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

person Yanfeng Xi Department of Pathology, Shanxi Cancer Hospital, Taiyuan, China info_outline Yanfeng Xi, Wei Cui, Yuan Tan, Qin Zhang, Qianqian Duan, Dong-sheng Chen

Authors person Yanfeng Xi Department of Pathology, Shanxi Cancer Hospital, Taiyuan, China info_outline Yanfeng Xi, Wei Cui, Yuan Tan, Qin Zhang, Qianqian Duan, Dong-sheng Chen Organizations Department of Pathology, Shanxi Cancer Hospital, Taiyuan, China, Shanxi Province Cancer Hospital, Taiyuan, Shanxi, China, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd., The State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, Jiangsu, China, The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd., the State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China Abstract Disclosures Research Funding National Natural Science Foundation of China 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 .

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