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Int J Cancer. 2019 Nov 15;145(10):2619-2628. doi: 10.1002/ijc.32194. Epub 2019 Feb 20.

Genetic variants in ELOVL2 and HSD17B12 predict melanoma-specific survival.

Dai W1,2,3, Liu H2,3, Xu X2,3, Ge J2,3, Luo S4, Zhu D5, Amos CI5, Fang S6, Lee JE6, Li X7,8, Nan H7,8, Li C1, Wei Q2,3,9.

Author information

1
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
2
Duke Cancer Institute, Duke University Medical Center, Durham, NC.
3
Department of Population Health Sciences, Duke University School of Medicine, Durham, NC.
4
Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC.
5
Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX.
6
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
7
Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, IN.
8
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
9
Department of Medicine, Duke University School of Medicine, Durham, NC.

Abstract

Fatty acids play a key role in cellular bioenergetics, membrane biosynthesis and intracellular signaling processes and thus may be involved in cancer development and progression. In the present study, we comprehensively assessed associations of 14,522 common single-nucleotide polymorphisms (SNPs) in 149 genes of the fatty-acid synthesis pathway with cutaneous melanoma disease-specific survival (CMSS). The dataset of 858 cutaneous melanoma (CM) patients from a published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used as the discovery dataset, and the identified significant SNPs were validated by a dataset of 409 CM patients from another GWAS from the Nurses' Health and Health Professionals Follow-up Studies. We found 40 noteworthy SNPs to be associated with CMSS in both discovery and validation datasets after multiple comparison correction by the false positive report probability method, because more than 85% of the SNPs were imputed. By performing functional prediction, linkage disequilibrium analysis, and stepwise Cox regression selection, we identified two independent SNPs of ELOVL2 rs3734398 T>C and HSD17B12 rs11037684 A>G that predicted CMSS, with an allelic hazards ratio of 0.66 (95% confidence interval = 0.51-0.84 and p = 8.34 × 10-4 ) and 2.29 (1.55-3.39 and p = 3.61 × 10-5 ), respectively. Finally, the ELOVL2 rs3734398 variant CC genotype was found to be associated with a significantly increased mRNA expression level. These SNPs may be potential markers for CM prognosis, if validated by additional larger and mechanistic studies.

KEYWORDS:

cutaneous melanoma; fatty acid synthesis; genome-wide association study; melanoma-specific survival; single-nucleotide polymorphism

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