W Dai1,2,3,4, H Liu2,3, Y Liu2,3, X Xu2,3, D Qian2,3, S Luo5, E Cho6,7,8, D Zhu9, C I Amos9, S Fang10, J E Lee10, X Li8,11, H Nan8,11, C Li4, Q Wei2,3,12. 1. Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. 2. Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA. 3. Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA. 4. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. 5. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27710, USA. 6. Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, RI, 02912, USA. 7. Department of Epidemiology, Brown University School of Public Health, Providence, RI, 02912, USA. 8. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA. 9. Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA. 10. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA. 11. Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, IN, 46202, USA. 12. Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710, USA.
Abstract
BACKGROUND: Folate metabolism plays an important role in DNA methylation and nucleic acid synthesis and thus may function as a regulatory factor in cancer development. Genome-wide association studies (GWASs) have identified some single-nucleotide polymorphisms (SNPs) associated with cutaneous melanoma-specific survival (CMSS), but no SNPs were found in genes involved in the folate metabolic pathway. OBJECTIVES: To examine associations between SNPs in folate metabolic pathway genes and CMSS. METHODS: We comprehensively evaluated 2645 (422 genotyped and 2223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas MD Anderson Cancer Center and performed the validation in another GWAS of 409 patients from the Nurses' Health Study and Health Professionals Follow-up Study, in which 95/858 (11·1%) and 48/409 (11·7%) patients died of cutaneous melanoma, respectively. RESULTS: We identified two independent SNPs (MTHFD1 rs1950902 G>A and ALPL rs10917006 C>T) to be associated with CMSS in both datasets, and their meta-analysis yielded an allelic hazards ratio of 1·75 (95% confidence interval 1·32-2·32, P = 9·96 × 10-5 ) and 2·05 (1·39-3·01, P = 2·84 × 10-4 ), respectively. The genotype-phenotype correlation analyses provided additional support for the biological plausibility of these two variants' roles in tumour progression, suggesting that variation in SNP-related mRNA expression levels is likely to be the mechanism underlying the observed associations with CMSS. CONCLUSIONS: Two possibly functional genetic variants, MTHFD1 rs1950902 and ALPL rs10917006, were likely to be independently or jointly associated with CMSS, which may add to personalized treatment in the future, once further validated. What is already known about this topic? Existing data show that survival rates vary among patients with melanoma with similar clinical characteristics; therefore, it is necessary to identify additional complementary biomarkers for melanoma-specific prognosis. A hypothesis-driven approach, by pooling the effects of single-nucleotide polymorphisms (SNPs) in a specific biological pathway as genetic risk scores, may provide a prognostic utility, and genetic variants of genes in folate metabolism have been reported to be associated with cancer risk. What does this study add? Two genetic variants in the folate metabolic pathway genes, MTHFD1 rs1950902 and ALPL rs10917006, are significantly associated with cutaneous melanoma-specific survival (CMSS). What is the translational message? The identification of genetic variants will make a risk-prediction model possible for CMSS. The SNPs in the folate metabolic pathway genes, once validated in larger studies, may be useful in the personalized management and treatment of patients with cutaneous melanoma.
BACKGROUND:Folate metabolism plays an important role in DNA methylation and nucleic acid synthesis and thus may function as a regulatory factor in cancer development. Genome-wide association studies (GWASs) have identified some single-nucleotide polymorphisms (SNPs) associated with cutaneous melanoma-specific survival (CMSS), but no SNPs were found in genes involved in the folate metabolic pathway. OBJECTIVES: To examine associations between SNPs in folate metabolic pathway genes and CMSS. METHODS: We comprehensively evaluated 2645 (422 genotyped and 2223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas MD Anderson Cancer Center and performed the validation in another GWAS of 409 patients from the Nurses' Health Study and Health Professionals Follow-up Study, in which 95/858 (11·1%) and 48/409 (11·7%) patients died of cutaneous melanoma, respectively. RESULTS: We identified two independent SNPs (MTHFD1rs1950902 G>A and ALPLrs10917006 C>T) to be associated with CMSS in both datasets, and their meta-analysis yielded an allelic hazards ratio of 1·75 (95% confidence interval 1·32-2·32, P = 9·96 × 10-5 ) and 2·05 (1·39-3·01, P = 2·84 × 10-4 ), respectively. The genotype-phenotype correlation analyses provided additional support for the biological plausibility of these two variants' roles in tumour progression, suggesting that variation in SNP-related mRNA expression levels is likely to be the mechanism underlying the observed associations with CMSS. CONCLUSIONS: Two possibly functional genetic variants, MTHFD1rs1950902 and ALPLrs10917006, were likely to be independently or jointly associated with CMSS, which may add to personalized treatment in the future, once further validated. What is already known about this topic? Existing data show that survival rates vary among patients with melanoma with similar clinical characteristics; therefore, it is necessary to identify additional complementary biomarkers for melanoma-specific prognosis. A hypothesis-driven approach, by pooling the effects of single-nucleotide polymorphisms (SNPs) in a specific biological pathway as genetic risk scores, may provide a prognostic utility, and genetic variants of genes in folate metabolism have been reported to be associated with cancer risk. What does this study add? Two genetic variants in the folate metabolic pathway genes, MTHFD1rs1950902 and ALPLrs10917006, are significantly associated with cutaneous melanoma-specific survival (CMSS). What is the translational message? The identification of genetic variants will make a risk-prediction model possible for CMSS. The SNPs in the folate metabolic pathway genes, once validated in larger studies, may be useful in the personalized management and treatment of patients with cutaneous melanoma.
Authors: Victoria L Stevens; Marjorie L McCullough; Alexandre L Pavluck; Jeffrey T Talbot; Heather S Feigelson; Michael J Thun; Eugenia E Calle Journal: Cancer Epidemiol Biomarkers Prev Date: 2007-06 Impact factor: 4.254
Authors: S R Rao; A E Snaith; D Marino; X Cheng; S T Lwin; I R Orriss; F C Hamdy; C M Edwards Journal: Br J Cancer Date: 2016-12-22 Impact factor: 7.640
Authors: Stein Emil Vollset; Robert Clarke; Sarah Lewington; Marta Ebbing; Jim Halsey; Eva Lonn; Jane Armitage; JoAnn E Manson; Graeme J Hankey; J David Spence; Pilar Galan; Kaare H Bønaa; Rex Jamison; J Michael Gaziano; Peter Guarino; John A Baron; Richard F A Logan; Edward L Giovannucci; Martin den Heijer; Per M Ueland; Derrick Bennett; Rory Collins; Richard Peto Journal: Lancet Date: 2013-03-23 Impact factor: 79.321