Investigation of the presence of BAP1, PBRM1, SETD2 mutations in patients with clear cell renal cell carcinoma and evaluation of immunohistochemical correlation

Aim: Molecular testing of tumor samples is becoming increasingly important to guide patients to the right treatment. The aim of this study is to examine the effects of clinicopathological, histomorphological features and mutations in BAP1, PBRM1 and SETD2 genes and their correlation with IHC and to guide the treatment, prognosis and management of patients with clear cell renal cell carcinoma. Materials and Methods: 80 ccRCC cases who underwent nephrectomy between 2015-2021 and evaluated in İnönü University Turgut Özal Medical Center Medical Pathology laboratory were included in the study. These cases were evaluated with BAP-1, PBRM-1, SETD-2 IHC staining. Twelve cases were investigated molecularly by whole exome sequencing. Results: Immunohistochemical staining loss was found in 41% of 80 cases with PBRM-1, 17.5% with BAP-1, and 47.5% with SETD-2. No relationship was found between PBRM-1 and BAP-1 and gender, age, tumor localization, size, stage, grade, metastasis. BAP-1 negativity was associated with poor overall survival. A correlation was found between SETD-2 negativity and advanced stage and tumor size. The coexistence of PBRM-1 and BAP-1 negativity was significant; the association of PBRM1/SETD2, BAP1/SETD2 was not significant. No significant mutations were detected for VHL, PBRM-1, BAP-1, SETD-2 in any of the 12 cases by exome sequencing. SNP mutations were detected in ARSD in 7 and SLC25A5 gene in 9 cases. Conclusion: IHC staining rates with BAP-1 and PBRM-1 were the same as in the literature, and the rate with SETD-2 was higher than the literature. Exome sequencing did not detect any significant mutations in all 3 genes in any of the 12 cases, while high rates of mutations were observed in ARSD and SLC25A5 genes. Studies on these genes will contribute to directing both the molecular mechanism of RCC and possible targeted therapies. Keywords: BAP1, exome sequencing, immunohistochemistry, PBRM1, renal cell carcinoma, SETD2