A new study comprehensively profiled a multi-institutional cohort of previously untreated primary RMC samples and identified molecular and immune hallmarks that distinguish RMC from other closely related malignancies and can be therapeutically exploited.
Distinct molecular and immune hallmarks of RMC
The study found that RMC is characterized by 8q gain, high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. DNA replication stress induced by SMARCB1 was noted to be a hallmark of RMC that can be therapeutically targeted by drugs inhibiting DNA damage repair or agents aggravating replication stress including platinum salts (cisplatin or carboplatin), topoisomerase inhibitors such as doxorubicin, and DNA synthesis inhibitors such as gemcitabine.
Other identified molecular hallmarks of RMC include the upregulation of the lncRNA UCA1 (305-fold increase in RMC tumors compared with adjacent normal kidney), and activation of the NOTCH pathway.