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Kidney Cancer Multiomics Study Reveals Subtypes, Suggests New Treatment Strategies

NEW YORK – A research team led by investigators at Tongji Medical College has uncovered four molecular subtypes of clear cell renal cell carcinoma (ccRCC), including one with "distinctive" metabolic features and poor treatment outcomes.

Their study, published in Nature Genetics on Thursday, "suggests new treatment opportunities for patients with treatment-resistant RCC," according to co-corresponding author Ke Chen, a researcher at Tongji Medical College, and colleagues from China and the US.

For their effort, the researchers began by performing exome sequencing, RNA sequencing, and mass spectrometry-based proteomic and metabolomic profiling on 100 treatment-naïve ccRCC samples from individuals in the Tongji Hospital RCC cohort. Together with clinical data and multiomic profiling on matched normal adjacent tissue samples from 50 of the participants, the tumor data pointed to four molecular ccRCC subtypes with distinct immune and tumor microenvironment features.

"Metabolic deregulation is a key characteristic of ccRCC," the authors explained, noting that "most clinical and metabolomic studies have focused solely on metabolomic profiling, leaving the relationship between genomic, epigenomic, or other alterations and metabolic disorders largely unexplored."

Along with the so-called IM1, IM2, and IM3 immune subtypes, the team's analyses highlighted a metabolically altered IM4 subtype that was marked by poorer overall and progression-free survival, high rates of somatic copy number changes, higher tumor grade, and enhanced expression of acute inflammatory response and complement cascade pathways.

By incorporating single-nucleus RNA-seq data, 10x spatial transcriptomic profiles, and spatial metabolomic insights gained with "air flow-assisted desorption electrospray ionization-mass spec imaging" analyses on a handful of tumors from each molecular group, the researchers flagged five key cell types and 41 cell subclusters in the ccRCC subtypes, which showed shared or distinct activity within and across the molecular subtypes.

In addition to analyses on the immune features found in the tumors, the team took a closer look at the biological and metabolic features found in the prognostically poor IM4 subtype. The IM4 tumors, dubbed "de-clear cell differentiated" (DCCD) ccRCC, were marked by increased nutrient uptake and enhanced proliferation capabilities, despite showing dialed-down metabolic activity.

Likewise, these tumors showed low or negligible lipid droplet accumulation and lower levels of reactive oxygen species, the researchers reported.

They also found altered treatment response patterns and clinical outcomes in their retrospective analyses of three ccRCC clinical trials with published treatment, patient outcome, and tumor RNA-seq data, and made recommendations for treating the various subtypes.

While the team's review of treatment data on hand indicated that ccRCC cases involving lipid droplet-accumulating IM2 tumors tend to respond to tyrosine kinase inhibitor treatment, for example, tumors with partial or full DCCD features appeared more apt to respond to combination treatments that included immune checkpoint blockade immunotherapy.

On the other hand, because ccRCC patients with kidney-restricted, early-stage cancers with DCCD features seemed to fare worse than patients with other ccRCC subtypes, the authors argued that "surgery alone is unlikely to cure these patients."

"Our data suggest that patients with localized DCCD-ccRCC should be identified and offered further treatment after surgery," they wrote.