Role of rs873601 Polymorphisms in Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy

Abstract

Background: Lung cancer is still the most lethal malignancy in the world, according to the report of Cancer Statistics in 2021. Platinum-based chemotherapy combined with immunotherapy is the first-line treatment in lung cancer patients. However, the 5-year survival rate is always affected by the adverse reactions and drug resistance caused by platinum-based chemotherapy. DNA damage and repair system is one of the important mechanisms that can affect the response to chemotherapy and clinical outcomes in lung cancer patients.

Objective: The objective of this study is to find the relationship between the polymorphisms of DNA repair genes with the prognosis of platinum-based chemotherapy in lung cancer patients.

Patients and methods: We performed genotyping in 17 single nucleotide polymorphisms (SNPs) of Excision Repair Cross-Complementation group (ERCC) genes and X-ray Repair Cross-Complementing (XRCC) genes of 345 lung cancer patients via Sequenom MassARRAY. We used Cox proportional hazard models, state, and plink to analyze the associations between SNPs and the prognosis of lung cancer patients.

Results: We found that the ERCC5 rs873601 was associated with the overall survival time in lung cancer patients treated with platinum-based chemotherapy (p = 0.031). There were some polymorphisms that were related to the prognosis in specific subgroups of lung cancer. Rs873601 showed a great influence on the prognosis of patients more than 55 years, Small Cell Lung Cancer (SCLC), and smoking patients. Rs2444933 was associated with prognosis in age less than 55 years, SCLC, metastasis, and stage III/IV/ED patients. Rs3740051 played an important role in the prognosis of SCLC and metastasis patients. Rs1869641 was involved in the prognosis of SCLC patients. Rs1051685 was related to the prognosis in non-metastasis patients.

Conclusion: The ERCC5 rs873601 (G>A) was a valuable biomarker for predicting the prognosis in lung cancer patients treated with platinum-based chemotherapy.

Keywords: ERCC5; genetic polymorphism; lung cancer; platinum-based chemotherapy; prognosis.

Figure 1

The ERCC5 rs873601 polymorphisms are significantly associated with the prognosis in lung cancer patients treated with platinum-based chemotherapy, and the A variant allele of ERCC5 rs873601 are protective allele. Patients who carry the AA or GA genotypes have a longer MST-OS than GG (p = 0.031 *). The dashed line, the overall survival rate is 0.5 or 50%.

Figure 2

The polymorphisms of ERCC5 rs873601, PNKY rs2444933, and STIR1 rs1051685 were related to the overall survival (OS) significantly. (A) The ERCC5 rs873601 polymorphisms were significantly associated with the overall survival (OS) in age > 56 and smoking patients. (B) The variants of PNKY rs2444933 were related to the prognosis significantly in age ≤ 56, metastasis, non-smoker, and clinical in III/IV/ED patients. (C) The polymorphisms of STIR1 rs3740051 were significantly associated with the overall survival in SCLC and metastasis patients. Dashed line, merged BETA value. *, p < 0.05.

Figure 3

The polymorphisms of ERCC5 rs873601, PNKY rs2444933, rs1849641, and XRCC5 rs1051685 were significant with the progress-free survival (PFS) significantly. (A–C) The ERCC5 rs873601, PNKY rs2444933, and rs1869641 polymorphisms were significantly associated with progression-free survival (PFS) in SCLC patients. (D) The variants of XRCC5 rs1051685 were related to the prognosis significantly in non-metastasis patients. Dashed line, merged BETA value. *, p < 0.05.

Figure 4

The polymorphisms of ERCC5 rs873601 can affect the prognosis of lung cancer patients. Rs873601 is a mutation located in the 3′UTR of ERCC5, it can affect the mRNA of ERCC5 to translation protein. It can also regulate the RNA-binding protein and the protein-to-protein interaction of ERCC5. These may have an influence on the DNA damage and repair in the NER pathway, which is a vital regulator in the prognosis of lung cancer patients treated with platinum-based chemotherapy.