Researching Kidney Cancer
Since many cancer genes seem to contribute to cancer development in only a small fraction of tumors, distinguishing among infrequently mutated cancer genes and those with random clusters of passenger mutations requires the analysis of large sample sets.
Investigators at the Cancer Genome Project, Wellcome Trust Sanger Institute, systematically resequenced the genomes of 210 human cancers. The investigators found more than 1,000 somatic mutations in 274 megabases (Mb) of DNA that corresponded to the coding exons of 518 protein kinase genes.
The investigators reported a substantial variation in the number and pattern of mutations in individual cancers, reflecting different exposures, DNA repair defects, and cellular origins. Most somatic mutations, they noted, may be passengers that do not contribute to oncogenesis. However, there was evidence for driver mutations contributing to the development of the cancers studied in approximately 120 genes.
The research team concluded that systematic sequencing of cancer genomes reveals the evolutionary diversity of cancers and “implicates a larger repertoire of cancer genes than previously anticipated.” Scientists had hoped, for example, that in the case of the most common form of adult kidney cancer, VHL gene alterations could serve as a prognostic and predictive marker for what seemed a fairly homogenous type of cancer. Clear cell renal cell carcinoma (ccRCC) accounts for more than 75% of this disease in adults. Germline mutations of the VHL suppressor gene cause the hereditary form of the disease, and more than 50% of sporadic ccRCCs have biallelic VHL mutations.
The protein product of VHL, pVHL, has functions including targeting hypoxia-inducible factors (HIFs) for degradation by the cell. Under the conditions of an abnormal VHL, HIF is not eliminated, becomes more active, and produces 200 or so proteins, one of them being VEGF.
Nicholas Vozelgang, M.D., a professor of medicine at the University of Nevada and a renal cancer specialist, noted that “we now know that of the clear cell tumors—70 to 80 percent of all kidney cancers are clear cell—a majority are VHL mutated. Therefore, it is probable that all these new agents—sunitinib, sorafenib, and anti-VEGF drugs—only are working on those kidney cells that produce HIF and HIF-driven proteins. The nonclear cell tumors and perhaps some of the clear cell tumors are not producing the HIF-driven proteins.”
We could group clear cell tumors into two categories: VHL mutated and VHL nonmutated, he said, but “we don’t have an easy way to quickly measure that in the blood or in the protein. The hypothesis is that the very well-differentiated renal cells will be responsive to these agents and the very poorly differentiated, aggressive tumors will not.”
However, loss of VHL alone has shown to be insufficient for tumor initiation and some of ccRCCs retain wild-type VHL alleles, indicating a requirement for additional or alternative genetic alterations for tumor development.