TY - JOUR
T1 - Genetic variants in TKT and DERA in the nicotinamide adenine dinucleotide phosphate pathway predict melanoma survival
AU - Gu, Ning
AU - Dai, Wei
AU - Liu, Hongliang
AU - Ge, Jie
AU - Luo, Sheng
AU - Cho, Eunyoung
AU - Amos, Christopher I.
AU - Lee, Jeffrey E.
AU - Li, Xin
AU - Nan, Hongmei
AU - Yuan, Hua
AU - Wei, Qingyi
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/9
Y1 - 2020/9
N2 - Background: Cutaneous melanoma (CM) is the most lethal type of skin cancers. Nicotinamide adenine dinucleotide phosphate (NADPH) plays an important role in anabolic reactions and tumorigenesis, but many genes are involved in the NADPH system. Methods: We used 10,912 single-nucleotide polymorphisms (SNPs) (2018 genotyped and 8894 imputed) in 134 NADPH-related genes from a genome-wide association study (GWAS) of 858 patients from The University of Texas MD Anderson Cancer Center (MDACC) in a single-locus analysis to predict CM survival. We then replicated the results in another GWAS data set of 409 patients from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Results: There were 95 of 858 (11.1%) and 48 of 409 (11.7%) patients who died of CM, respectively. In multivariable Cox regression analyses, we identified two independent SNPs (TKT rs9864057 G > A and deoxyribose phosphate aldolase (DERA) rs12297652 A > G) to be significantly associated with CM-specific survival [hazards ratio (HR) of 1.52, 95% confidence interval (CI) = 1.18–1.96, P = 1.06 × 10−3 and 1.51 (1.19–1.91, 5.89 × 10−4)] in the meta-analysis, respectively. Furthermore, an increasing number of risk genotypes of these two SNPs was associated with a higher risk of death in the MDACC, the NHS/HPFS, and their combined data sets (Ptrend<0.001, = 0.004 and <0.001, respectively). In the expression quantitative trait loci analysis, TKT rs9864057 G > A and DERA rs12297652 A > G were also significantly associated with higher mRNA expression levels in sun-exposed lower-leg skin (P = 0.043 and 0.006, respectively). Conclusions: These results suggest that these two potentially functional SNPs may be valuable prognostic biomarkers for CM survival, but larger studies are needed to validate these findings.
AB - Background: Cutaneous melanoma (CM) is the most lethal type of skin cancers. Nicotinamide adenine dinucleotide phosphate (NADPH) plays an important role in anabolic reactions and tumorigenesis, but many genes are involved in the NADPH system. Methods: We used 10,912 single-nucleotide polymorphisms (SNPs) (2018 genotyped and 8894 imputed) in 134 NADPH-related genes from a genome-wide association study (GWAS) of 858 patients from The University of Texas MD Anderson Cancer Center (MDACC) in a single-locus analysis to predict CM survival. We then replicated the results in another GWAS data set of 409 patients from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Results: There were 95 of 858 (11.1%) and 48 of 409 (11.7%) patients who died of CM, respectively. In multivariable Cox regression analyses, we identified two independent SNPs (TKT rs9864057 G > A and deoxyribose phosphate aldolase (DERA) rs12297652 A > G) to be significantly associated with CM-specific survival [hazards ratio (HR) of 1.52, 95% confidence interval (CI) = 1.18–1.96, P = 1.06 × 10−3 and 1.51 (1.19–1.91, 5.89 × 10−4)] in the meta-analysis, respectively. Furthermore, an increasing number of risk genotypes of these two SNPs was associated with a higher risk of death in the MDACC, the NHS/HPFS, and their combined data sets (Ptrend<0.001, = 0.004 and <0.001, respectively). In the expression quantitative trait loci analysis, TKT rs9864057 G > A and DERA rs12297652 A > G were also significantly associated with higher mRNA expression levels in sun-exposed lower-leg skin (P = 0.043 and 0.006, respectively). Conclusions: These results suggest that these two potentially functional SNPs may be valuable prognostic biomarkers for CM survival, but larger studies are needed to validate these findings.
KW - Cutaneous melanoma
KW - Genome-wide association study
KW - Melanoma-specific survival
KW - Nicotinamide adenine dinucleotide phosphate
KW - Single-nucleotide polymorphism
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U2 - 10.1016/j.ejca.2020.04.049
DO - 10.1016/j.ejca.2020.04.049
M3 - Article
C2 - 32659474
AN - SCOPUS:85087739886
SN - 0959-8049
VL - 136
SP - 84
EP - 94
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -