Focus on BAP1 for the diagnosis and therapy of kidney cancer and uveal melanoma

The research of Peña-Llopis’ team focusses on cancer relevant gene mutations such as the epigenetic modifier BAP1. The protein BAP1 has an important role in silencing certain genes involved in the development of kidney tumors and other types of cancer. The work of Samuel Peña-Llopis showed that BAP1 is mutated and inactivated in 15% of clear-cell renal cell carcinoma (ccRCC) patients, the most common type of kidney cancer, and its mutations are mutually exclusive to another tumor suppressor gene, PBRM1. Remarkably, loss of BAP1 was associated with higher tumor aggressiveness and poorer patient survival, whereas tumors with loss of PBRM1 were associated with better prognosis. This set the foundation for the first molecular genetic classification of this tumor type based on gene mutations, providing a rationale for subtype-specific treatments. Other genomic attempts to classify this tumor type are based on multiple parameters, such as gene activity, the levels of small molecules such as non-coding RNAs or both, and thus, less likely to be used in the clinic, since they may differ among hospitals. The results led to the development of an immunohistochemistry test for BAP1 detection, which is now routinely used in many hospitals as biomarker of BAP1 inactivation and prognosis not only in ccRCC, but also in other tumor types, including uveal melanoma, mesothelioma and cholangiocarcinoma. These breakthroughs were later confirmed by many other investigators and are progressively being used in clinical practice, especially in US hospitals, to stratify kidney cancer patients and guide clinical decision making.

Within DKTK, the team of Samuel Peña-Llopis is currently aiming to elucidate the molecular mechanism of tumor aggressiveness and metastasis caused by mutations in BAP1 and trying to identify genetic vulnerabilities of BAP1 loss that could be exploited therapeutically. Additionally, his group is generating patient-derived organoids from renal cell carcinoma and uveal melanoma as preclinical models. According to Samuel, “The close collaboration with DKTK Professor Jens Siveke (Head of the Division of Translational Oncology in Solid Tumors) and other researchers at the Essen University Hospital, as well as the excellent network of DKTK partner sites, offers a wonderful opportunity for translational cancer research in Europe, where genomic and molecular biology findings might be suitable to be applied in the clinic in a safe manner and eventually benefit cancer patients”.

Dr. Peña-Llopis received his PhD in Biochemistry from the University of Valencia (Spain) and was a postdoctoral fellow at Harvard University, UT Southwestern Medical Center and, most recently, in the laboratory of Prof. Stefan Fröhling at DKFZ. 

Go to Peña-Llopis group and selected publications.