Nuevos biomarcadores para la clasificación del cáncer renal

Resum

The therapeutic management of patients with metastatic clear cell renal cell carcinoma (ccRCC) is based on the angiogenic inhibition and immune response regulation and has achieved a significant improvement in survival in recent years. However, the availability of a molecular classification implemented in clinical practice is still a great challenge in kidney cancer to adequately stratifying patients and guiding therapeutic decisions, as well as identifying potential new targets. Therefore, an integrated study of DNA and RNA analysis, including non-coding RNA, is proposed for the stratification of patients with metastatic ccRCC in the PROANG-SOGUG study, a multicenter and retrospective trial. Patients included in this study were diagnosed of a metastatic ccRCC and had been treated homogeneously with first-line antiangiogenic agents and could not have received immunotherapy throughout their therapy. The study included 242 patients for whom demographic and clinical data related to the oncological disease were available to evaluate their potential association with the molecular characterization. Adequate histological tumor tissue was available for DNA-seq, based on a customized panel of 187 samples, and for RNA-seq, 57 samples were available. The integrated analysis identified two genes whose alterations regulated the expression of other genes. Thus, VHL mutations were associated with AGO3 expression and MPL mutations were associated with HRNR expression. In the analysis of both biological layers performed separately and including their correlation with clinical objectives, the DNA-seq identified, on the one hand, a higher mutational frequency of CDKN1A, NPM1, IDH1, TSC1 and PBRM1 genes in the group of patients with good prognosis according to the IMDC criteria and of KDM5C, KDR and FBXW7 genes in the group of long-responder patients to antiangiogenic agents. On the other hand, a set of genes that included CHEK2, KDM5C, KRAS, MDM2, PTK2 and BLM showed a high mutational frequency defining a group of patients with a poor prognosis according to the IMDC criteria, but with clear benefit to antiangiogenic treatment. Concerning the analysis of RNA-seq performed separately, 3 subgroups of patients were identified that, although not statistically significantly different, integrated genes whose expression could help to discriminate a specific molecular subgroup characterized by the promotion of cell migration and invasion, metabolism reprogramming and associated with a lower probability of response to antiangiogenic treatment. It should be noted that the differentially expressed genes between clinical groups were different from those found in the DNA-seq analysis, as well as the implication of non-coding RNA in this characterization. These results highlight the relevance of tumor heterogeneity in renal cancer with a predominance of indel alterations and epigenetic regulation that promote its development and progression. Furthermore, these findings reveal the difficulty to develop a globally accepted classification of renal cancer representing a great challenge for the future supported by advanced technology to elucidate the interrelationship between the different biological layers and the patients´ outcome.