EIKCS 2022: Gene Expression Profiling of nccRCC Identifies a Unique Spectrum of Transcriptional Signatures with Potential Clinical Relevance

(UroToday.com) In the fourteenth session of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting focusing on treatment approaches for patient with non-clear cell renal cell carcinoma (nccRCC), Dr. Pedro Barata presented real world based analysis of gene expression profiling of patients with non-clear cell renal cell carcinoma (nccRCC).

To set the stage for this work, Dr. Barata highlighted that the emergence of multiple active treatment approaches in advanced RCC has created a real need for predictive biomarkers. In the context of clear cell RCC, gene expression data from clinical trials including IMmotion151 and JAVELIN Renal 101 have been used to generate angiogenic and immune signatures that may be associated with response to therapy. This tumor gene expression profiling has now, in updated form with seven clusters, been shown to characterise distinct transcriptional profiles that are predictive of the response to anti-angiogenic therapy and immune checkpoint inhibition.

To date, most of this work has taken place in the context of clinical trial populations and small cohorts from single centers of excellence and is focused on patients with clear cell RCC. Thus, Dr. Barata’s work sought to determine gene expression signatures in nccRCC using transcriptional profiles of patients with nccRCC treated in real world practice.

To do so, they performed DNA/RNA next generation sequencing on tumor samples submitted to a commercial lab (Caris Life Sciences). Central pathology reviewed both primary kidney samples and metastatic sites. Gene signatures were constructed using composite scores for each molecular subgroup with a weighting of z-scores. Using the highest composite score, each tumor sample was allocated to a single molecular subgroup.

The cohort comprised predominately patients with clear cell histology (77%), though nccRCC was well represented: papillary (9.6%), chromophobe (4.6%), medullary (1.2%), and others. The authors further examined specimens from not just the kidney (n=340), but also lung (n=64), bone (n=50), soft tissue (n=40), and numerous other sites.

They found that, while most ccRCC samples were classified as angiogenic or angio/stromal, these were poorly represented in the nccRCC subset where a proliferative signature was much more common.

Interestingly, they further found that the molecular distribution differs on the basis of site of metastasis. Considering a potential immunotherapy-related biomarker, he cited data that sarcomatoid and rhabdoid histological features were associated with the T-effector/proliferative and stromal/proliferative subsets. This also correlated with PD-L1 positivity.

The authors then examined cellular subtype abundance according to molecular subtype. They found that high expression of immune checkpoint genes and an increased abundance of pro-immune cells was seen in the T-effector/proliferative subtype while immunsuppressive cells were seen most commonly in stromal/proliferative tumors. Epithelial cells were most common in angiogenic and angio/stromal subtype tumors.

In conclusion, Dr. Barata highlighted that the proliferative subtype was strongly associated with nccRCC histology. Further, the gene signature appears to differ between tumor samples from the kidney primary and various metastatic sites. Further work utilizing independent cohorts with linked clinical outcomes as well as biomarker driven trials will be needed to validate this approach for clinical use.