Genomic drivers of a poorly understood kidney cancer

Researchers have identified many of the altered genes and cell signaling pathways that drive papillary renal cell carcinoma, a poorly understood form of cancer that accounts for about 15 percent of kidney tumors.

The findings, published today in the New England Journal of Medicine, are likely to affect clinical recommendations, and should help guide the development of more precisely targeted therapies. No effective treatment exists for advanced papillary renal cell carcinoma.

Paul Spellman, Ph.D., a professor of molecular and medical genetics at OHSU and member of the Knight Cancer Institute, worked with senior co-author W. Marston Linehan, M.D., at the National Cancer Institute and collaborators at 39 other institutions to complete a comprehensive characterization of gene changes in 161 papillary kidney tumors. The project is part of The Cancer Genome Atlas.

The researchers found that specific gene alterations define the two main types of papillary kidney cancer. In type 1 tumors, a gene calledMET is often mutated. In type 2 cases, tumors are characterized by silencing of the CDKN2A gene, mutations of the SETD2 gene, fusions of the TFE3 gene, and increased expression of the NRF2-ARE pathway.

Tumors classified as type 2 can be further divided into at least three subgroups based on molecular differences, and these characteristics influence patient survival. In one of these subgroups, DNA is modified by methylation of regions called CpG islands, and a gene, fumarate hydratase, is often mutated. These changes are linked to poor survival. Also in type 2, loss of the gene called CDKN2A may indicate a poor prognosis. The researchers have made their data freely available at The Cancer Genome Atlas (TCGA) online data portal.

The paper notes several ways the findings could be used to inform treatment decisions, identify candidates for clinical trials and focus research:

Alteration of MET or gain of chromosome 7 was observed in a large percentage (81%) of type 1 tumors. Antitumor activity of an agent targeting the MET and VEGFR2 pathways has been shown in a phase 2 trial involving patients with papillary renal-cell carcinoma, with a particularly high response rate among patients who had tumors with MET mutations. Mutation of the Hippo pathway tumor suppressor, NF2, was observed in a number of papillary renal-cell carcinomas. This pathway has been targeted in other cancers with agents such as dasatinib, an inhibitor of the YES1 kinase that interacts with the YAP transcription factor that is up-regulated with Hippo pathway dysregulation. The CIMP-associated tumors showed a Warburg-like metabolic shift, similar to that observed in fumarate hydratase–deficient tumors in patients with the hereditary leiomyomatosis and renal-cell cancer syndrome. A clinical trial targeting this metabolic shift in papillary renal-cell carcinoma is currently under way. Increased expression of the NRF2-ARE pathway has been observed in both hereditary and sporadic type 2 papillary renal-cell carcinomas. Immunohistochemical analysis for NQO1 could provide a valuable marker of activation of the NRF2-ARE pathway. Currently, there is intense interest in the NRF2-ARE pathway in cancer, and novel strategies have recently been developed to target this pathway.

The figure above from the NEJM paper shows the key pathways and genes implicated in papillary renal cell cancer. The tumors are arranged, left to right, by histologic type, and from top to bottom by the altered gene or pathway.

One of the most surprising results of the study is the subset of tumors in which the researchers could not find altered genes or signaling pathways that were driving the cancer. “They have mutations, but those events are not things that we understand as oncogenic on their own,” Spellman said in an OHSU news release. “So as much as we’ve learned about the biology of these tumors, there is a lot that we still need to learn.”