A massive search involving cancer researchers across the U.S. and Canada has revealed many of the altered genes and cell signaling pathways that drive a poorly understood form of kidney cancer, primary papillary renal cell carcinoma.
The findings, published today in the New England Journal of Medicine, should help physicians better understand the clinical risks for people with papillary kidney tumors, which account for 15 percent of kidney cancer cases. The insights also point the way to new ideas for more effective therapies.
“The goal is to have a comprehensive molecular understanding for every tumor type,” says Paul Spellman, Ph.D., a professor of molecular and medical genetics in the Oregon Health & Science University School of Medicine and a member of the OHSU Knight Cancer Institute. Spellman and senior co-author W. Marston Linehan, M.D., at the National Cancer Institute worked with physicians and scientists from 39 other institutions involved in The Cancer Genome Atlas Research Network to release the findings.
No effective therapies exist for advanced papillary kidney cancer. The disease is highly variable, with some tumors slow-growing and others aggressive and highly lethal. Based on tumor tissue characteristics, cancer specialists have divided the disease into type 1 and type 2 classifications.
In the study led by Linehan and Spellman, researchers performed a comprehensive characterization of gene changes in 161 papillary kidney tumors. They searched for DNA mutations as revealed by sequencing all of the protein-coding genes. They also looked for duplications of chromosomes, modifications of DNA that switch genes on and off, and changes in gene expression.
They found that specific gene alterations define the two main types of papillary kidney cancer. In type 1 tumors, a gene called MET 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, although the researchers say that requires further validation.
The authors say the findings will affect clinical recommendations, and should help point the way for the development of new therapies that more precisely target kidney cancer subtypes. For example:
- Alteration of the MET gene, found in many type 1 tumors, could help identify patients who are good candidates for clinical trials. A drug targeting the MET signaling pathway already has shown antitumor activity in a Phase II trial in patients with papillary renal cell carcinoma.
- Mutation of a gene called NF2, a tumor suppressor active in a signaling pathway called Hippo, was observed in a number of papillary kidney tumors. This pathway has been targeted in other cancers with agents such as dasatinib (Sprycel), a drug already approved for some types of leukemia.
- Altered NRF2/ARE signaling discovered in type 2 papillary tumors bolsters previous evidence that drugs targeting this pathway could be potent new treatments against cancer.
The work also identified a mystery. A subset of type 1 tumors do not have MET gene mutations, and the researchers could not find the altered genes or signaling pathways that were driving those tumors.
“They have mutations, but those events are not things that we understand as oncogenic on their own,” Spellman says. “So as much as we’ve learned about the biology of these tumors, there is a lot that we still need to learn.”
The altered genes and pathways that have been uncovered provide a solid foundation for understanding the molecular basis of all papillary kidney cancers. The researchers have made their detailed findings freely available at The Cancer Genome Atlas (TCGA) online data portal.
This research was funded by numerous grants from the National Institutes of Health (U24 CA143799, U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, and P30 CA016672).