Inherited renal cell cancer is known to occur in a number of familial cancer syndromes, most notably the von Hippel-Lindau (VHL) syndrome. This syndrome is characterized by alterations in the VHL
gene and predisposition to a number of diseases among family members, including the clear cell subtype of renal cell cancer.82
Only a very small proportion of renal cell cancer patients are known to occur in families with these rare syndromes, although the exact percentage is difficult to pinpoint. However, sporadic renal cell cancers have been shown to have a familial predisposition, with a recent meta-analysis showing a greater than twofold risk among individuals having a first-degree relative diagnosed with kidney cancer.83
The interplay of exposures to environmental risk factors and genetic susceptibility of exposed individuals is believed to influence the risk of developing sporadic renal cell cancer.
Renal cell cancer patients were found to have shorter telomere length in blood DNA compared to control subjects, and the association appeared to be modified by cigarette smoking.84
Low mitochondrial DNA (mtDNA) content in peripheral blood lymphocytes also was associated with elevated risks of renal cell cancer in a dose-response manner.85
Although mtDNA content was significantly lower among smokers than non-smokers, smoking did not modify the association between mtDNA and renal cell cancer risk. The findings with telomere length and mtDNA have yet to be confirmed, preferably in larger studies with prospectively collected genomic DNA samples. Studies of signature tumor DNA alterations may also provide clues to relevant environmental carcinogen exposures.86
Although an earlier link of VHL
mutations in renal cell cancer to heavy TCE exposure87
has yet to be replicated in other occupational studies,88
recent advancement in tumor analysis likely will enhance the opportunities for such discoveries.89,90
Renal cell cancer risk has been evaluated in relation to a number of common genetic variants in blood DNA (). Most of the studies to date were based on candidate gene approach, identifying a few genes in a pathway that may be relevant for renal carcinogenesis and a few single nucleotide polymorphisms (SNP) in the selected genes.12
The results for most of the genes and SNPs have yet to be replicated in future investigations (, under Limited Evidence).
Genetic variants associated with renal cell cancer risk
Genes encoding the glutathione S-transferase (GST) enzymes, including GSTM1, GSTT1
, and GSTP1
, are by far the most studied in relation to renal cell cancer risk (). The GST enzymes are active in the detoxification of polycyclic aromatic hydrocarbons in tobacco smoke, halogenated solvents, and other xenobiotics. Although the GST
genes generally have not been linked to renal cell cancer risk, associations with tobacco smoke, exposure to TCE or pesticides, and consumption of cruciferous vegetables have been shown to vary among subgroups defined by genotype status. However, inconsistency in subgroup findings among studies, small numbers of exposed individuals, and lack of replication data for some findings suggest that further investigations are needed to clarify these associations.12
, a gene encoding the N-acetyltransferase 2 enzyme that is involved in the metabolism of arylamine in tobacco smoke, also has been evaluated in a few studies of renal cell cancer. Smoking-related risk was found to be higher among those carrying the slow than the rapid acetylator genotype,91
a finding consistent with that observed for bladder cancer92
but not yet replicated in renal cell cancer.
Vitamin D maintains calcium homeostasis and has been shown to play a role in cell proliferation and progression to a number of cancers.93
Genes in the vitamin D pathway have been investigated in relation to renal cell cancer risk, but the findings are not consistent across the few studies.12
Recently, a relatively large study from Central and Eastern Europe comprehensively examined eight vitamin D pathway genes with complete genomic coverage, and found increased risk associated with variant haplotypes of the vitamin D receptor gene.94
The same study also comprehensively examined genes related to lipid peroxidation, blood pressure control, and cellular growth, differentiation, and apoptosis.95-97
Elevated renal cell cancer risk was associated with two SNPs in the regulatory region of the apolipoprotein E gene, which was replicated in a second large study in the United States.95
Associations also were observed with the apoptosis genes CASP1/5/4/12
and blood pressure gene AGT
, but replication is needed to confirm these findings.96,97
Recently, high throughput methods for genome-wide scanning of tagging SNPs and copy number alterations have been developed, and large studies with consortium efforts in relation to disease risks have flourished. Such efforts for renal cell cancer also are underway and likely will accelerate the discovery of common genetic variations and how their interactions with environmental exposures may influence renal carcinogenesis.