Biomarker For Renal Cell Carcinoma Patients Research Articles

Abstract 1383: Histone H3 lysine 9 methyltransferase SUV39H1 is associated with clinical outcome of renal clear cell carcinoma patients

Abstract Background: Epigenetic alternations have three important components including DNA methylation, histione modifications, and non-coding RNA. The epigenetic changes are highly dynamic and also reversible, which regulate a variety of biological processes. Euchromatin which is a loosely packed form of chromatin is highly associated with active gene expression. In contrast, heterochromatin is associated with high histone methylation and DNA methylation but low RNA transcription. SUV39H1 catalyzes the histone 3 lysine 9 trimethylation (H3K9me3) in heterochromatin regions, which also mediates DNA methylation at pericentric heterochromatin. Currently, the oncogenic role of SUV39H1 in renal cell carcinoma (RCC) pathogenesis is poorly understood. To this end, we assessed the role of SUV39H1 in renal RCC cells and association with clinical outcome of RCC patients. Results: In SUV39H1 knocked down cells, we observed global H3K9me3 level reduction and cell growth inhibition. Proximal ligation assay was used to determine the H3K9me3 and 5-methylcytosine (5mC) interaction in RCC cells. Knocking down of SUV39H1 gene significantly reduced the co-localization of H3K9me3 and 5mC in pericentric repetitive sequences. Moreover, Southern blot demonstrated that expansion of a pentanucleotide (GGAAT) repeats was associated with upregulation of SUV39H1, which is linked to SUV39H1 function with microsatellite instability and rearrangement. In The Cancer Genome Atlas (TCGA) database, we found that SUV39H1 gene expression was upregulated in RCC tissues compared to normal tissues, and high SUV39H1 expression predicted a worse overall survival outcome (p = 0.002) in RCC patients. Conclusion: SUV39H1 upregulation promotes cell proliferation and microsatellite instability. SUV39H1 expression could serve as a prognostic biomarker for RCC patients. Citation Format: Wei Meng, Ri Cui, Saikh Jaharul Haque, Carlo M. Croce, Arnab Chakravarti. Histone H3 lysine 9 methyltransferase SUV39H1 is associated with clinical outcome of renal clear cell carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1383. doi:10.1158/1538-7445.AM2017-1383

PD-1 Expression on Peripheral Blood Cells Increases with Stage in Renal Cell Carcinoma Patients and Is Rapidly Reduced after Surgical Tumor Resection

Programmed death-1 (PD-1) receptor is an inhibitory receptor on hematopoietic cells that can negatively regulate immune responses, particularly responses to tumors, which often upregulate PD-1 ligands. PD-1/PD-1 ligand blocking antibodies can reverse the inhibition and show significant therapeutic promise in treating renal cell carcinoma (RCC), lung cancer, and melanoma. While PD-1 expression on tumor-infiltrating lymphocytes has been associated with poor outcome in RCC, we sought to define immune cell biomarkers, including PD-1, on peripheral blood mononuclear cells (PBMC) that could predict disease progression of RCC patients before and after nephrectomy. We analyzed expression of numerous immune cell markers on fresh PBMCs from 90 RCC patients preoperatively and 25 age-matched healthy controls by 10-color flow cytometry. Postoperative blood samples were also analyzed from 23 members of the RCC patient cohort. The most striking phenotypic immune biomarker in RCC patients was a significant increase in PD-1 expression on certain PBMCs in a subset of patients. Increased PD-1 expression on CD14(bright) myelomonocytic cells, effector T cells, and natural killer (NK) cells correlated to disease stage, and expression was significantly reduced on all cell types soon after surgical resection of the primary tumor. The results indicate that PD-1 expression on fresh peripheral blood leukocytes may provide a useful indicator of RCC disease progression. Furthermore, measuring PD-1 levels in peripheral blood may assist in identifying patients likely to respond to PD-1 blocking antibodies, and these therapies may be most effective before and immediately after surgical resection of the primary tumor, when PD-1 expression is most prominent.

Significance of serum tumor necrosis factor-related apoptosis-inducing ligand as a prognostic biomarker for renal cell carcinoma

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is endogenously expressed in immune cells and contributes to immunosurveillance for cancer. TRAIL induces apoptosis preferentially in various cancer cells, including renal cell carcinoma (RCC) cells. In this study, the serum TRAIL level was examined using an enzyme-linked immunosorbent assay in 52 healthy controls and in 84 RCC patients prior to surgery and its significance as a biomarker was evaluated. The median serum TRAIL level was lower in RCC patients compared to the healthy controls (55.9 vs. 103.1 pg/ml; P=0.019). RCC with lymph node metastasis (N1-2), distant metastasis (M1), stage III-IV, or microscopic venous invasion was associated with decreased serum TRAIL levels (P=0.032, 0.067, 0.020 and 0.011). When comparing serum TRAIL levels in the same RCC patients prior and subsequent to surgery (n=11), the levels were significantly higher after surgery (P=0.031). The cause-specific survival rate was significantly higher in RCC patients with high serum TRAIL levels compared to those with low serum TRAIL levels (P=0.0451). TRAIL was estimated to contribute 64 and 13% of the lymphocyte-mediated cytotoxicity against human RCC ACHN and Caki-1 cells, respectively. These data suggest that the serum TRAIL level may be useful as a prognostic biomarker in RCC patients.