Overexpression of KMT2A is associated with worse prognosis and specific immune signatures in patients with TP53-mutated hepatocellular carcinomas

Abstract Background: Aberrant expression of epigenetic regulators is often associated with pathogenesis. Histone H3K4 methyltransferase, known as KMT2A, has been implicated in regulation of chromosome segregation, mitosis and DNA replication in pediatric leukemia and myeloma. However, the role of KMT2A expression in solid tumors is under-investigated. Here we examine the implications of KMT2A overexpression in prognosis, gene pathway enrichment, aneuploidy and immune infiltration patterns using a large, real-world clinical HCC dataset. Methods: A total of 403 HCC samples underwent comprehensive molecular profiling at Caris Life Sciences, including DNA-(592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq) and RNA- (NovaSeq, whole transcriptome sequencing, WTS) sequencing. Wilcoxon, Fisher’s exact test were used to determine statistical significance (p value without and q value with multi comparison correction). Aneuploidy scores were generated from CNVkit. Apoptotic index (AI), GSEA were assessed using mRNA levels (FDR<0.25 as cutoff). Overall survival was calculated from date of tissue collection to date of last contact from insurance claims data and used for Kaplan-Meier method. Results: Overexpression of KMT2A predicts poor survival in patients with HCC (HR 2.6, 95% CI [1.4 - 5.2], p<.01). KMT2Ahigh HCC has higher TP53 (57.9% vs 28.8%, p<.001) and lower CTNNB1 (14.1% vs 34.6%, p <.01) mutation rates (mt). GSEA analysis showed that pathways such as mitotic spindle (NES = 2.1), DNA repair (NES = 2.0), E2F regulation (NES = 2.0) and MYC (NES = 1.9) are significantly enriched in KMT2Ahigh HCC. Interestingly, in KMT2Ahigh HCC, TP53 mutation status is a stratification factor for several HCC features: 1) TP53 mt HCC displayed significantly lower aneuploidy score (median 6 vs 13.5, p<.01) and higher apoptotic index (median 1.1 vs 1.2, p<.05); 2) inflammatory response pathways (NES = 2.1) and IL6 JAK STAT3 signaling (NES = 2.1) are specifically enriched in TP53 mt HCC and 3) TP53 mt HCC has more infiltration of B cells (5.3% vs 3.3%, q<.05), Macrophage M1 (6.4% vs 2.9%, q<.01), CD8 + T cells and myeloid dendritic cells (1.1% vs 1%, q<.01) while TP53 wt is associated with more infiltration of Macrophage M2 (5.5% vs 3.3%, q<.05) cells. Conclusions: KMT2A could act as an independent prognostic marker in HCC. The negative correlation between KMT2A expression and aneuploidy scores in TP53 mt indicates potential roles of KMT2A in maintaining genome stability. Furthermore, our results suggest TP53 status is an important stratification factor for HCC with KMT2A overexpression. Our results warrant further investigation on the impact of KMT2A level on immune modulation and may define a subset of HCC that responds most effectively to immune checkpoint inhibition. Citation Format: Liang Sha, Jun Yin, Sungming Kim, Woojin An, Jian Zhang, Alex Farrell, Joanne Xiu, David Spetzler, Shuanzeng Wei, Dave S. Hoon, Stephen V. Liu, Emil Lou, Misako Nagasaka, Wafik S. El-Deiry, Benedito A. Carneiro, Wolfgang Michael Korn, Heinz-Josef Lenz, Yali Dou. Overexpression of KMT2A is associated with worse prognosis and specific immune signatures in patients with TP53-mutated hepatocellular carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5699.