Dataset Information

Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma.

ABSTRACT: 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.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.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.Our results suggest that SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival.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.

SUBMITTER: Zhang W

PROVIDER: S-EPMC4573541 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma.

Zhang Weikang W Liu Hongliang H Liu Zhensheng Z Zhu Dakai D Amos Christopher I CI Fang Shenying S Lee Jeffrey E JE Wei Qingyi Q

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20150507 7

<h4>Background</h4>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.<h4>Methods</h4>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 stepw ...[more]

PMID: 25953768

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Project description:BackgroundFolate metabolism plays an important role in DNA methylation and nucleic acid synthesis and thus may function as a regulatory factor in cancer development. Genome-wide association studies (GWASs) have identified some single-nucleotide polymorphisms (SNPs) associated with cutaneous melanoma-specific survival (CMSS), but no SNPs were found in genes involved in the folate metabolic pathway.ObjectivesTo examine associations between SNPs in folate metabolic pathway genes and CMSS.MethodsWe comprehensively evaluated 2645 (422 genotyped and 2223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas MD Anderson Cancer Center and performed the validation in another GWAS of 409 patients from the Nurses' Health Study and Health Professionals Follow-up Study, in which 95/858 (11·1%) and 48/409 (11·7%) patients died of cutaneous melanoma, respectively.ResultsWe identified two independent SNPs (MTHFD1 rs1950902 G>A and ALPL rs10917006 C>T) to be associated with CMSS in both datasets, and their meta-analysis yielded an allelic hazards ratio of 1·75 (95% confidence interval 1·32-2·32, P = 9·96 × 10-5 ) and 2·05 (1·39-3·01, P = 2·84 × 10-4 ), respectively. The genotype-phenotype correlation analyses provided additional support for the biological plausibility of these two variants' roles in tumour progression, suggesting that variation in SNP-related mRNA expression levels is likely to be the mechanism underlying the observed associations with CMSS.ConclusionsTwo possibly functional genetic variants, MTHFD1 rs1950902 and ALPL rs10917006, were likely to be independently or jointly associated with CMSS, which may add to personalized treatment in the future, once further validated. What is already known about this topic? Existing data show that survival rates vary among patients with melanoma with similar clinical characteristics; therefore, it is necessary to identify additional complementary biomarkers for melanoma-specific prognosis. A hypothesis-driven approach, by pooling the effects of single-nucleotide polymorphisms (SNPs) in a specific biological pathway as genetic risk scores, may provide a prognostic utility, and genetic variants of genes in folate metabolism have been reported to be associated with cancer risk. What does this study add? Two genetic variants in the folate metabolic pathway genes, MTHFD1 rs1950902 and ALPL rs10917006, are significantly associated with cutaneous melanoma-specific survival (CMSS). What is the translational message? The identification of genetic variants will make a risk-prediction model possible for CMSS. The SNPs in the folate metabolic pathway genes, once validated in larger studies, may be useful in the personalized management and treatment of patients with cutaneous melanoma.

Dataset Information

Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma.

Publications

Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma.

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