Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma‐specific survival |
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| Authors: | William Xue Hongliang Liu Yinghui Xu Qiong Shi Wenting Wu Dakai Zhu Christopher I Amos Shenying Fang Jeffrey E Lee Terry Hyslop Yi Li Jiali Han Qingyi Wei |
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| Institution: | 1. Duke Cancer Institute, Duke University Medical Center, Durham, NC;2. Department of Medicine, Duke University School of Medicine, Durham, NC;3. Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China;4. Department of Dermatology, Xijing Hospital, Xi'an, Shanxi, China;5. Department of Epidemiology, Fairbanks School of Public Health, and Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN;6. Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH;7. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX;8. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC;9. Department of Biostatistics, University of Michigan, Ann Arbor, MI;10. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA;11. Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China |
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| Abstract: | Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases‐related genes and cutaneous melanoma‐specific survival (CMSS) by re‐analyzing a published melanoma genome‐wide association study (GWAS) and validating the results in another melanoma GWAS. In the single‐locus analysis of 36,018 SNPs in 129 Rho‐related genes, 427 SNPs were significantly associated with CMSS (p < 0.050 and false‐positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e ., RHOU rs10916352 G > C, ARHGAP22 rs3851552 T > C, ARHGAP44 rs72635537 C > T and ARHGEF10 rs7826362 A > T) were independently predictive of CMSS (a meta‐analysis derived p = 9.04 × 10?4, 9.58 × 10?4, 1.21 × 10?4 and 8.47 × 10?4, respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (p trend=1.47 × 10?7 and 3.12 × 10?5). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five‐year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (p = 1.8 × 10?6) and ARHGAP22 (p = 5.0 × 10?6), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment. |
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| Keywords: | genome‐wide association study Rho GTPase GTPase‐activating protein cutaneous melanoma‐specific survival |
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