Abstract 6074: Germline and somatic genomic profiling of urothelial carcinoma
Authors: Feng Bing-Jian , Kohlmann Wendy , Nix David A. , Atkinson Aaron , Boucher Kenneth M. , Carroll Courtney , Kolesar Jill , Singer Eric A. , Edge Stephen B. , Sahu Kamal , Sanchez Alejandro , Larson Mikaela , Churchman Michelle L. , Graham Laura , Carpten John D. , Zakharia Yousef , Byrne Lindsey , Jain Rohit K. , Nepple Kenneth G. , Shabsigh Ahmad , Chahoud Jad , Gupta Sumati 
Published: April 2023

Abstract
Urothelial carcinoma (UC) presents most frequently as bladder cancer and is the most common cancer of the urinary system in the United States. UC relapse and progression are common and impose a significant negative impact on the lives of patients and healthcare resources. To elucidate the biological mechanisms of UC and find novel biomarkers, we analyzed the clinical and genomic data in the Oncology Research Information Exchange Network (ORIEN). We conducted gene-based and gene-set based association tests on rare germline variants comparing the exome sequencing of 336 UC patients and genome sequencing of 366 healthy controls (42 unrelated individuals from the Centre d'Etudes du Polymorphisme Humain [CEPH] families and 324 from the University of Utah Heritage 1000 [H1K] Projects). The analysis of loss-of-function (LoF) variants revealed that the forkhead box (FOX) J2 gene set was significantly associated with UC at the genome-wide level (Bonferroni-corrected p-value=0.01). Genes in this gene set contain a motif that matches the FOXJ2 transcription factor binding site. Firth-penalized Cox proportional hazard regression on overall survival identified LoF variants in genes down-regulated in naive CD8 T cells to be associated with worse prognosis (Bonferroni-corrected p-value=0.032, hazard ratio=28.2, and 95% confidence interval 6.66 to 119.0). In exome sequencing of tumor tissues, we searched for driver genes and pathways by testing for higher variant allelic fractions than the genome average. The tests yielded eleven genes with genome-wide significance (Table 1). By gene set analysis using the MSigDB Hallmark database, significant pathways included the P53 pathway (p&lt;2 × 10−16), Wnt beta-catenin signaling (p&lt;2 × 10−16), E2F targets (p=8 × 10−13), PI3K/AKT/mTOR signaling (4 × 10−7), and apoptosis (p=9 × 10−7). These results reveal the germline predisposition variants and somatic oncogenic drivers in UC and suggest immune evasion as a contributing factor for poor clinical outcomes in UC patients.
Table 1. Genes with high allelic fractions Gene P-value Number of Variants TP53 &lt;2 × 10−16 203 RB1 2.42 × 10−16 67 ELF3 2.06 × 10−7 38 TSC1 4.05 × 10−7 32 KMT2D 7.59 × 10−7 91 ZFP36L1 8.80 × 10−7 33 CDKN1A 2.47 × 10−6 40 FGFR3 1.11 × 10−5 37 ARID1A 1.28 × 10−5 62 SMARCA4 1.53 × 10−5 17 PIK3CA 2.00 × 10−5 53
Citation Format: Bing-Jian Feng, Wendy Kohlmann, David A. Nix, Aaron Atkinson, Kenneth M. Boucher, Courtney Carroll, Jill Kolesar, Eric A. Singer, Stephen B. Edge, Kamal Sahu, Alejandro Sanchez, Mikaela Larson, Michelle L. Churchman, Laura Graham, John D. Carpten, Yousef Zakharia, Lindsey Byrne, Rohit K. Jain, Kenneth G. Nepple, Ahmad Shabsigh, Jad Chahoud, Sumati Gupta. Germline and somatic genomic profiling of urothelial 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 6074.