Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma.
Abstract
BACKGROUND: The Notch signaling pathway is constitutively activated in human cutaneous
melanoma to promote growth and aggressive metastatic potential of primary melanoma
cells. Therefore, genetic variants in Notch pathway genes may affect the prognosis
of cutaneous melanoma patients. METHODS: We identified 6,256 SNPs in 48 Notch genes
in 858 cutaneous melanoma patients included in a previously published cutaneous melanoma
genome-wide association study dataset. Multivariate and stepwise Cox proportional
hazards regression and false-positive report probability corrections were performed
to evaluate associations between putative functional SNPs and cutaneous melanoma disease-specific
survival. Receiver operating characteristic curve was constructed, and area under
the curve was used to assess the classification performance of the model. RESULTS:
Four putative functional SNPs of Notch pathway genes had independent and joint predictive
roles in survival of cutaneous melanoma patients. The most significant variant was
NCOR2 rs2342924 T>C (adjusted HR, 2.71; 95% confidence interval, 1.73-4.23; Ptrend
= 9.62 × 10(-7)), followed by NCSTN rs1124379 G>A, NCOR2 rs10846684 G>A, and MAML2
rs7953425 G>A (Ptrend = 0.005, 0.005, and 0.013, respectively). The receiver operating
characteristic analysis revealed that area under the curve was significantly increased
after adding the combined unfavorable genotype score to the model containing the known
clinicopathologic factors. CONCLUSIONS: Our results suggest that SNPs in Notch pathway
genes may be predictors of cutaneous melanoma disease-specific survival. IMPACT: Our
discovery offers a translational potential for using genetic variants in Notch pathway
genes as a genotype score of biomarkers for developing an improved prognostic assessment
and personalized management of cutaneous melanoma patients.
Type
Journal articleSubject
AdolescentAdult
Aged
Aged, 80 and over
Amyloid Precursor Protein Secretases
DNA, Neoplasm
DNA-Binding Proteins
Female
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Male
Melanoma
Membrane Glycoproteins
Middle Aged
Nuclear Proteins
Nuclear Receptor Co-Repressor 2
Polymorphism, Genetic
Prognosis
Survival Rate
Texas
Transcription Factors
Young Adult
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https://hdl.handle.net/10161/10668Published Version (Please cite this version)
10.1158/1055-9965.EPI-14-1380-TPublication Info
Zhang, Weikang; Liu, Hongliang; Liu, Zhensheng; Zhu, Dakai; Amos, Christopher I; Fang,
Shenying; ... Wei, Qingyi (2015). Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival
of Patients with Cutaneous Melanoma. Cancer Epidemiol Biomarkers Prev, 24(7). pp. 1101-1110. 10.1158/1055-9965.EPI-14-1380-T. Retrieved from https://hdl.handle.net/10161/10668.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Zhensheng Liu
Assistant Professor of Medicine
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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