Clinicopathologic Significance of VHL Gene Alteration in Clear-Cell Renal Cell Carcinoma: An Updated Meta-Analysis and Review
Abstract
:1. Introduction
2. Results
2.1. Results of Search
2.2. Characteristics of the Included Studies
2.3. Impact of VHL Gene Alteration on Pathological Features
2.4. Impact of VHL Variations on Overall Survival
2.5. Publication Bias
3. Discussion
4. Materials and Methods
4.1. Searching Strategy
4.2. Inclusion Criteria
4.3. Data Extraction
4.4. Statistical Analyses
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ccRCC | clear-cell renal cell carcinoma |
CI | confidence interval |
DSS | disease-specific survival |
HR | hazard ratio |
LOF | loss of function |
LOH | loss of heterozygosity |
NG | nuclear grade |
OR | odd ratio |
OS | overall survival |
PCR | polymerase chain reaction |
VHL | von Hippel-Lindau |
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First Author (Year) [Ref] | Country | Detection Methods | No. of Patients | VHL Alteration (Yes, No) (%) | Grade III–IV (Yes vs. No) p-Value OR for Grade III–IV (95% CI) | Stage III–IV (Yes vs. No) p-Value OR for Stage III–IV (95% CI) | HR for OS (95% CI) p-Value |
---|---|---|---|---|---|---|---|
Yao (2002) [22] | Japan | DNA-SSCP + direct sequencing | 187 | Mutations (yes: 98, no: 89) (52.4%) Methylation (yes: 10, no 177) (5.3%) | 29/108 (26.9%) vs. 20/79 (25.3%) p = 0.463 1.08 (0.56–2.10) | 56/108(51.8%) vs. 43/79 (54.4%) p = 0.463 0.9 (0.50–1.61) | Mutations: 0.36 (0.13–0.97) p = 0.023 |
Dulaimi (2004) [23] | USA | MS-PCR | 50 | Methylation (yes: 8, no: 42) (16%) | 3/8(37.5%) vs. 21/41 (51.2%) NS 0.57 (0.12–2.71) | NA | NA |
Kim (2005) [24] | Korea | DNA-SSCP + direct sequencing MS-PCR | 56 | Mutations or methylation (yes: 16, no: 40) (28.6%) | 10/16 (62.5%) vs. 17/40 (42.5%) p = 0.487 2.25 (0.69–7.42) | 6/16 (37.5%) vs. 13/40 (32.5%) p = 0.809 1.25 (0.37–4.18) | NA |
Smits (2008) [25] | Netherlands | DNA-SSCP + direct sequencing MS-PCR | 185 | LOF mutations or methylation (yes: 106, no: 79) (57.3%) Methylation (yes: 16, no: 131) (10.9%) | 45/106 (42.5%) vs. 30/79 (38%) p = 0.537 1.20 (0.66–2.19) | 59/106 (55.7%) vs. 38/79 (48.1%) p = 0.681 1.35 (0.75–2.43) | 1.08 (0.69–1.68) p = 0.461 Mutations: 1.02 (0.66–1.58) Methylation: 1.04 (0.48–2.22) p = 0.439 |
Patard (2008) [26] | France, USA | PCR + direct sequencing | 100 | Mutations (yes: 58, no: 42) (58%) | 32/58 (55.2%) vs. 29/42 (69%) p = 0.16 0.55 (0.24–1.27) | NA | 0.53 (0.25–1.09) p = 0.084 |
Baldewijns (2009) [27] | Belgium | PCR + direct sequencing MS-PCR | 134 | LOF mutations or methylation (yes: 96, no: 38) (71.6%) | 20/45 (44.4%) vs. 32/60 (53.5%) p = 0.762 0.70 (0.32–1.52) | 16/45 (35.6%) vs. 18/60 (30%) p = 0.212 1.29 (0.57–2.93) | 0.42 (0.14–1.23) p = 0.423 Mutations: 0.39 (0.14–1.11) p = 0.078 Methylation: 0.44 (0.06–3.11) p = 0.411 |
Young (2009) [28] | UK | PCR + DNA sequencing MS-PCR | 177 | Mutations (yes: 127, no: 42) (75.1%) Methylation (yes: 51, no: 112) (31.3%) | 84/127 (66.1%) vs. 35/42 (83.3%) 0.39 (0.16–0.95) 42/51 (82.4%) vs. 71/112 (63.4%) | 74/127 (58.3%) vs. 27/42 (64.3%) 0.78 (0.38–1.60) 33/51 (64.7%) vs. 66/112 (58.9%) | 1.10 (0.74–1.63) p = 0.63 Mutations: 0.87 (0.30–2.56) p = 0.80 Methylation: 1.14 (0.75–1.73) p = 0.54 |
Dagher (2016) [29] | France | PCR + sequencing reaction MS-MLPA | 98 | Mutations, LOH, or methylation (yes: 87, no: 11) (88.8%) | NA | NA | 0.24 (0.075–0.766) p = 0.016 |
Serrano-Oviedo (2017) [30] | Spain | PCR + direct sequencing | 50 | Mutations (yes: 13, no: 37) (26%) | 3/13 (23.1%) vs. 22/37 (59.5%) p = 0.036 0.20 (0.05–0.87) | 6/13 (46.2%) vs. 15/37 (40.5%) NS 1.26 (0.35–4.49) | NA |
Salinas-Sanchez (2017) [31] | Spain | PCR + automatic DNA sequencing MS-PCR | 46 | Methylation (yes: 10, no: 36) (21.7%) | NA | NA | Methylation: 4.45 (1.40–14.84) p = 0.012 |
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Kim, H.S.; Kim, J.H.; Jang, H.J.; Han, B.; Zang, D.Y. Clinicopathologic Significance of VHL Gene Alteration in Clear-Cell Renal Cell Carcinoma: An Updated Meta-Analysis and Review. Int. J. Mol. Sci. 2018, 19, 2529. https://doi.org/10.3390/ijms19092529
Kim HS, Kim JH, Jang HJ, Han B, Zang DY. Clinicopathologic Significance of VHL Gene Alteration in Clear-Cell Renal Cell Carcinoma: An Updated Meta-Analysis and Review. International Journal of Molecular Sciences. 2018; 19(9):2529. https://doi.org/10.3390/ijms19092529
Chicago/Turabian StyleKim, Hyeong Su, Jung Han Kim, Hyun Joo Jang, Boram Han, and Dae Young Zang. 2018. "Clinicopathologic Significance of VHL Gene Alteration in Clear-Cell Renal Cell Carcinoma: An Updated Meta-Analysis and Review" International Journal of Molecular Sciences 19, no. 9: 2529. https://doi.org/10.3390/ijms19092529