Endometrial cancer is the one of the most common malignant tumors of the female reproductive system. In recent years, the morbidity and mortality of endometrial cancer have increased worldwide. Early diagnosis, surgery, and chemotherapy reduce endometrial cancer mortality. However, there is a subset of low-grade, early stage, well-differentiated endometrioid tumors in which unexpected recurrences and poor outcomes do occur. For women diagnosed with a clinically aggressive histologic subtype of the disease, such as serous, clinical outcomes worsen considerably with recurrent or advanced disease (1, 2). Traditional endometrial cancer typing (Bokhman) has limited predictive value for prognosis, because it does not consider the genetic variation and heterogeneity of the tumor. The Cancer Genome Atlas (TCGA) published a comprehensive genomic study of serous and endometrioid histotypes and reported four genomic subtypes: polymerase-epsilon (POLE), microsatellite instability (MSI), copy-number low and copy-number high (3). Intracellular mutation accumulation caused by POLE mutations or MSI, leads to high tumor mutational burden (TMB), increased expression of new antigens and abundant tumor infiltrating lymphocytes, which result in sensitivity to immune checkpoint inhibitors (4).
Immunotherapy, the most promising research direction in cancer treatment, regulates the tumor immune microenvironment to kill tumor cells by activating or regulating the body's immune system. Multiple clinical trials have proven that the type of POLE hypermutation and MSI are potential beneficiaries of programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1) immunotherapy in endometrial cancer (3, 5, 6). The expression of PD-L1 was typically detected by immunohistochemistry to predict the effect of immunotherapy for endometrial cancer. However, some clinical studies have indicated that patients with positive PD-1 expression do not respond to PD-1/PD-L1 immunotherapy (6, 7). Coincidentally, the latest research by Dou et al. found that the efficiency of antigen expression varies greatly in MSI-type endometrial cancer, and the down-regulation of antigen presentation ability would alter the effect of immunotherapy (7, 8). It is urgent to identify new targets for diagnosis and treatment to improve the effect of immunotherapy in endometrial cancer.
Epigenetics is the study of heritable phenotype changes, most often involving changes that affect gene activity and expression, but do not involve DNA sequence alterations. Due to epigenetic changes, tumor cell immunogenicity and immune recognition mechanisms are destroyed (9, 11). In addition, epigenetic silencing affects antigen processing and presentation (12). Chromatin remodeling is an important part of epigenetics. Impaired chromatin remodeling leads to the accumulation of epigenetic abnormalities. Several studies have found, in malignant tumors, that the gene related to chromatin remodeling has high mutation frequency and plays an important role in tumor immune escape (13, 14). The adenomatous polyposis coli (APC) gene, located on chromosome 5q21, is the chromatin-remodeling related gene and a typical tumor suppressor. APC protein is involved in the modification of transcription activation and cell cycle regulation. APC has an oligomerization domain, a 15- or 20-residue repeat domain important for binding to β-catenin, SAMP repeats for axin binding, a basic domain for microtubule binding and C-terminal domains that bind to EB1 and DLG proteins (15). The basal region and the C-terminal region, combined with microtubules, interact with EB1 to promote chromosome aggregation (16). APC inactivation leads to the loss of spindle function in mitosis and the instability of the genome and chromosome (17). Aberrant structure or expression of APC has been reported to be associated with various cancers. For example, high APC expression is an unfavorable prognostic factor for T4 gastric cancer and may be used as a novel biomarker for pathogenesis research, diagnosis, and treatment of gastric cancer (18). Loss of APC function leading to Wnt/β-catenin signaling hyper-activation is considered one of the driving forces of colorectal cancer tumorigenesis (19). APC mutation occurs in 20–45% of endometrial cancer (20), and the methylation of APC is associated with endometrial cancer occurrence (21). Recent studies have shown that APC mutation can induce endometrial hyperplasia and endometrial cancer by preventing estrogen signal transduction in endometrial epithelium (22). Therefore, we speculated that APC may have an important role in the pathogenesis and clinical progression of endometrial cancer.
The objective of this study was to demonstrated that APC as a new target for the diagnosis and treatment of endometrial cancer. We used data from TCGA and tumor samples from an endometrial cancer cohort to characterize endometrial cancer with and without the APC mutation. And our findings support that APC may play an important role in the immunotherapy of endometrial cancer.