Novel genetic variants of PIP5K1C and MVB12B of the endosome-related pathway predict cutaneous melanoma-specific survival.
Abstract
Endosomes 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.
Type
Journal articleSubject
Genome-wide association studycutaneous melanoma-specific survival
endosome pathway
immunity
single-nucleotide polymorphism
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https://hdl.handle.net/10161/21771Collections
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Show full item recordScholars@Duke
Sheng Luo
Professor of Biostatistics & Bioinformatics
Qingyi Wei
Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director
for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology
and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally
recognized epidemiologist focused on the molecular and genetic epidemiology of head
and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and
genetic determinants for the DNA repair deficient phenotype and
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