A new study has identified at least 3 distinct subtypes of clear cell renal cell carcinoma (ccRCC), a common and often treatment-resistant form of kidney cancer, revealing new information that may inform overall patient survival and response to treatment.

Data show that ccRCC accounts for 75% of all kidney cancers, translating to approximately 65,000 new cases annually, according to the study. Currently, there are no effective treatments for cancers that spread beyond the kidney, yet 30% of patients present with advanced disease at diagnosis. Furthermore, ccRCC has been found to be resistant to conventional chemotherapy and radiation, with limited responses seen for FDA-approved drugs.

The study, published in Cell, included tumor samples from 110 patients who had not yet received treatment, such as chemotherapy and radiation, and 84 samples of healthy tissue surrounding the tumors.

Using genomic and proteomic technologies, the researchers identified proteogenomic characteristics, defined as genetic makeup, chemical modifications to DNA, messenger RNA located in cells that serve as template to make proteins, and proteins and their modification by phosphate group.

According to the findings, the researchers found that the loss of chromosome 3p occurred in almost all of the tumor samples in the study.

In addition, 4 distinct immune-based subtypes were identified based on their tumor microenvironment signatures:
 
  1. CD8-positive inflamed tumors had a high amount of CD8-positive immune cells and responded to cell signaling pathways associated with an immune response.
  2. CD8-negative inflamed tumors had a near absence of CD8-positive immune cells but did have cells such as fibroblasts, which promote wound healing, and macrophages, which fight cancers and other foreign substances.
  3. Vascular endothelial growth factor (VEGF) immune desert tumors had no immune cells but had a strong presence of endothelial cells associated with the development of new blood vessel growth in tumor progression.
  4. Metabolic immune desert cells were more pure tumor cells with almost no immune cells and very few fibroblasts.

According to lead study author David J. Clark, PhD, the findings indicated that those with CD8-positive inflamed tumors would have worse overall survival (OS), whereas those with VEGF immune desert tumors would have better OS.

Using new predictive models, the researchers found that those with CD8-positive tumors would have the best response to immune checkpoint therapies and those with VEGF immune desert tumors would show the best response to anti-angiogenesis therapies.

“Our results illustrate the complexity of cancer development, and that we can use proteomics and phosphoproteomics in addition to genomics to learn more about cancer phenotypes and their heterogeneity,” co-principal study author Hui Zhang, PhD, professor of pathology and oncology, and director of the Mass Spectrometry Core Facility at the Johns Hopkins University School of Medicine, said in a press release.

References

Clark DJ, Dhanasekaran SM, Petralia F, et al. Integrated proteogenomic characterization of clear cell renal cell carcinoma. Cell. 2019. Doi: https://doi.org/10.1016/j.cell.2019.10.007

Kidney Cancer Study Uncovers New Subtypes and Clues to Better Diagnosis and Treatment [news release]. Johns Hopkins Medicine’s website. https://www.hopkinsmedicine.org/news/newsroom/news-releases/kidney-cancer-study-uncovers-new-subtypes-and-clues-to-better-diagnosis-and-treatment. Accessed October 30, 2019.