Comprehensive Genomic Features, Therapeutic Biomarkers Identified in Clear Cell Renal Cell Carcinoma

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Investigators reported comprehensive genomic features of patients with clear cell renal cell carcinoma, potentially giving providers a better understanding of the molecular features associated with the disease.

In a recent study, investigators reported the comprehensive genomic features of patients with clear cell renal cell carcinoma (ccRCC), which detailed the relationship between immunotherapy biomarkers and gene alterations. The analysis was published in Frontiers in Oncology.

“This is the first large-scale comprehensive genomic analysis for Chinese ccRCC patients, and these results might provide a better understanding of molecular features in Chinese ccRCC patients, which can lead to an improvement in the personalized treatment for these patients,” wrote the investigators.

ccRCC is the most common subtype of RCC, accounting for 70% to 85% of RCC cases, and is almost uniformly lethal and is considered critical. ccRCC often lacks sensitivity to radiation and chemotherapy and many efforts are being made to establish a biomarker-oriented therapy.

Some targeted therapies targeting vascular endothelial growth factor (VEGF) have greatly improved the prognosis of patients with ccRCC and the use of an immune checkpoint inhibitor, either alone or in combination with other medications, may also be a potential therapeutic target for patients with ccRCC.

Although some studies have reported on the genomic landscape of ccRCC, most of the data had been collected from patients from Western countries or focused on how gene alterations can help determine disease prognosis. Because of this, the genomic landscape in Chinese patients with ccRCC is in need of further investigation.


“Revealing comprehensive genomic features is of great importance for understanding ccRCC and developing new therapeutic lines for patients with ccRCC,” the investigators said.

The investigators analyzed genomic profiling of DNA of Chinese patients with ccRCC, who had undergone next-generation sequencing (NGS) between January 2017 and March 2020. In total, 880 patients with ccRCC and NGS data were included in the analysis. Immunohistochemistry staining for programmed death-ligand 1 (PD-L1) expression was also conducted for 460 patients of those patients.

PD-L1 expression is associated with improved overall response rates and longer progression-free survival in patients with metastatic RCC who are being administered immunotherapy.

Among the patients, 95.8% harbored at least 1 pathogenic mutation, with somatic alterations for VHL being the most commonly detected mutation among the samples (59.7%). Mutations in PBRM1 were detected in 18.0% of samples and SETD2 alteration were identified in 12.2% of samples. BAP1 alterations were found in 10.2% of samples and TP53 mutations were found in 9.4%.

When comparing the results to the Center Genome Atlas database, the investigators found a higher mutation frequency of VHL (50.0% vs 59.7%; P < .001) and TP53 (3.5% vs 9.4%; P < .001) among the Chinese cohort. Additionally, the Chinese cohort had a lower mutation frequency of PBRM1 than the database (18.0% vs 31.0%; P < .001).

VHL is a tumor suppressor gene that plays a prominent role in cellular oxygen sensing of ccRCC as well as the tumorigenesis that is associated with the disease. Inactivation of VHL is not associated with anti-VEGF receptor inhibitors, but it may help providers predict the effectiveness of hypoxia-inducible factor-2 inhibitors in ccRCC.

Of the patients who were evaluated for expression of PD-L1, 139 (30.2%) were positive for PD-L1 expression. Five (0.7%) patients were classified as microsatellite instability-high. Moreover, 5.9% (n = 52) of the patients were identified to carry pathogenic or likely pathogenic germline mutations for 22 cancer predisposition genes.

The retrospective nature of the analysis was listed as a study limitation as it prevented the investigators from eliminating a potential selection bias. Another limitation involved the lack of information on the cancer subtypes, treatment histories, and survival outcomes of the patients.

“Thus, the effect of the biomarkers on treatment decisions and its correlation with survival outcomes need to be further confirmed in further studies,” the investigators suggested.


Huang J, Cai W, Cai B, et al. Comprehensive genomic landscape in Chinese clear cell renal cell carcinoma patients. Front Oncol. Published online September 9, 2021. doi: 10.3389/fonc.2021.697219