Unique Genomic Profiles in Distant Metastatic Sites in Patients With Renal Cell Carcinoma

Researchers, led by Rana R. McKay, MD, examined genomic alterations and transcriptional signatures in patients with renal cell carcinoma (RCC) in an effort to identify the biology driving metastatic spread to specific organ sites. Their findings, presented in the Emerging Biomarkers and Therapies in Renal Cell Carcinoma session at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, demonstrated “differential patterns of molecular alterations among sites of metastasis in RCC.”

Given their findings, Dr. McKay and colleagues suggested that “application of predictive signatures by site of metastasis may help inform personalized therapy strategies in advanced RCC. Further studies are warranted to validate our findings.”

Researchers acquired 657 RCC tissue samples from 653 patients. Samples originated from the kidney (n = 340, 51.8%), lung (n = 75, 11.4%), bone (n = 45, 6.8%), lymph nodes (n = 34, 5.2%), liver (n = 28, 4.3%), endocrine glands (n = 23, 3.5%), brain or central nervous system (n = 16, 2.4%), and other metastatic sites (n = 96, 14.6%). Genomic profiles were sequenced with a certified assay, and the researchers assessed molecular subgroups—based on IMmotion151 RCC subtypes—and PD-L1 expression per site.

The study’s authors observed that several genes were mutated at higher rates in certain distant metastatic sites when compared to the kidney, including PBRM1 (59.5% bone, 59.1% endocrine, and 45.9% lung vs. 33.8% kidney, p <0.05) and KDM5C (27.8% endocrine, 29.2% lymph nodes, and 35.3% soft tissue vs. 9.3% kidney, p <0.05). Furthermore, bone metastases specimens exhibited a significantly higher proportion of “angio/stromal” tumors than kidney specimens (n = 19, 42.2%; vs n = 52, 15.4%; p< 0.0001), while liver specimens had a higher proportion of “complement/?-oxidation’ subgroup” tumors (n = 17, 60.7%; vs n = 48, 14.1%; p< 0.0001). Lastly, the expression of PD-L1 in distant metastatic sites was not significantly different than in the kidney.

Overall, the study’s collaborators felt their results demonstrated a conclusive pattern of distinct molecular alterations among metastatic sites in patients with RCC. “Our observations elucidate the biology underlying heterogeneous disease outcomes associated with site of metastasis,” summarized Dr. McKay.