Rs3212986 polymorphism, a possible biomarker to predict smoking‐related lung cancer, alters DNA repair capacity via regulating ERCC1 expression

Abstract

Single nucleotide polymorphisms (SNPs) in 3′UTR of key DNA repair enzyme genes are associated with inter‐individual differences of DNA repair capacity (DRC) and susceptibility to a variety of human malignancies such as lung cancer. In this study, seven candidate SNPs in 3′UTR of DRC‐related genes including ERCC1 (rs3212986, rs2336219, and rs735482), OGG1 (rs1052133), MLH3 (rs108621), CD3EAP (rs1007616), and PPP1R13L (rs6966) were analyzed in 300 lung cancer patients and controls from the northeast of China. Furthermore, we introduced ERCC1 (CDS+3′UTR) or CD3EAP (CDS) cDNA clone to transfect HEK293T and 16HBE cells. Cell viability between different genotypes of transfected cells exposed to BPDE was detected by CCK‐8 assay, while DNA damage was visualized using γH2AX immunofluorescence and the modified comet assay. We found that minor A‐allele of rs3212986 could reflect a linkage with increasing risk of NSCLC. Compared with CC genotype, AA genotype of ERCC1 rs3212986 was a high‐risk factor for NSCLC (OR = 3.246; 95%CI: 1.375‐7.663). Particularly stratified by smoking status in cases and controls, A allele of ERCC1 rs3212986 also exhibited an enhanced risk to develop lung cancer in smokers only (P < 0.05). Interestingly, reduced repair efficiency of DNA damage was observed in 293T ERCC1(AA) and 16HBE ERCC1(AA), while no significant difference was appeared in two genotypes of CD3EAP (3′ adjacent gene of ERCC1) overexpressed cells. Our findings suggest that rs3212986 polymorphism in 3ʹUTR of ERCC1 overlapped with CD3EAP may affect the repair of the damage induced by BPDE mainly via regulating ERCC1 expression and become a potential biomarker to predict smoking‐related lung cancer.

Benzo[a]pyrene diol epoxide‐induced transformed cells identify the significance of hsa_circ_0051488, a ERCC1‐derived circular RNA in pulmonary squamous cell carcinoma

“…Our previous studies investigated genetic polymorphisms in the 3′‐untranslated region and a long noncoding RNA originating from ERCC1 and their use as biomarkers for prediction of repair of DNA damage and susceptibility to lung cancer. Our results indicate that ERCC1 is significantly regulated at the posttranscriptional level 7,16,17 . Alternative splicing is an important mechanism that regulates gene expression and generates RNA diversity 18 .…”

“…However, when DNA repair by ERCC1 in damaged lung cells is insufficient, these cells cannot effectively remove the genetic damage caused by carcinogens, and this increases the risk of lung cancer 36 . Posttranscriptional regulation has a strong impact on the level of ERCC1 , and studies on lung cancer showed that noncoding RNA affect the susceptibility to environmental carcinogens and prognosis by regulating ERCC1 expression 7,16,17,37 . As a critical noncoding RNA produced by posttranscriptional regulation, circRNAs play important roles in tumors induced by carcinogens 38,39 .…”

Integrated Analysis of Nine Prognostic RNA-Binding Proteins in Soft Tissue Sarcoma

“…CD3EAP (also known as ASE1, CAST, ERCC1 antisense) is a component of the RNA polymerase I complex, which is involved in ribosome biosynthesis and promotes cell proliferation similar to BYSL (54). CD3EAP has been reported to be involved in the occurrence and metastasis of lung cancer tissues (55).…”

Promoter polymorphisms of TOP2A and ERCC1 genes as predictive factors for chemotherapy in non‐small cell lung cancer patients

“…Previous genetic studies had shown that rs3212986 and rs11615 ERCC1 gene polymorphisms may be a predictive factor for chemotherapy in NSCLC patients. Moreover, some polymorphic variants of these SNPs may affect the risk of lung cancer . Yu et al revealed that NSCLC patients carrying the A/A genotype in rs3212986 of ERCC1 gene had a higher risk of lung cancer, especially in the smoking population .…”

“…Moreover, some polymorphic variants of these SNPs may affect the risk of lung cancer . Yu et al revealed that NSCLC patients carrying the A/A genotype in rs3212986 of ERCC1 gene had a higher risk of lung cancer, especially in the smoking population . Zhou et al observed that rs3212986 ERCC1 gene polymorphism may be a useful predictor of OS in advanced NSCLC patients treated with platinum‐based chemotherapy.…”