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An international scientific collaboration led by researchers at UNC has revealed new insights into the unique genetic alterations that contribute to a rare form of kidney cancer.

Kimryn Rathmell, MD, PhD

The team, which was co-chaired by Kimryn Rathmell, MD, PhD, Associate Professor of Medicine, Urology, and Genetics at UNC Lineberger and Chad Creighton, PhD, Associate professor of Medicine at Baylor College of Medicine. The two shared co-senior authorship on the study, which published the information revealed by a comprehensive integrated analysis of the molecular and genetic features of chromophobe renal cell carcinoma, a rare form of kidney cancer that affects only a little more than 2,000 new patients each year, in the journal Cancer Cell. Other featured authors on the manuscript from UNC include Dr. Kate Hacker and Catherine Fahey, both graduate students in the Genetics and Molecular Biology Curriculum, and Dr. Angela Smith and Dr. Eric Wallen of the Department of Urology. The project was undertaken as part of The Cancer Genome Atlas, an international collaboration led by the National Institutes of Health.

“Although most cases of chromophobe kidney cancer carry a good prognosis, we all have cared for patients who died from metastatic chromophobe kidney cancers,” said Dr. Rathmell. “This report is incredibly exciting for physicians who care for these patients because all of the treatment plans we have had to this point have been based on the biology of the more common kidney cancer type, as if chromophobe must be a close relative of that disease.”

The project represents a new initiative for The Cancer Genome Atlas (TCGA), a joint project of the National Cancer Institute and the National Human Genome Research Institute, moving from projects focusing on common tumor types to rare cancers. Researchers at UNC have taken lead roles in several of the TCGA sequencing projects.

“As with other TCGA papers, UNC played several roles. We were the RNA analysis site, a tissue source site contributing samples for the study, and worked on the data analysis. In all there were 27 authors from UNC who contributed to this manuscript.” said Dr. Rathmell.

The analysis of 66 tumor samples revealed frequent mutations in the TP53 and PTEN genes as well as a loss, whole or in part, of chromosomes necessary for DNA packaging and replication.

We made two major discoveries. The first was that genes involved in oxidative phosphorylation are generally upregulated in this tumor, and that mutations in mitochondrial genes occur extensively in electron transport complex 1 and are associated with expression increases in genes involved in mitochondrial function.

“The second was that some tumors have a rearrangement affecting the TERT promoter region that appears to influence TERT expression. This has not been described previously,” said Dr. Rathmell.

The findings could change the ways that physicians treat the tumor, pointing to future therapies that target the unique biology of the tumor. Currently, physicians treat the cancer the same way as the more common clear cell renal carcinoma, which the study revealed is genetically distinct from kidney chromophobe.

We found virtually no similarities between these cancers. They appear to originate from different segments of the kidney nephron, have completely distinct genetic patterns, and differ in methylation profiles,” said Dr. Rathmell.

The study did find a resemblance between kidney chromophobe and other tumors like breast cancer and bladder cancer in the high frequency of p53 mutations. Dr. Rathmell said that she hopes the findings will lead to the discovery of other tumors that share similar genetic features to help guide future therapy advances.

“This study has made me even more interested in studying the rare types of kidney cancers, since it demonstrates how even rare diseases can reveal new insights into cancer biology,” said Dr. Rathmell.