title: Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival.
abstract: To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re-analyzing a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated significant SNPs in another GWAS from Harvard University. In the MDACC study, 1,148 SNPs were significantly associated with CM-specific survival (CMSS) (p ≤ 0.050 and false-positive report probability ≤ 0.20), and nine SNPs were validated in the Harvard study (p ≤ 0.050). Among these, three independent SNPs (i.e., DOCK1 rs11018104 T > A, rs35748949 C > T and PAK2 rs1718404 C > T) showed a predictive role in CMSS, with an effect-allele attributed adjusted hazards ratio [adjHR of 1.50 (95% confidence interval (CI) = 1.18-1.90, p = 7.46E-04), 1.53 (1.18-1.97, 1.18E-03) and 0.58 (0.45-0.76, 5.60E-05), respectively]. Haplotype analysis revealed that a haplotype carrying two risk alleles A-T in DOCK1 was associated with the poorest survival in both MDACC (adjHR = 1.73, 95% CI = 1.19-2.50, p = 0.004) and Harvard (adjHR = 1.95, 95% CI = 1.14-3.33, p = 0.010) studies. In addition, patients with an increasing number of unfavorable genotypes (NUGs) for these three SNPs had a poorer survival. Incorporating NUGs with clinical variables showed a significantly improved ability to classify CMSS (AUC increased from 86.8% to 88.6%, p = 0.031). Genetic variants in the integrin signaling pathway may independently or jointly modulate the survival of CM patients. Further large, prospective studies are needed to validate these findings.
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.|Department of Gastroenterology, Shenyang Northern Hospital, Shenyang, Liaoning, 110840, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.
authors.forename: Hongliang
authors.identifier: 0000-0001-7639-0904
authors.initials: H
authors.lastname: Liu
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.|Department of Dermatology, Xijing Hospital, Xi'an, Shanxi, 710032, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.|Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Epidemiology, Fairbanks School of Public Health, Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN.
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.affiliation: Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH.
authors.forename: Dakai
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH.
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, TX.
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, TX.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Epidemiology, Fairbanks School of Public Health, Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
authors.forename: Jiali
authors.initials: J
authors.lastname: Han
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.|Department of Medicine, Duke University School of Medicine, Durham, NC.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000502:physiology*; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality; D055815:Young Adult; D054462:p21-Activated Kinases / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000235:genetics
chemical_list: C099818:DOCK1 protein, human; D016023:Integrins; D009363:Neoplasm Proteins; C515907:PAK2 protein, human; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins
keywords: cutaneous melanoma; cutaneous melanoma-specific survival; genome-wide association study; integrin signaling pathway; single-nucleotide polymorphism