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Genome-wide Association Study on Platinum-induced Hepatotoxicity in Non-Small Cell Lung Cancer Patients.

Cao S, Wang C, Ma H, Yin R, Zhu M, Shen W, Dai J, Shu Y, Xu L, Hu Z, Shen H - Sci Rep (2015)

Bottom Line: To identify SNPs that modify the risk of hepatotoxicity in NSCLC patients receiving platinum-based chemotherapy, we performed a genome-wide association scan in 334 subjects followed by a replication study among 375 subjects.Consistent associations with platinum-induced hepatotoxicity risk was identified for SNP rs2838566 located at 21q22.3, as the minor A allele could significantly increase the risk of liver injury (OR = 3.78, 95%CI = 1.99-7.19, P = 4.90 × 10(-5) for GWAS scan, OR = 1.89, 95%CI = 1.03-3.46, P = 0.039 for replication, and OR = 2.56, 95%CI = 1.65-3.95, P = 2.55 × 10(-5) for pooled population).These results suggested that genetic variants at 21q22.3 may contribute to the susceptibility of platinum-induced hepatotoxicity in NSCLC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.

ABSTRACT
Platinum-based chemotherapy has been shown to improve the survival of advanced non-small cell lung cancer (NSCLC) patients; the platinum-induced toxicity severely impedes the success of chemotherapy. Genetic variations, such as single nucleotide polymorphisms (SNPs), may contribute to patients' responses to the platinum-based chemotherapy. To identify SNPs that modify the risk of hepatotoxicity in NSCLC patients receiving platinum-based chemotherapy, we performed a genome-wide association scan in 334 subjects followed by a replication study among 375 subjects. Consistent associations with platinum-induced hepatotoxicity risk was identified for SNP rs2838566 located at 21q22.3, as the minor A allele could significantly increase the risk of liver injury (OR = 3.78, 95%CI = 1.99-7.19, P = 4.90 × 10(-5) for GWAS scan, OR = 1.89, 95%CI = 1.03-3.46, P = 0.039 for replication, and OR = 2.56, 95%CI = 1.65-3.95, P = 2.55 × 10(-5) for pooled population). These results suggested that genetic variants at 21q22.3 may contribute to the susceptibility of platinum-induced hepatotoxicity in NSCLC patients.

No MeSH data available.


Related in: MedlinePlus

Genome-wide association results for platinum-induced hepatotoxicity in Han Chinese NSCLC patients.Scatter plot of P values in –log10 scale from GWAS results of the additive model on 588,732 SNPs.
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f1: Genome-wide association results for platinum-induced hepatotoxicity in Han Chinese NSCLC patients.Scatter plot of P values in –log10 scale from GWAS results of the additive model on 588,732 SNPs.

Mentions: P values for the discovery cohort were presented in the scatter plot with multiple suggestive associations (P < 1 × 10−4 in additive model; See Fig. 1). Eleven SNPs with P < 1 × 10−4 were selected for the validation while 9 other SNPs were excluded because of high LD with the selected ones (Table 2). In the replication stage, only the minor A allele of rs2838566 at 21q22.3 was found to be significantly associated with platinum-induced hepatotoxicity in the same direction with the GWAS scan (OR = 3.78, 95%CI = 1.99–7.19, P = 4.90 × 10−5 in GWAS scan, and OR = 1.89, 95%CI = 1.03–3.46, P = 0.039 in replication), compared with G allele (Table 3). When we pooled the subjects of GWAS and replication cohorts, rs2838566 was still associated with hepatotoxicity, with the P values being 2.55 × 10−5 (pooled OR = 2.56, 95%CI = 1.65–3.95). We then performed stratification analyses of rs2838566 in the pooled population to evaluate the effects of variant genotypes on the risk of platinum-induced hepatotoxicity by age, gender, smoking status, histology, stage, surgical operation, and platinum compounds (Table 4). The results showed that the association between rs2838566 and platinum-induced hepatotoxicity was significant in every stratum except among female-only populations. However, we didn’t observe any significant heterogeneity between each two stratums (P > 0.05) in (Table 4). The results for other 10 selected SNPs in replication phase and pooled population were shown in Supplementary Table S1 and Supplementary Table S2.


Genome-wide Association Study on Platinum-induced Hepatotoxicity in Non-Small Cell Lung Cancer Patients.

Cao S, Wang C, Ma H, Yin R, Zhu M, Shen W, Dai J, Shu Y, Xu L, Hu Z, Shen H - Sci Rep (2015)

Genome-wide association results for platinum-induced hepatotoxicity in Han Chinese NSCLC patients.Scatter plot of P values in –log10 scale from GWAS results of the additive model on 588,732 SNPs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4477405&req=5

f1: Genome-wide association results for platinum-induced hepatotoxicity in Han Chinese NSCLC patients.Scatter plot of P values in –log10 scale from GWAS results of the additive model on 588,732 SNPs.
Mentions: P values for the discovery cohort were presented in the scatter plot with multiple suggestive associations (P < 1 × 10−4 in additive model; See Fig. 1). Eleven SNPs with P < 1 × 10−4 were selected for the validation while 9 other SNPs were excluded because of high LD with the selected ones (Table 2). In the replication stage, only the minor A allele of rs2838566 at 21q22.3 was found to be significantly associated with platinum-induced hepatotoxicity in the same direction with the GWAS scan (OR = 3.78, 95%CI = 1.99–7.19, P = 4.90 × 10−5 in GWAS scan, and OR = 1.89, 95%CI = 1.03–3.46, P = 0.039 in replication), compared with G allele (Table 3). When we pooled the subjects of GWAS and replication cohorts, rs2838566 was still associated with hepatotoxicity, with the P values being 2.55 × 10−5 (pooled OR = 2.56, 95%CI = 1.65–3.95). We then performed stratification analyses of rs2838566 in the pooled population to evaluate the effects of variant genotypes on the risk of platinum-induced hepatotoxicity by age, gender, smoking status, histology, stage, surgical operation, and platinum compounds (Table 4). The results showed that the association between rs2838566 and platinum-induced hepatotoxicity was significant in every stratum except among female-only populations. However, we didn’t observe any significant heterogeneity between each two stratums (P > 0.05) in (Table 4). The results for other 10 selected SNPs in replication phase and pooled population were shown in Supplementary Table S1 and Supplementary Table S2.

Bottom Line: To identify SNPs that modify the risk of hepatotoxicity in NSCLC patients receiving platinum-based chemotherapy, we performed a genome-wide association scan in 334 subjects followed by a replication study among 375 subjects.Consistent associations with platinum-induced hepatotoxicity risk was identified for SNP rs2838566 located at 21q22.3, as the minor A allele could significantly increase the risk of liver injury (OR = 3.78, 95%CI = 1.99-7.19, P = 4.90 × 10(-5) for GWAS scan, OR = 1.89, 95%CI = 1.03-3.46, P = 0.039 for replication, and OR = 2.56, 95%CI = 1.65-3.95, P = 2.55 × 10(-5) for pooled population).These results suggested that genetic variants at 21q22.3 may contribute to the susceptibility of platinum-induced hepatotoxicity in NSCLC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.

ABSTRACT
Platinum-based chemotherapy has been shown to improve the survival of advanced non-small cell lung cancer (NSCLC) patients; the platinum-induced toxicity severely impedes the success of chemotherapy. Genetic variations, such as single nucleotide polymorphisms (SNPs), may contribute to patients' responses to the platinum-based chemotherapy. To identify SNPs that modify the risk of hepatotoxicity in NSCLC patients receiving platinum-based chemotherapy, we performed a genome-wide association scan in 334 subjects followed by a replication study among 375 subjects. Consistent associations with platinum-induced hepatotoxicity risk was identified for SNP rs2838566 located at 21q22.3, as the minor A allele could significantly increase the risk of liver injury (OR = 3.78, 95%CI = 1.99-7.19, P = 4.90 × 10(-5) for GWAS scan, OR = 1.89, 95%CI = 1.03-3.46, P = 0.039 for replication, and OR = 2.56, 95%CI = 1.65-3.95, P = 2.55 × 10(-5) for pooled population). These results suggested that genetic variants at 21q22.3 may contribute to the susceptibility of platinum-induced hepatotoxicity in NSCLC patients.

No MeSH data available.


Related in: MedlinePlus