Gene May Play Bigger Role in Kidney Cancer Than Previously Thought

PHILADELPHIA (February 10, 2020)—Its involvement in causing over 50 percent of all cancers makes p53 one of the most well-known cancer genes. When the p53 gene mutates, it unleashes many processes that lead to the uncontrolled cell growth that is a hallmark of cancer. But there are some malignancies, like kidney cancer, that rarely have p53 mutations.

In order to understand whether the inactivation of the p53 pathway might contribute to kidney cancer development, Haifang Yang, PhD, a researcher with the Sidney Kimmel Cancer Center – Jefferson Health, probed kidney cancer gene protein products for interactions with the p53 protein. Joseph R. Testa, PhD, FACMG, the Carol and Kenneth Weg Chair in Human Genetics at Fox Chase Cancer Center, was a study co-author, as was Robert G. Uzzo, MD, MBA, FACS, chair of the Department of Surgical Oncology at Fox Chase.

Earlier work found that protein produced by PBRM1, the second most mutated gene in kidney cancer, could interact with p53. However, other researchers were unable to definitively show that it was truly an important mechanism in kidney cancer.

Rather than looking at the p53 protein itself, first author Weijia Cai, PhD, a postdoctoral fellow in Yang’s lab, and other collaborators looked at an activated version of p53, one that is studded with an additional chemical marker—an acetyl group—at many specific spots.

In a paper published recently in the prestigious journal Nature Communications, Yang, an assistant professor of Pathology, Anatomy and Cell Biology at Jefferson, examined whether PBRM1 can be a “reader,” or translator, of the activated p53.

“This research is notable because it addresses a puzzling feature of clear cell renal cell carcinoma, also known as ccRCC. That is, why do these kidney tumors generally have less complicated genomes and only rare mutations of the p53 gene when compared to carcinomas occurring in most other organs?” said Dr. Testa.

“Because PBRM1 mutations compromise, but do not totally abolish p53 function, PBRM1 deficiency probably does not recapitulate all of the features of p53 loss, such as genomic instability,” he added.

With the help of a number of biochemical and molecular tests using both human cancer cell lines and mouse and human tumor samples, they noticed that PBRM1 uses its bromodomain 4 to bind to p53, but only in its activated form, with the acetyl group in one specific spot. Tumor-derived point mutations in bromodomain 4 can disrupt this interaction, and the resulting mutant PBRM1 loses its ability to suppress tumor growth.

The research suggests that PBRM1 is strongly linked to a long studied and well-understood cancer pathway. Because PBRM1 is present in other cell types and cancers, this finding may be applicable to other cancers as well.

“This shows us that even though p53 isn’t directly mutated in many kidney cancers, the cancer is still disrupting the p53 pathway to drive cancer initiation and growth,” said Yang. “This suggests that there might be a therapeutic window for drugs that activate the p53 pathway, which may preferentially impact PBRM1-defective kidney tumors while sparing normal tissues.”

Testa said the findings have implications for the future: “Since this research shows that a genetic change that occurs in a relatively high percentage of ccRCCs disrupts, at least partially, p53—a critical checkpoint protein that regulates DNA damage repair, cell cycle progression and programmed cell death—these findings hold promise for informing the design of future drug screens aimed at identifying agents that might reactivate the p53 pathway and selectively kill ccRCC cells that harbor a mutation in PBRM1.”

The next steps for the research are to identify the drug or drugs and the therapeutic window. The researchers also plan to determine whether it can be combined with other known therapeutics and investigate which kidney tumor genotypes are most likely to respond to the treatment.

The research utilized the Translational Pathology Shared Resource at Sidney Kimmel Cancer Center at Jefferson Health and was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA056036, a pilot award from VHL alliance and R01 CA211732. The publication was also supported in part by grant number P30 CA006927 awarded to Fox Chase by the National Cancer Institute and by support from the Gitlin Kidney Cancer Fund.

The article, “PBRM1 Acts as a Novel p53 Lysine-Acetylation Reader to Suppress Renal Tumor Growth,” was published in Nature Communications.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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