title: Genetic variants in Hippo pathway genes YAP1, TEAD1 and TEAD4 are associated with melanoma-specific survival.
abstract: Cutaneous melanoma (CM) is the most lethal form of skin cancers. The Hippo pathway controls cell migration, development and sizes of the organs in diverse species, and deregulation of this pathway may affect CM progression and prognosis. Therefore, we hypothesized that genetic variants of Hippo pathway genes might predict survival of CM patients. We used the genotyping data of 1,115 common single nucleotide polymorphisms (SNPs) in the 12 pathway core genes (i.e., MST1, MST2, SAV1, LATS1, LATS2, MOB1A, MOB1B, YAP1, TEAD1, TEAD2, TEAD3 and TEAD4) from the dataset of our previously published CM genome-wide association study and comprehensively analyzed their associations with CM-specific survival (CSS) in 858 CM patients by using the Kaplan-Meier analyses and Cox proportional hazards regression models. We found a predictive role of YAP1 rs11225163 CC, TEAD1 rs7944031 AG+GG and TEAD4 rs1990330 CA+AA in the prognosis of CM. In addition, patients with an increasing number of unfavorable genotypes (NUG) had a markedly increased risk of death. After incorporating NUG in the model with clinical variables, the new model showed a significantly improved discriminatory ability to classify CSS (AUC increased from 82.03% to 84.56%). Our findings suggest that genetic variants of Hippo pathway genes, particularly YAP1 rs11225163, TEAD1 rs7944031 and TEAD4 rs1990330, may independently or jointly modulate survival of CM patients. Additional large, prospective studies are needed to validate these findings.
authors: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.|Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors: Hua
authors: H
authors: Yuan
authors: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.
authors: Hongliang
authors: H
authors: Liu
authors: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.
authors: Zhensheng
authors: Z
authors: Liu
authors: Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH.
authors: Dakai
authors: D
authors: Zhu
authors: Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH.
authors: Christopher I
authors: CI
authors: Amos
authors: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors: Shenying
authors: S
authors: Fang
authors: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors: Jeffrey E
authors: JE
authors: Lee
authors: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.
authors: Qingyi
authors: Q
authors: Wei
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D000090683:Hippo Signaling Pathway; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012372:ROC Curve; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D000091102:YAP-Signaling Proteins; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; C486309:TEAD4 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Cox regression; Hippo pathway; cancer specific survival; cutaneous melanoma; single nucleotide polymorphisms
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