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

Xu, Yinghui

Wang, Yanru

Liu, Hongliang

Shi, Qiong

Zhu, Dakai

Amos, Christopher I

Fang, Shenying

Lee, Jeffrey E

Hyslop, Terry

Li, Xin

Han, Jiali

Wei, Qingyi

2019-05-01T18:36:46Z

2019-05-01T18:36:46Z

2018-01

2019-05-01T18:36:46Z

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.

0899-1987

1098-2744

https://hdl.handle.net/10161/18518

eng

Wiley

Molecular carcinogenesis

10.1002/mc.22716

Humans

Melanoma

Skin Neoplasms

Procollagen N-Endopeptidase

Prognosis

Proportional Hazards Models

Gene Frequency

Genotype

Polymorphism, Single Nucleotide

Middle Aged

Female

Male

Matrix Metalloproteinase 9

Matrix Metalloproteinase 16

Genome-Wide Association Study

Tolloid-Like Metalloproteinases

Kaplan-Meier Estimate

ADAMTS Proteins

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

Journal article

Wei, Qingyi|0000-0002-3845-9445|0000-0003-4115-4439

22

31

1

School of Medicine

Duke

Duke Cancer Institute

Institutes and Centers

Biostatistics & Bioinformatics

Basic Science Departments

Population Health Sciences

Medicine, Medical Oncology

Medicine

Clinical Science Departments

Published

57