Abstract 1904: Somatic copy number alterations and gene expression signatures are associated with aggressive tumor biology in African Americans and European Americans with renal cell carcinoma

Abstract

Abstract Background: Renal cell carcinoma (RCC) is the deadliest of all urologic cancers in the US. RCC survival is highly dependent on histology. Survival rates range between 55-60% for clear cell RCC (ccRCC) and 80-90% for papillary RCC (pRCC) patients. African Americans (AAs) have lower survival rates when compared to their European American (EA) counterparts for both histologies (ccRCC 67.1 vs 72.6, pRCC 80.5 vs 87.5). RCC survival disparities may be accredited to population differences in tumor biology, such as somatic copy number alteration (SCNA) profiles of tumor suppressor and oncogenes, and differential gene expression signatures with associated cellular pathway dysregulation. SCNAs are the most common structural change in the human genome and ccRCC and pRCC-specific SCNAs have been associated with clinical outcomes. ClearCode34, a 34 gene expression signature, was developed to classify ccRCC tumors into two distinct ccRCC subtypes (ccA and ccB). The ccB subtype is associated with worse survival and features like increased tumor size, grade, and metastasis rates. We hypothesize there are more aggressive tumor biology phenotypes in AA RCC patients compared to their European counterparts. Methods: Comparative genome-wide, chromosomal, and gene SCNA analyses were performed in AA and EA ccRCC and pRCC patients in TCGA using Partek Genomics Suite 7 (1-way ANOVA, P<0.05). Prediction analysis of microarray in R was used to classify ccRCC patients into ccA and ccB subtypes by race based on the ClearCode34 gene expression signature (t-test, P<0.05). Differentially expressed genes (DEGs) between AA and EA patients were identified using Partek Genomics Suite 7 (1-way ANOVA, P<0.05). Gene Set Enrichment Analysis (GSEA) was performed using a pre-ranked gene list (Fold changes >2 or <-2, P<0.01) and two Molecular Signatures Database collections (C6 oncogenic signatures, C7 immunologic signatures). Results: AA-enriched SCNVs were identified on chromosomes 1, 3, 6, 7, and 12 in ccRCC patients, and chromosomes 1, 4, 6, 7, 8, 10, 16 and 20 in pRCC patients. Six cytobands and genes experienced a SCNV across both histologies (1p21.1, 1p21.3, 6p12.1, 6p12.3, 6p21.1, 6q12), BMP5 (on 6p12.1), CD2AP (on 6p12.3), ENPP4 (on 6p21.1), and SLC44A3-AS1 (on 1p21.3). AAs and EAs had significantly different frequencies of ccA (AA 33.9% vs EA 52.2%) and ccB subtypes (AA 66.1% vs EA 47.8%). Unique DEGs were found between AA and EA ccA and ccB patients (131 ccA only, 165 ccB only), which corresponded with up- and down-regulation in kidney cancer with oncogenic KRAS (C6) and various immunologic pathways (C7). Conclusions: Population-specific SCNAs, ccB subtypes, and pathways may help explain differences in RCC tumor biology amongst AA and EA patients. Future Directions: Replicate these findings in the Cooperative Human Tissue Network/Geisinger validation cohort. Citation Format: Samantha Greenberg, Alex Bart, Destiny Ortiz Fernandez, Heinric Williams, Khadijah A. Mitchell. Somatic copy number alterations and gene expression signatures are associated with aggressive tumor biology in African Americans and European Americans with renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1904.