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Association of CHEK2 polymorphisms with the efficacy of platinum-based chemotherapy for advanced non-small-cell lung cancer in Chinese never-smoking women.

ABSTRACT: BACKGROUND:Cell cycle checkpoint kinase 2 (CHEK2) plays an essential role in the repair of DNA damage. Single nucleotide polymorphisms (SNPs) in DNA repair genes are thought to influence treatment effects and survival of cancer patients. This study aimed to investigate the relationship between polymorphisms in the CHEK2 gene and efficacy of platinum-based doublet chemotherapy in never-smoking Chinese female patients with advanced non-small-cell lung cancer (NSCLC). METHODS:Using DNA from blood samples of 272 Chinese advanced NSCLC non-smoking female patients treated with first-line platinum-based chemotherapy, we have analyzed the relationships between four SNPs in the CHEK2 gene and clinical outcomes. RESULTS:We found that overall survival (OS) was significantly associated with CHEK2 rs4035540 (Log-Rank P=0.020), as well as the CHEK2 rs4035540 dominant model (Log-Rank P=0.026), especially in the lung adenocarcinoma group. After multivariate analysis, patients with rs4035540 A/G genotype had a significantly better OS than those with the G/G genotype (HR =0.67, 95% CI, 0.48-0.93; P=0.016). In the toxicity analysis, it was observed that patients with the CHEK2 rs4035540 A/A genotype had a higher risk of gastrointestinal toxicity than the G/G genotype group (P=0.009). However, there are no significant associations between chemotherapy treatments and genetic variations. CONCLUSIONS:Our findings indicate that SNPs in CHEK2 are related to Chinese advanced NSCLC never-smoking female patients receiving platinum-based doublet chemotherapy in China. Patients with rs4035540 A/G genotype have a better OS. And patients with rs4035540 A/A genotype have a higher risk of gastrointestinal toxicity. These results point to a direction for predicting the prognosis for Chinese never-smoking NSCLC female patients. However, there are no significant associations between chemotherapy treatments and SNPs in CHEK2, which need more samples to the further study.

SUBMITTER: Xu W

PROVIDER: S-EPMC5059261 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Association of <i>CHEK2</i> polymorphisms with the efficacy of platinum-based chemotherapy for advanced non-small-cell lung cancer in Chinese never-smoking women.

Xu Wen W Liu Di D Yang Yang Y Ding Xi X Sun Yifeng Y Zhang Baohong B Xu Jinfu J Su Bo B

Journal of thoracic disease 20160901 9

<h4>Background</h4>Cell cycle checkpoint kinase 2 (CHEK2) plays an essential role in the repair of DNA damage. Single nucleotide polymorphisms (SNPs) in DNA repair genes are thought to influence treatment effects and survival of cancer patients. This study aimed to investigate the relationship between polymorphisms in the <i>CHEK2</i> gene and efficacy of platinum-based doublet chemotherapy in never-smoking Chinese female patients with advanced non-small-cell lung cancer (NSCLC).<h4>Methods</h4> ...[more]

PMID: 27747004

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Project description:Background Platinum-based chemotherapy (PC) and immunotherapy plus platinum-based chemotherapy (IPC) remain the first-line treatment for advanced NSCLC. But only a minority patients benefit from PC, and existing biomarkers, such as PD-L1, have been shown to be defective in predicting the efficacy of IPC. Highlighting the need to identify novel biomarkers for the efficacy of PC and IPC. DNA damage repair (DDR) mutations are known to predict response to PC in solid tumors. However, the predictive value of DDR in PC and IPC of NSCLC remains unclear. Methods Patients diagnosed with advanced or metastatic NSCLC were retrospectively included if they underwent next generation sequencing prior to starting treatment. Primary endpoints were to explore whether DDR mutations (DDRmut) are associated with clinical outcomes of PC and IPC. Secondary end point were to explore the association between DDRmut and the choice to add immunotherapy to chemotherapy, and the impact of different DDR pathways on efficacy in PC and IPC. Results DDRmut showed a strong association with tumor mutation burden-high (TMB-H) versus DDR wild-type (DDRwt) and higher rates of PD-L1 TPS ≥50% positivity. In 63 patients treated with PC, ORRs were 15.38% and 2.86% for DDRmut and DDRwt subgroup (P=0.1536), and DCRs were 88.46% and 45.72% (P=0.00097) at 6 months after PC. The DDRmut patients had significantly improved median PFS (mPFS) and median overall survival (mOS) than DDRwt group (mPFS: 7.6 vs. 3.9 months, HR =1.93, 95% CI: 1.09 to 3.14, P=0.0220. mOS: 29.9 vs. 20.7 months, HR =2.31, 95% CI: 1.09 to 4.9, P=0.0250). Moreover, among 37 patients treated with IPC, ORRs were 45% and 11.76% for DDRmut and DDRwt patients (P=0.0365), and the DCRs were 95% and 70.58% (P=0.0752), respectively at 6 months after IPC. The DDRmut patients had significantly improved mPFS compared to the DDRwt group (19.5 vs. 4.5 months, HR =3.28, 95% CI: 1.53 to 9.56, P=0.0022). In DDRmut group, mPFS of IPC recipients was significantly better than that of PC recipients (19.5 vs. 7.6 months, HR =2.09, 95% CI: 0.98 to 4.42, P=0.050). Conclusions There is potential for DDR to serve as a positive predictor of PC and IPC in advanced NSCLC patients.

Project description:BackgroundThe mechanism of rapidly increased non-small cell lung cancer (NSCLC) among never-smoking Chinese women has not been elucidated. Ovarian sex steroid hormones have been suggested to counteract lung cancer development, and sex hormone-binding globulin (SHBG) is essential in sex hormones regulation. This study aims to exploring single nucleotide polymorphisms (SNPs) in genomic regions associated with SHBG concentrations that contributed to never-smoking female NSCLC.MethodsCandidate genes were selected by a genome-wide association (GWAS) meta-analysis and gene expression profiles of never-smoking NSCLC of Chinese women. The candidate SNPs limited to common minor allele frequency (MAF), missense variant, ethnic heterogeneous distribution, and SNPs were genotyped using the TaqMan method. A two-stage case-control design was adopted for exploration and validation of associations between candidate SNPs and risk of NSCLC. All participants were never-smoking Chinese women. Chi-square test and multivariate logistic regression were applied.ResultsBeginning with 12 genomic regions associated with circulating SHBG concentrations and gene expression profiles from never-smoking NSCLC in Chinese women, candidate SNP rs12233719 and rs7439366 both located in candidate gene UGT2 B7, which may be related to circulating SHBG concentrations and cancer risk, were identified. A two-stage case-control study was conducted in Shenyang and Tianjin represented as the training stage and validation stage, respectively. Under the dominant model, compared to individuals with the wild G/G genotype, the adjusted OR of those with the T allele was 1.58 (95% CI: 1.15-2.16) in Chinese Shenyang training set, and was 1.49 (95% CI: 1.02-2.18) in Chinese Tianjin validation set, both accompanied with a significant trend relationship consistently. UGT2B7 was upregulated in female NSCLC patients' tumor tissues and was associated with a poor prognosis in NSCLC.ConclusionOur findings indicated that a sex hormones regulation-related SNP rs12233719 was associated with never-smoking female lung cancer risk, which might partially explain NSCLC-susceptibility in Chinese women.

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Dataset Information

Association of CHEK2 polymorphisms with the efficacy of platinum-based chemotherapy for advanced non-small-cell lung cancer in Chinese never-smoking women.

Publications

Association of <i>CHEK2</i> polymorphisms with the efficacy of platinum-based chemotherapy for advanced non-small-cell lung cancer in Chinese never-smoking women.

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