Clinical Impact of X-Ray Repair Cross-Complementary 1 (XRCC1) and the Immune Environment in Colorectal Adenoma–Carcinoma Pathway Progression

Abstract

Yu Zhang,1,2,* Xin Zhang,3,* Zhuoyi Jin,2 Huiyan Chen,4 Chenjing Zhang,2 wangyue Wang,2 Jiyong Jing,5 Wensheng Pan1,2 1Department of Clinical Medicine, Medical College of Soochow University, Suzhou, 215006, People’s Republic of China; 2Department of Gastroenterology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of China; 3Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of China; 4School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wensheng PanDepartment of Gastroenterology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College; Institute of Gastrointestinal Diseases, Hangzhou Medical College; Zhejiang Provincial Engineering Laboratory of Diagnosis, Treatment and Pharmaceutical Development of Gastrointestinal Tract Tumors, No. 158 Shangtang Road, Hangzhou, 310014, People’s Republic of ChinaTel/Fax [phone]Email [email protected] JingZhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, 310014, People’s Republic of ChinaEmail [email protected]: Colorectal cancer (CRC) can develop via a hypermutagenic pathway characterized by frequent somatic DNA base-pair mutations. Alternatively, the immunogenicity of tumor cells themselves may influence the anticancer activity of the immune effector cells. Impaired DNA repair mechanisms drive mutagenicity, which then increase the neoantigen load and immunogenicity. However, no studies have analyzed immune checkpoint protein expression, particularly programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), in adenoma–carcinoma progression and its relationship with the emergence of other DNA repair gene mutation.Materials and Methods: We investigated mutations of 10 genes involved in DNA repair function: XRCC1, TP53, MLH1, MSH, KRAS, GSTP, UMP, MTHF, DPYD, and ABCC2. We performed sequencing to determine mutations and immunohistochemistry of immune checkpoints in clinical samples and determined changes in XRCC1 expression during progression through the adenoma–carcinoma pathway. We further investigated the prognostic associations of gene XRCC1 according to the expression, mutational profile, and immune profile using The Cancer Genome Atlas-colon adenocarcinoma (TCGA-COAD) dataset.Results: From clinical samples, XRCC1 mutation demonstrated the strongest association with adenomas with a mutation frequency of 56.2% in adenomas and 34% in CRCs (p =0.016). XRCC1 was abnormally expressed and altered by mutations contributing to adenoma carcinogenesis. High expression of XRCC1, CD4, FOXP3, and PD-1/PD-L1 showed an overall upward trend with increased lesion severity (all p < 0.01). PD-1/PD-L1 expression and CD4+ intraepithelial lymphocytes (IELs) correlated with cytological dysplasia progression, specifically in patients with wild-type XRCC1 (all p < 0.01), whereas FOXP3 expression was independently associated with adenoma–carcinoma progression. From TCGA-COAD analysis, XRCC1 expression was associated with patients survival, tumor-infiltrating lymphocytes and immune marker expression.Conclusion: Increased IEL density and PD-1/PD-L1 expression correlate with cytological dysplasia progression and specifically with the XRCC1 mutation status in CRC. Our findings support a stepwise dysplasia-carcinoma sequence of adenoma carcinogenesis and an XRCC1 hypermutated phenotypic mechanism of lesions.Keywords: adenoma–carcinoma, immune environment, PD-1/PD-L1, tumor-infiltrating lymphocytes, XRCC1

Keywords

• adenoma-carcinoma
• immune environment
• pd-1/pd-l1
• tumor-infiltrating lymphocytes
• xrcc1