title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Duke University School of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Weikang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Duke University School of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicine, Duke University School of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Zhensheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
authors.forename: Dakai
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Shenying
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Medicine, Duke University School of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina. qingyi.wei@duke.edu.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011379:Prognosis; D012878:Skin Neoplasms; D015996:Survival Rate / Q000639:trends; D013781:Texas / Q000453:epidemiology; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C471297:MAML2 protein, human; D008562:Membrane Glycoproteins; C539130:NCOR2 protein, human; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; D015534:Trans-Activators; D014157:Transcription Factors; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases