Molecular correlates of MAEA expression in colorectal cancer (CRC).

Abstract

3128 Background: Macrophage Erythroblast Attacher (MAEA) plays an important role in actin cytoskeleton rearrangement in macrophages and erythroid cells. We previously reported that MAEA suppresses migration, invasion and enhances chemosensitivity in CRC cell lines. Here we aimed to characterize the molecular features associated with MAEA gene expression in CRC. Methods: 14416 CRC were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS). Top quartile transcripts per million (TPM) for MAEA expression were considered high (Q4) while bottom quartile low (Q1). Consensus molecular subtypes (CMS) were assessed using RNAseq. Cell infiltration (CI) in the tumor microenvironment (TME) was estimated by QuantiSEQ. X2 and Fisher-Exact tests were used and significance was determined as P-value adjusted for multiple comparisons ( Q < 0.05). Results: MAEA expression was highest in rectal tumors (13.6 median TPM) followed by transverse and right-sided tumors (13.0 and 12.8, respectively) and lowest in left-sided tumors (12.5). Overall, MAEA TPM were associated with higher tumor mutational burden (≥ 10 Mut/Mb) (11.8% vs. 8.2%) and dMMR/MSI-H (8.7% vs. 5.1%) ( Q < 0.0001); however, the association with TMB was not observed in MSS tumors. In the MSS cohort, MAEA expression was the highest in CMS4 (14.9 median TPM) followed by CMS1 (12.5), CMS2 (11.9), and the lowest in CMS3 (10.3, all intergroup Q < 0.05). MAEA high was associated with lower mutation rates of APC and amplification of FLT1/ FLT3 while higher mutation rates of ASXL1, KMT2A/C/D, SMARCA4, FBXW7, PTEN, RNF43, BRCA2, HNF1A in the overall cohort ( Q < 0.05). In the MSS cohort, FBXW7 mutation significance with MAEA high expression held true ( Q < 0.05) while MAEA high expression trended to associate with higher mutation rates of KMT2D, SMARCA4, PTEN, BRCA2 mutations, and a lower frequency of FLT1/ FLT3 CNA ( P < 0.05 but Q > 0.05). High MAEA was associated with higher immune CI in the TME, including B cells, macrophages (M1 and M2), neutrophils, NK cells, Tregs, CD4+ T cells and myeloid dendritic cells both in the overall cohort and in MSS tumors (fold change: 1.11-1.33, all Q < 0.001). Conclusions: Our data show a strong association between MAEA gene expression and distinct molecular features (including CMS and immune biomarkers) and TME cell infiltration in CRC. These findings suggest that targeting MAEA may have relevant clinical applications in selected CRC subgroups and MAEA may be an important player in determining the composition of the TME.