Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival

Hongyu Li, Yanru Wang, Hongliang Liu, Qiong Shi, Yinghui Xu, Wenting Wu, Dakai Zhu, Christopher I. Amos, Shenying Fang, Jeffrey E. Lee, Jiali Han, Qingyi Wei

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1270-1279
Number of pages10
JournalInternational Journal of Cancer
Volume140
Issue number6
DOIs
StatePublished - Mar 15 2017

Fingerprint

Integrins
Melanoma
Single Nucleotide Polymorphism
Skin
Survival
Genes
Genome-Wide Association Study
Confidence Intervals
Haplotypes
Alleles
Genotype
Neoplasms
Area Under Curve
Prospective Studies

Keywords

  • cutaneous melanoma
  • cutaneous melanoma-specific survival
  • genome-wide association study
  • integrin signaling pathway
  • single-nucleotide polymorphism

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival. / Li, Hongyu; Wang, Yanru; Liu, Hongliang; Shi, Qiong; Xu, Yinghui; Wu, Wenting; Zhu, Dakai; Amos, Christopher I.; Fang, Shenying; Lee, Jeffrey E.; Han, Jiali; Wei, Qingyi.

In: International Journal of Cancer, Vol. 140, No. 6, 15.03.2017, p. 1270-1279.

Research output: Contribution to journalArticle

Li, H, Wang, Y, Liu, H, Shi, Q, Xu, Y, Wu, W, Zhu, D, Amos, CI, Fang, S, Lee, JE, Han, J & Wei, Q 2017, 'Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival', International Journal of Cancer, vol. 140, no. 6, pp. 1270-1279. https://doi.org/10.1002/ijc.30545
Li, Hongyu ; Wang, Yanru ; Liu, Hongliang ; Shi, Qiong ; Xu, Yinghui ; Wu, Wenting ; Zhu, Dakai ; Amos, Christopher I. ; Fang, Shenying ; Lee, Jeffrey E. ; Han, Jiali ; Wei, Qingyi. / Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival. In: International Journal of Cancer. 2017 ; Vol. 140, No. 6. pp. 1270-1279.
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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.",
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author = "Hongyu Li and Yanru Wang and Hongliang Liu and Qiong Shi and Yinghui Xu and Wenting Wu and Dakai Zhu and Amos, {Christopher I.} and Shenying Fang and Lee, {Jeffrey E.} and Jiali Han and Qingyi Wei",
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AU - Wang, Yanru

AU - Liu, Hongliang

AU - Shi, Qiong

AU - Xu, Yinghui

AU - Wu, Wenting

AU - Zhu, Dakai

AU - Amos, Christopher I.

AU - Fang, Shenying

AU - Lee, Jeffrey E.

AU - Han, Jiali

AU - Wei, Qingyi

PY - 2017/3/15

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N2 - 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.

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