cells.  The second stage is promotion, during which tumor formation is stimulated in tissues that have been exposed to the initiating agent.  These tissue and culture changes during the long latency period before the appearance of the first autonomous cancer cell l are usually reversible.   The stepwise evolution of cancer cells as they become progressively more malignant is called progression.
     All chemical carcinogens can form directly or are metabolized to reactive electrophilic forms.  Can attack the many nucleophilic sites in molecules such as proteins and nucleic acids to form covalent addition products.  The carcinogens produce lethal damage, probably targeting DNA. Some forms of DNA damage can be repaired by cellular enzymes; there is increased susceptibility to cancer in patients with certain DNA-repair-deficiency diseases.(10)
 
 

    Inactivation of the VHL gene is the most frequent genetic event in kidney cancer. pVHL, the product of the VHL tumor suppressor gene, plays an important role in the regulation of cell growth and differentiation of human kidney cells. The 213 amino acid coding sequence of the VHL gene is represented in three exons at chromosome 3p25. The biochemical function of pVHL is still unknown.  pVHL resides mostly in the cytoplasm and to a lesser extent in nucleus and in association with cell membranes.(15)
    Normally, the VHL protein associates with several other proteins that regulate transcription and control the cell cycle.  Cells in which pVHL is defective also overexpress other genes that are regulated by several factors, including hypoxia.  Results suggest the protein may affect the post-transcriptional stability of mRNAs involved in the transduction of signals that detect oxygen levels.(16)
    pVHL tumor suppressor also participates in the process of ubiquitination.  Recombinant pVHL associates with  ubiquitination-promoting activity in human cell extracts.  Examination of various mutants of pVHL stably expressed in RCC cells revealed that certain naturally occurring mutants of pVHL demonstrate loss of ubiquitination-promoting activity in conjunction with the universally required components E1, E2 and ubiquitin. The capacity of pVHL to recruit ubiquitin-promoting activity may be important for its role as a tumor suppressor. (15)
     The VHL tumor-suppressor gene mRNA is expressed widely during embyrogenesis and in adult tissues.  There is a strong connection between certain specific missense mutations (about 30% of germline VHL gene mutations)and susceptibility to RCC.  Tumors from VHL patients characteristically demonstrate loss of the wild type allele.  VHL disease accounts for less than 2% of all cases of kidney cancer, but somatic VHL gene mutations are found in most nonfamilial RCC.  This is usually associated with the loss of the other VHL allele, such that RCC cells lack a wild-type copy of the VHL gene. The majority of sporadic and hereditary (VHL disease-associated) clear cell renal carcinoma do not have functional pVHL.  Hence, VHL appears to play a 'gatekeeper' role with respect to the development of clear cell renal carcinoma.  The reintroduction of wild-type pVHL into VHL (-/-) clear cell RCC cell lines does not consistently suppress RCC cell growth in vitro, but it does suppress the ability of RCC cells to form tumors in nude mouse xenograft assays.  Thus, as predicted from the genetic analyses, pVHL is a tumor-suppressor protein and loss of its function is an early, frequent, and possibly necessary step in renal carcinogenesis.(17)
 
 

    Von Hippel-Lindau disease is a hereditary cancer syndrome characterized by susceptibility to a variety of tumors including bilateral clear cell carcinomas of the kidney. It is caused by germline mutations of the VHL gene. VHL gene is inherited as an autosomal dominant gene with a 50% risk of acquiring the disease for each offspring.(8) (9) Functional inactivation of both VHL alleles also occurs in the majority of sporadic clear cell renal carcinomas.  Therefore, inactivation of the VHL tumor-suppressor gene appears to be a requisite step in the development of clear cell renal carcinoma.

    Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized (distinct from VHL disease)  by a predisposition to develop multiple, bilateral papillary renal tumors.  The pattern of inheritance of HPRC is autosomal dominant with reduced penetrance. Malignant papillary renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation and or by hypermethylaion.  Missense mutations located in the MET proto-oncogene may lead to constitutive activation of the MET protein and papillary renal carcinomas.  Missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas.  Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occuring mutations. (18)

    A reciprocal translocation between chromosomes 3 and 8 (t[318][p14;q14]) was described in a family with 60% of bilateral renal cancer in three generations. (5)  Additional study has shown that the translocation from chromosome 3 to chromosome 8 involved c-myc as a cellular oncogene.  Various studies have suggested a possible role for chromosome 3 in the etiology of nonfamilial renal cell cancer, as well.  Rearrangements in chromosome 3 or DNA sequence deletion on the short arm of chromosome 3 and 11 has been shown in patients with RCC (also chromosome 6).  Familial and sporadic forms of RCC are associated with structural alterations of the short arm of chromosome 3 or 3p. (8) Translocation between the tumor suppressor gene from the short arm of chromosome 3 to chromosomes 6, 8 and 11 have been associated with familial, von Hippel-Lindau, and most spontaneous renal cell cancers.  Theoretically, replacement of this gene onto chromosome 3 could suppress tumorigenicity.