Abstract 452: TGF-β signaling pathway-related gene mutations are associated with increased neoantigen counts, enhanced cytolytic activity, and improved survival outcomes in TP53-mutated endometrial carcinoma
Authors: Bae William H. , Hwang Jin Young , Hur Won Kyung , Nam Myungwoo , Choi Yoonhee , Kim Leeseul , Lee Yeun Ho , Cheng William , Kim Eugene , Yu Emma , Jung Chan Mi , Chuang Jeff , Wang Victor , Chae Young Kwang 
Published: July 2021

TP53-mutation is a poor prognostic marker for uterine corpus endometrial carcinoma (UCEC). TGF-β is known to promote tumor progression via immune suppression, particularly NK and T cell-mediated cytotoxicity, in the tumor microenvironment. We aimed to analyze the impact of TGF-β signaling pathway-related gene mutation on the immune landscape and survival outcomes in TP53-mutated UCEC patients. cBioPortal was queried to obtain the UCEC The Cancer Genome Atlas cohort data (TCGA, 529 patients). The neoantigen counts were predicted using the CloudNeo pipeline. Survival outcomes were compared in the TGF-β signaling pathway-related gene mutated group, which were defined as genetic variances in TGFBR1, TGFBR2, ACVR2A, ACVR1B, SMAD2, SMAD3, or SMAD4, and the TGF-β signaling pathway-related gene non-mutated group. The cytolytic activity score was defined as a geometric mean of mRNA expression of perforin and granzyme. The duration of overall survival and disease-free survival were also obtained from cBioPortal. Out of the 529 UCEC patients, 192(36.3%) cancer tissues with TP53 mutations were analyzed for this study. 44 patients (22.9%) had more than one mutation in their TGF-β signaling pathway-related genes. TGF-β signaling pathway-related gene mutated group, when compared to a non-mutated group, was associated with significantly increased neoantigen counts (519.3 vs. 20.34 ; p&lt;0.0001) and a significantly enhanced cytolytic activity (407.2 vs. 142.2; p&lt;0.001). But there were no significant differences in PD-L1 expression level. The TGF-β pathway-related gene mutation was associated with improved disease-free survival (HR 0.29; 95% CI 0.13-0.67; p &lt;0.05) and improved overall survival in TP53-mutated UCEC patients (HR, 0.32; 95% CI, 0.17-0.59; P &lt; 0.001). In our analysis, TGF-β pathway-related gene mutations were correlated with significantly increased neoantigen count, higher cytolytic activity, and improved survival outcomes in TP53 mutated UCEC patients. Thus, TGF-β pathway-related gene mutations in TP53 mutated UCEC may be associated with increased cancer immunogenicity. Clinical treatment outcomes of UCEC with TGF-β pathway-related gene mutations should be explored in larger prospective studies.

Citation Format: William H. Bae, Jin Young Hwang, Won Kyung Hur, Myungwoo Nam, Yoonhee Choi, Leeseul Kim, Yeun Ho Lee, William Cheng, Eugene Kim, Emma Yu, Chan Mi Jung, Jeff Chuang, Victor Wang, Young Kwang Chae. TGF-β signaling pathway-related gene mutations are associated with increased neoantigen counts, enhanced cytolytic activity, and improved survival outcomes in TP53-mutated endometrial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 452.