DNA Repair Gene Mutations Found in Patients with Early Onset Renal Cancer

Sanjeevani Arora, PhD, assistant professor in the Cancer Prevention and Control program at Fox Chase and one of the study's authors.
Sanjeevani Arora, PhD, assistant professor in the Cancer Prevention and Control program at Fox Chase and one of the study's authors.

PHILADELPHIA (October 30, 2020) – Pathogenic variants in DNA damage response and repair (DDRR) genes have been identified in patients with early onset renal cancer, according to a recent study by researchers at Fox Chase Cancer Center.

“These results indicate that patients diagnosed with early-onset renal cancer may benefit from undergoing comprehensive multigene panel testing that includes genes outside of the scope of those currently known to increase renal cancer risk,” said Sanjeevani Arora, PhD, assistant professor in the Cancer Prevention and Control program at Fox Chase and one of the study’s authors.

Early onset renal cancer—defined as being diagnosed at age 60 or younger—is typically linked with hereditary renal cancer syndromes and pathogenic variants, inherited genetic changes that affect gene function in a series of “renal cancer-specific” genes. However, many patients diagnosed with early-onset renal cancer do not have any pathogenic variants in the known renal cancer specific genes, leaving many cases genetically undefined.

The researchers sought to identify additional genes that might be related to risk for early-onset disease. DDRR genes are known to play an important role in maintaining genome integrity, and mutations in DDRR genes have been linked to increased cancer risk for several other tumor types, but not renal cancer.

In addition to Arora, other Fox Chase researchers on the study included Tiffiney Roberts Hartman, PhD, a visiting scientist; Michael J. Hall, MD, MS, chair of the Department of Clinical Genetics; Mary Daly, MD, PhD, FACP, director of the Risk Assessment Program; and Erica Golemis, PhD, Deputy Chief Science Officer.

Using de-identified data from a cohort of 491 patients diagnosed with early-onset renal cancer, the study looked for pathogenic variants in 49 genes that had previously been linked to risk for some forms of cancer, but most of which had unclear significance as risk factors for renal cancer.

“Of the patients who were found to have a pathogenic variant, the majority were in DDRR genes,” Arora said. In all, 12.8% of cases had pathogenic variants. Of these cases, 3.7% had variants in renal cancer-specific genes and 8.55% had variants in DDRR genes.

Among the most common DDRR genes were CHEK2, BRCA1, BRCA2, and ATM. Surprisingly, although BRCA genes are typically associated with hereditary breast and ovarian cancers, among the small percentage of patients who were found to have BRCA1 or BRCA2 mutations, less than half reported a personal history of these cancers.

However, almost 60% of renal cancer patients included in the study reported having had at least one additional cancer. “Mutations in DDRR genes generally lead to a spectrum of cancers,” Arora said. “The finding that so many patients had more than one cancer supports the idea that the patients we studied have DDRR gene pathogenic variants.”

In the future, Arora and colleagues hope to conduct studies to examine if the renal cancer occurred as a result of the DDRR gene pathogenic variants. “Even if we don’t yet know that these genes are important for increasing risk for renal cancer, if the tumors are vulnerable in DNA repair processes, it does open up options for patients who perhaps may not respond to treatments that are typically used for renal cancer,” she said.

The paper, “Prevalence of Pathogenic Variants in DNA Damage Response and Repair Genes in Patients Undergoing Cancer Risk Assessment and Reporting a Personal History of Early-Onset Renal Cancer,” was published in Scientific Reports.

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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