Identification of APC Mutation as a Potential Predictor for Immunotherapy in Colorectal Cancer

Abstract

To date, anticancer immunotherapy has presented some clinical benefits to most of advanced mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) patients. In addition to MSI status, we aimed to reveal the potential predictive value of adenomatous polyposis coli (APC) gene mutations in CRC patients. A total of 238 Chinese CRC patients was retrospectively identified and analyzed for clinical features and gene alternations in APC-mutant type (MT) and APC-wild-type (WT) groups. Clinical responses were then evaluated from the public TCGA database and MSKCC immunotherapy database. Although programmed cell death ligand 1 (PD-L1) level, MSI status, loss of heterogeneity at the human leukocyte antigen (HLA LOH), and tumor neoantigen burden (TNB) level were not statistically different between the APC-MT group and APC-WT group, tumor mutation burden (TMB) level was significantly higher in APC-MT patients ( <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"> <a:mi>P</a:mi> <a:mo>&lt;</a:mo> <a:mn>0.05</a:mn> </a:math> ). Furthermore, comutation analysis for APC mutations revealed co-occurring genomic alterations of PCDHB7 and exclusive mutations of CTNNB1, BRAF, AFF3, and SNX25 ( <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" id="M2"> <c:mi>P</c:mi> <c:mo>&lt;</c:mo> <c:mn>0.05</c:mn> </c:math> ). Besides, overall survival from MSKCC-CRC cohort was longer in the APC-WT group than in the APC-MT group (HR 2.26 (95% CI 1.05–4.88), <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" id="M3"> <e:mi>P</e:mi> <e:mo>&lt;</e:mo> <e:mn>0.05</e:mn> </e:math> ). Furthermore, most of patients in the APC-WT group were detected as high-grade immune subtypes (C2–C4) comparing with those in the APC-MT group. In addition, the percentages of NK T cells, Treg cells, and fibroblasts cells were higher in APC-WT patients than in APC-MT patients ( <g:math xmlns:g="http://www.w3.org/1998/Math/MathML" id="M4"> <g:mi>P</g:mi> <g:mo>&lt;</g:mo> <g:mn>0.05</g:mn> </g:math> ). In summary, APC mutations might be associated with poor outcomes for immunotherapy in CRC patients regardless of MSI status. This study suggested APC gene mutations might be a potential predictor for immunotherapy in CRC.