APC mutations as a predictive marker of endometrial cancer immunotherapy: a retrospective cohort study

Abstract

The APC regulator of WNT signalling pathway gene (previously known as adenomatous polyposis coli gene; APC), located on 5q22.2, is a chromatin remodelling-related gene and a typical tumour suppressor. Patients with high expression of PD-L1 or a high tumour mutational burden have been reported to benefit from immunotherapy in endometrial cancer. The objective of this study was to show that APC is a new biomarker target for the diagnosis and treatment of endometrial cancer by analysing the correlation of APC mutations with PD-L1 expression or tumour mutational burden. We did an integrative analysis of a commercially available panel (Burning Rock Biotech, Guangzhou, China) including 520 cancer-related genes on 99 tumour samples from an endometrial cancer cohort in China and DNA-seq data from The Cancer Genome Atlas to identify new gene mutations as endometrial cancer immunotherapy markers. To discover the effect of gene mutations on endometrial cancer, we assessed the correlation between gene mutations and tumour immune microenvironment, and explored the immune microenvironment in endometrial cancer, including tumour mutational burden, PD-L1 expression, and lymphocytic infiltration. We found that the relevant mutated genes were related to the chromatin state and generated a discovery set including 12 mutated genes that significantly correlated with PD-L1 expression and tumour mutational burden. We pinpointed the APC gene, which was mutated in 18 (18%) of 99 tumour samples, as a new potential biomarker for immunotherapy. Further analysis showed that tumours with an APC mutation had a high tumour mutational burden, increased expression of PD-L1, and increased lymphocytic infiltration. By assessing the relationship between immunotherapy biomarkers and APC, we verified that APC has inactive mutations (eg, missense mutations, truncating mutations, and a mixture of missense and truncating mutations) in endometrial cancer, which might affect the immune response, including PD-L1 expression, microsatellite instability, and lymphocytic infiltrate. From The Cancer Genome Atlas data, we also found that patients with the APC mutation had longer overall survival. Our study shows that APC could have an important role in enhancing the response to endometrial cancer treatment, particularly immunotherapy. The study was supported by the National Natural Science Foundation of China (grant numbers 81472427, 32070583, 81672574, and 81702547), the Shanghai Health System Outstanding Talents Program (grant number 2018YQ23), the Shanghai New Frontier Technology Project (grant number SHDC12015110), and the Shanghai Municipal Medical and Health Discipline Construction Projects (grant number 2017ZZ02015).