Ning Gu1, Wei Dai2, Hongliang Liu3, Jie Ge3, Sheng Luo4, Eunyoung Cho5, Christopher I Amos6, Jeffrey E Lee7, Xin Li8, Hongmei Nan8, Hua Yuan9, Qingyi Wei10. 1. Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA; Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710, USA. 2. Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA; Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710, USA; Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. 3. Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA; Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710, USA. 4. Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27710, USA. 5. Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, RI, 02912, USA; Department of Epidemiology, Brown University School of Public Health, Providence, RI, 02912, USA. 6. Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA. 7. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA. 8. Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, IN, 46202, USA. 9. Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210029, China. Electronic address: yuanhua@njmu.edu.cn. 10. Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA; Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA. Electronic address: qingyi.wei@duke.edu.
Abstract
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.
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 (TKTrs9864057 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, TKTrs9864057 G > A and DERArs12297652 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.