2026-06-14T14:34:14Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/231302024-11-29T08:33:53Zcom_20.500.12105_2173com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19597col_20.500.12105_16969

00925njm 22002777a 4500 dc Santos, María author Lanillos, Javier author Caleiras, Eduardo author Valdivia, Carlos author Roldan-Romero, Juan M author Laínez, Nuria author Puente, Javier author Beuselinck, Benoit author Oudard, Stéphane author Zucman-Rossi, Jessica author Navarro, Paloma author Robledo Batanero, Mercedes author Castellano, Daniel author de Velasco, Guillermo author García-Donas, Jesús author Rodriguez-Antona, Cristina author 2023-05-15 Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are key antiangiogenic drugs for renal cancer treatment. While Von Hippel-Lindau dysfunction constitutes the base for VEGFR-TKIs sensitivity, the role for individual and concurrent mutations in the genes encoding for the chromatin remodelers Polybromo-1 (PBRM1) and Lysine Demethylase 5C (KDM5C) is poorly understood. Here, we analyzed the tumor mutational and expression profiles of 155 unselected clear cell RCC (ccRCC) cases treated with first-line VEGFR-TKIs and the ccRCC cases of IMmotion151 trial were used for validation. We found that concurrent PBRM1 and KDM5C (PBRM1&KDM5C) mutations occurred in 4-9% of cases and were enriched in Memorial Sloan Kettering Cancer Center favorable-risk patients. In our cohort, tumors only mutated in PBRM1 or concurrently mutated in PBRM1 and KDM5C had increased angiogenesis (P=0.0068 and 0.039; respectively), and tumors only mutated in KDM5C showed a similar trend. Best response to VEGFR-TKIs corresponded to PBRM1&KDM5C mutated cases, followed by those mutated only in KDM5C or only in PBRM1 (P=0.050, 0.040 and 0.027 versus non-mutated cases, respectively), with a trend for longer progression free survival (PFS) in the group with only PBRM1 mutated (HR=0.64; P=0.059). Validation in the IMmotion151 trial revealed a similar correlation with increased angiogenesis and the PFS of patients in the VEGFR-TKI-arm was the longest in PBRM1&KDM5C mutated cases, intermediate for only PBRM1 or only KDM5C mutated patients and the shortest in non-mutated cases (P=0.009 and 0.025, for PBRM1&KDM5C and PBRM1 versus non-mutated cases). In conclusion, somatic PBRM1 and KDM5C mutations are common in patients with metastatic ccRCC and likely cooperate increasing tumor angiogenesis and VEGFR-TKI-based antiangiogenic therapy benefit. Am J Cancer Res . 2023;13(5):2116-212 2156-6976 American journal of cancer research 37293154 https://hdl.handle.net/20.500.12105/23130 PBRM1 and KDM5C cooperate to define high-angiogenesis tumors and increased antiangiogenic response in renal cancer