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Mol Carcinog. 2018 Jan;57(1):22-31. doi: 10.1002/mc.22716. Epub 2017 Aug 28.

Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival.

Xu Y1,2,3, Wang Y1,2, Liu H1,2, Shi Q4, Zhu D5, Amos CI5, Fang S6, Lee JE6, Hyslop T1,7, Li X8, Han J9, Wei Q1,2,10.

Author information

1
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China.
2
Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
3
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
4
Department of Dermatology, Xijing Hospital, Xi'an, Shanxi, China.
5
Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
6
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
7
Department of Biostatistics and Bioinformatics, Duke University and Duke Clinical Research Institute, Durham, North Carolina.
8
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
9
Department of Epidemiology, Fairbanks School of Public Health, and Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana.
10
Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina.

Abstract

Metzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM-specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC) which included 858 non-Hispanic white patients with CM, and then validated using the dataset from the Harvard GWAS study which had 409 non-Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C>A, ADAMTS3 rs788935 T>C, TLL2 rs10882807 T>C and MMP9 rs3918251 A>G) were identified as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) of 1.73 (1.32-2.29, 9.68E-05), 1.46 (1.15-1.85, 0.002), 1.68 (1.31-2.14, 3.32E-05) and 0.67 (0.51-0.87, 0.003), respectively, in the meta-analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (Ptrend  < 0.001). An improvement was observed in the prediction model (area under the curve [AUC] = 81.4% vs. 78.6%), when these risk genotypes were added to the model containing non-genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS.

KEYWORDS:

cutaneous melanoma; cutaneous melanoma-specific survival (CMSS); genome-wide association study (GWAS); metzincins; single-nucleotide polymorphism (SNP)

PMID:
28796414
PMCID:
PMC5716892
DOI:
10.1002/mc.22716
[Indexed for MEDLINE]
Free PMC Article

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