Impact of APC mutations on prognosis and tumor microenvironment in colorectal signet ring cell carcinoma.

Abstract

e15500 Background: Colorectal signet ring cell carcinoma (CRC-SRC) is a malignant tumour characterized by its aggressive nature and unfavourable prognosis. In spite of the fact that numerous studies have examined the molecular profile and therapeutic targets of CRC-SRC, the prognostic biomarkers for this malignancy continue to be unknown. Methods: We conducted a comprehensive analysis of multi-omics in 35 cases of CRC-SRC and 10 cases of colorectal adenocarcinomas (CRC-AC). This analysis involved various techniques, including immunohistochemistry, DNA sequencing, and RNA sequencing. Results: In CRC-SRC, despite a lower frequency of APC mutations at the genomic level (P = 0.01), they rank as the second most prevalent mutations (40%), surpassed only by TP53 mutations (65.71%). The findings revealed that 13 genes associated with immunotherapy response were found to be upregulated in CRC-AC. Additionally, the levels of CD3+, CD8+, and CD3+ & CD8+ T cells were found to be similar in tumor regions in CRC-SRC. These results suggest that CRC-SRC is more likely to have an immunosuppressive tumor immune microenvironment (TiME) compared to CRC-AC. Multivariate Cox proportional hazard regression analysis (hazard ratio: 3.54, 95% confidence interval: 3.93-117.3; p-value = 0.0004), in particular, shows that the presence of APC mutations is associated with a worse prognosis. In contrast, APC-mutant cases of CRC-AC have the same overall survival (OS) rate as APC-wildtype patients in the TCGA cohort. On RNA level, APC-mutant tumors exhibited higher expression levels of VEGFA ( P = 0.028) and Mki67 (P = 0.014), which are implicated in tumour invasion and proliferation. In contrast, APC-mutant CRC-AC did not exhibit differential expression on these genes within the TCGA cohort. GSEA showed that only the E2F hallmark was significantly enriched in APC-mutant CRC-SRC patients ( P = 0.0072). On protein expression level, APC-mutant patients had a significantly lower CD3 or CD68 positive ratio in the tumour region (CD3: P = 0.035; CD68: P = 0.039). This indicated that lymphocyte infiltration is decreased in APC-mutant CRC-SRC. Conclusions: To summarize, APC mutations may have distinct functions in CRC-AC and CRC-SRC. Colorectal cancer (CRC) with APC mutations showed a more unfavourable prognosis and a distinct tumour immune microenvironment compared to CRC with normal APC. Clinical trial information: ChiCTR2300072881.