Lu, GuiqingZhou, BingrongHe, YuanminLiu, HongliangLuo, ShengAmos, Christopher I.Lee, Jeffrey E.Yang, KemingQureshi, AbrarHan, JialiWei, Qingyi2022-01-102022-01-102020-10Lu, G., Zhou, B., He, Y., Liu, H., Luo, S., Amos, C. I., Lee, J. E., Yang, K., Qureshi, A., Han, J., & Wei, Q. (2020). Novel genetic variants of PIP5K1C and MVB12B of the endosome-related pathway predict cutaneous melanoma-specific survival. American Journal of Cancer Research, 10(10), 3382–3394.2156-6976https://hdl.handle.net/1805/27333Endosomes regulate cell polarity, adhesion, signaling, immunity, and tumor progression, which may influence cancer outcomes. Here we evaluated associations between 36,068 genetic variants of 228 endosome-related pathway genes and cutaneous melanoma disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). In multivariate Cox proportional hazards regression analysis, we found that two novel SNPs (PIP5K1C rs11666894 A>C and MVB12B rs12376285 C>T) predicted CMSS, with adjusted hazards ratios of 1.47 (95% confidence interval = 1.15-1.89 and P = 0.002) and 1.73 (1.30-2.31 and 0.0002), respectively. Combined analysis of risk genotypes of these two SNPs revealed a dose-dependent decrease in CMSS associated with an increased number of risk genotypes (P trend = 0.0002). Subsequent expression quantitative trait loci (eQTL) analysis revealed that PIP5K1C rs11666894 was associated with mRNA expression levels in lymphoblastoid cell lines from 373 European descendants (P<0.0001) and that MVB12B rs12376285 was associated with mRNA expression levels in cultured fibroblasts from 605 European-Americans (P<0.0001). Our findings suggest that novel genetic variants of PIP5K1C and MVB12B in the endosome-related pathway genes may be promising prognostic biomarkers for CMSS, but these results need to be validated in future larger studies.en-USAttribution-NonCommercial 4.0 InternationalGenome-wide association studysingle-nucleotide polymorphismendosome pathwaycutaneous melanoma-specific survivalimmunityArticle