Genome-wide association study of myelosuppression in non-small-cell lung cancer patients with platinum-based chemotherapy

Abstract

Platinum-induced myelosuppression severely impedes successful chemotherapy in non-small-cell lung cancer (NSCLC) patients. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy. We first carried out a genome-wide scan of 906 703 single-nucleotide polymorphisms (SNPs) to identify genetic variants associated with platinum-induced myelosuppression risk in 333 NSCLC patients with chemotherapy. Then, we replicated 24 SNPs that had P<1 × 10(-4) in another independent cohort of 876 NSCLC patients. With P<0.05 as the criterion of statistical significance, we found that rs13014982 at 2q24.3 and rs9909179 at 17p12 exhibited consistently significant associations with myelosuppression risk in both the genome-wide association studies (GWAS) scan and the replication stage (rs13014982: odds ratio (OR)=0.55, 95% confidence intervals (CIs): 0.41-0.74, P=7.29 × 10(-5) for GWAS scan and OR=0.77, 95% CI: 0.65-0.93, P=0.006 for replication stage; rs9909179: OR=0.51, 95% CI: 0.37-0.70, P=4.60 × 10(-5) for GWAS scan and OR=0.82, 95% CI: 0.68-0.99, P=0.040 for replication stage; both in additive model). In combined samples of genome-wide scan and replication samples, the minor alleles of rs13014982 and rs9909179 remained significant associations with the decreased risk of myelosuppression (rs13014982: OR=0.71, 95% CI: 0.61-0.83, P =1.36 × 10(-5); rs9909179: OR=0.76, 95% CI: 0.65-0.89, P=0.001). Rs13014982 at 2q24.3 and rs9909179 at 17p12 might be independent susceptibility markers for platinum-induced myelosuppression risk in NSCLC patients.

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

“…Single DNA biomarker may exhibit a slight effect on the clinical outcome . Recently, a genome‐wide association study (GWAS) was used to identify the genetic determinants of platinum‐induced myelosuppression . Unlike the dichotomized classification by the occurrence of grade 3–4 myelosuppression in previous studies, the GWAS used ordinal logistic regression to analyze the association of the myelosuppression grade with SNPs.…”

Genetic Polymorphisms and Platinum-Based Chemotherapy-Induced Toxicities in Patients With Lung Cancer: A Systematic Review and Meta-Analysis

“…Therefore, determining the association between polymorphisms and platinum-related toxicities will be beneficial for individualized chemotherapy. Previously, two genome-wide association studies and one wholeexome sequencing study were conducted to identify the genetic markers for platinum-induced toxicities (9)(10)(11). In addition, Yin et al aimed to establish models to explain and predict platinum toxicity interindividual difference by simultaneously incorporating multiple genetic and clinical factors to explore the association of their interactions with platinum-induced toxicities (12,13).…”

Rad52 deficiency decreases development of lung squamous cell carcinomas by enhancing immuno-surveillance

“…However, while lung cancer likely arises due to acquisiton of somatic mutations, contemporary evidence has begun to show that genetic variants also play a role in cancer progression and prognosis in patients [4, 5]. …”