Abstract 5752: Loss-of-function mutations in ACVR2A are correlated with microsatellite instability in gastric and colorectal cancer
Authors: Jia Yongning , Yuan Hongling , Xin Yaqun , Pang Fei , Shan Fei , Li Shuangxi , Zhu Honglin , Li Ziyu 
Published: June 2022

Abstract
Background: The activin type II receptor (ACVR2), which is a member of the transforming growth factor beta (TGF-β) receptor family, is frequently mutated in colorectal cancer (CRC) and gastric cancer (GC). However, the incidence of ACVR2 mutations in MSI-H patients remains unclear. The aim of this study is to evaluate ACVR2A mutation characteristics and to examine its associations between the high microsatellite instability (MSI-H) and ACVR2A mutations in CRC and GC.
Materials and Methods: We analyzed data from two cohorts: a Chinese cohort and the TCGA cohort. The Chinese cohort consisted of 1960 patients with CRC and GC, including 140 MSI-H samples and 1820 MSS samples. MSI status of these patients was derived from tumor-normal paired sequence data by targeted next generation sequencing (NGS). The TCGA cohort consists of 570 patients whose MSI status was determined. NGS data and clinical information were downloaded from the cBioPortal database (https://www.cbioportal.org). The abundance of tumor immune infiltrates was estimated by the Tumor Immune Estimation Resource (TIMER) 2.0 algorithm using gene expression data.
Results: In the Chinese cohort, ACVR2A mutations were identified in 204 (18.6%) of 1960 patients, including 125 (61%) MSI-H patients and 79 (39%) MSS patients. Meanwhile, in all 140 MSI-H samples, 125 (90%) samples harbored AVCR2A mutation. The main variant of ACVR2A is loss of function mutation (ACVR2ALOF), including p.K437del(65%, 132/204), p.D96del(5%, 11/204), p.Asp96ins(4%, 9/204), and etc. ACVR2ALOF were detected in 161 patients (78.9%, 161/204), of which 125 (77%) were MSI-H and 36 (22%) were MSS. In the TCGA cohort, there were 102 (102/570) MSI-H samples, and 43% (44/102) of MSI-H samples carried ACVR2A mutation. Compared to the Chinese cohort, the ACVR2A mutation frequency in MSI-H samples was significantly lower in the TCGA cohort (43% vs 90%, p&lt;0.01). The ACVR2ALOF mutations were observed in 30 MSI-H samples and 6 MSS samples. In both cohorts, patients with ACVR2ALOF mutations exhibited higher TMB (p&lt;0.05) and PD-L1 expression (p&lt;0.0001) than those without ACVR2ALOF mutations. Furthermore, in the TCGA cohort, we found that the Tumor Infiltrating Lymphocytes (TILs) of CD4+ T cells and macrophage cells were significantly lower in ACVR2ALOF samples than those without ACVR2ALOF mutations (p&lt;0.05).
Conclusions: The ACVR2ALOF was strongly correlated with MSI-H in patients of CRC and GC in both cohorts, especially in the Chinese population. Patients with ACVR2ALOF mutations have similar genomic characteristics to MSI-H, with high TMB, high PD-L1 expression, and therefore can serve as a potential biomarker for selecting candidates for immunotherapy.
Citation Format: Yongning Jia, Hongling Yuan, Yaqun Xin, Fei Pang, Fei Shan, Shuangxi Li, Honglin Zhu, Ziyu Li. Loss-of-function mutations in ACVR2A are correlated with microsatellite instability in gastric and colorectal cancer [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 5752.