Genetic variants in TKT and DERA in the nicotinamide adenine dinucleotide phosphate pathway predict melanoma survival.

Gu, Ning

Dai, Wei

Liu, Hongliang

Ge, Jie

Luo, Sheng

Cho, Eunyoung

Amos, Christopher I

Lee, Jeffrey E

Li, Xin

Nan, Hongmei

Yuan, Hua

Wei, Qingyi

2020-08-01T15:03:42Z

2020-08-01T15:03:42Z

2020-07-09

2020-08-01T15:03:41Z

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.

S0959-8049(20)30283-5

1879-0852

1879-0852

https://hdl.handle.net/10161/21217

eng

Elsevier BV

European journal of cancer (Oxford, England : 1990)

10.1016/j.ejca.2020.04.049

Cutaneous melanoma

Genome-wide association study

Melanoma-specific survival

Nicotinamide adenine dinucleotide phosphate

Single-nucleotide polymorphism

Genetic variants in TKT and DERA in the nicotinamide adenine dinucleotide phosphate pathway predict melanoma survival.

Journal article

Luo, Sheng|0000-0003-4214-5809

Wei, Qingyi|0000-0002-3845-9445|0000-0003-4115-4439

84

94

School of Medicine

Duke Cancer Institute

Population Health Sciences

Medicine, Medical Oncology

Duke

Institutes and Centers

Basic Science Departments

Medicine

Clinical Science Departments

Duke Clinical Research Institute

Biostatistics & Bioinformatics

Published

136