Lee, Annette

631 Background: For most clear cell renal cell carcinoma (ccRCC) patients with early stage disease, surgical resection offers definitive cure. However, for the small percentage of tumors that metastasize, analyzing gene expression profiles from the primary site at the time of nephrectomy can serve as a model to understand the molecular aberrations behind a metastatic phenotype. Differences in gene expression profiles between patients with Stage I and II ccRCC who experience metastasis versus patients who maintain cure after surgery may help elucidate significant molecular targets and stratify patients at higher risk for metastasis. Methods: Nineteen Stage I and twenty Stage II ccRCC tumors preserved in FFPE blocks after nephrectomy were included in this study. Patients were matched for age, gender, tumor size and grade. In both stages, approximately half the patients that experienced metastasis within 5 years of surgery were part of the experimental group, whereas the control group had > 5 years of follow-up without evidence of disease. Extracted RNA for Stage I patients was sequenced using Illumina TruSeq RNA Access Library. Gene counts were assessed by ht-seq counts and differential expression using DESeq2. Significant genes found were validated in the Stage II group using RT-qPCR. Results: In the Stage I experimental group, statistically significant upregulation of several genes associated with unfavorable prognosis in RCC were found: COL1A1, NUMBL, and STEAP3. Random forest classification accurately separated Stage I control versus experimental patients based on expression of COL1A1. Affected genes were consistent with molecular changes seen in TCGA analysis. In the Stage II group, a double-blinded analysis correctly identified the clinical outcome for the majority of the patients using qPCR expression of COL1A1, NUMBL, and STEAP3. Conclusions: Differences in gene expression profiles harbored in the primary site of early stage ccRCC may be employed to predict patients at high risk for developing metastasis. Validating these findings in a larger study carries the potential to better understand mechanisms of metastasis and identify an at risk cohort of patients with early stage disease.

ObjectiveTo identify new genetic associations with juvenile and adult dermatomyositis (DM).MethodsWe performed a genome‐wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single‐nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM.ResultsCompared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS‐level significance (P < 5 × 10–8) at 80 genotyped SNPs. An analysis of 141 non‐MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C–like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C‐C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM.ConclusionOur findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non‐MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.