Ischemia Is Related to Tumour Genetics in Uveal Melanoma
Abstract
:1. Introduction
2. Results
2.1. Expression of VHL, but Not HIF1a, Is Related to Clinical Characteristics
2.2. HIF1a and VHL Expression Are Related to the Presence of T Cells (CD3, CD8) and Macrophages (CD68)
2.3. HIF1a and VHL Expression Are Related to the Expression of Several Angiogenesis-Related Genes
2.4. Tumour Ischemia Is Related to Chromosome 3 and BAP1, but Not to Chromosome 8q
2.5. Ischemia Is More Related to Tumour Genetics Than to Tumour Size
3. Discussion
4. Materials and Methods
4.1. Patient Selection
4.2. Histopathology
4.3. Gene Expression
4.4. Chromosome Status and BAP1 Status
4.5. TCGA
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Total | HIF1a | VHL | |||
---|---|---|---|---|---|
Categorical | Cases (%) | Median | p-Value | Median | p-Value |
Gender | |||||
Male | 33 (52) | 7.20 | 0.32 # | 8.04 | 0.039 # |
Female | 31 (48) | 7.25 | 7.70 | ||
Side | |||||
Right eye (OD) | 30 (47) | 7.17 | 0.57 # | 7.84 | 0.84 # |
Left eye (OS) | 34 (53) | 7.24 | 7.82 | ||
TNM cat. (8th) | |||||
T1 | 6 (9) | 7.14 | 0.76 * | 7.96 | 0.32 * |
T2 | 25 (39) | 7.23 | 8.01 | ||
T3 | 31 (48) | 7.22 | 7.76 | ||
T4 | 2 (3) | 7.07 | 7.75 | ||
Tumour Pigmentation | |||||
Light | 43 (67) | 7.15 | 0.42 # | 8.04 | 0.29 # |
Dark | 20 (31) | 7.27 | 7.75 | ||
Cell Type | |||||
Spindle | 22 (34) | 7.14 | 0.095 # | 8.08 | 0.23 # |
Mixed + epithelioid | 42 (66) | 7.24 | 7.78 | ||
Ciliary Body Involvement | |||||
No | 40 (63) | 7.17 | 0.40 # | 8.03 | 0.022 # |
Yes | 23 (36) | 7.24 | 7.70 | ||
Metastasis | |||||
No | 27 (42) | 7.10 | 0.091 # | 8.18 | <0.001 # |
Yes | 37 (58) | 7.24 | 7.71 | ||
Melanoma-Related Death | |||||
No | 27 (42) | 7.10 | 0.091 # | 8.18 | <0.001 # |
Yes | 37 (58) | 7.24 | 7.71 | ||
Correlation | Correlation | ||||
Numerical | Total | Spearman | p-Value | Spearman | p-Value |
Age—Median | 61.6 | 0.201 | 0.11 | −0.331 | 0.008 |
LBD—Median | 13.0 | −0.088 | 0.49 | −0.274 | 0.028 |
Prominence—Median | 8.0 | 0.018 | 0.89 | −0.024 | 0.85 |
HIF1a | VHL | |||
---|---|---|---|---|
mRNA | Correlation | p-Value | Correlation | p-Value |
Ischemic Markers | ||||
HIF1A | NA | NA | −0.380 | 0.002 * |
VHL | −0.380 | 0.002 * | NA | NA |
Vascular Markers | ||||
VEGFA | 0.052 | 0.682 | −0.003 | 0.984 |
VEGFB | −0.333 | 0.007 * | 0.337 | 0.006 * |
VEGFC | −0.049 | 0.702 | −0.147 | 0.245 |
PECAM1 | 0.381 | 0.002 * | −0.381 | 0.002 * |
CD34 | 0.121 | 0.342 | −0.085 | 0.502 |
VWF | 0.321 | 0.010 * | 0.057 | 0.653 |
Immune Infiltrate | ||||
CD3D | 0.428 | <0.001 * | −0.257 | 0.040 * |
CD4 | 0.276 | 0.027 * | −0.167 | 0.188 |
CD8A | 0.452 | <0.001 * | −0.314 | 0.012 * |
CD68 | 0.549 | <0.001 * | −0.282 | 0.024 * |
Other | ||||
BAP1 | −0.330 | 0.008 * | 0.554 | <0.001 * |
Total | HIF1a | VHL | |||
---|---|---|---|---|---|
CATEGORICAL | Cases (%) | Median | p-Value | Median | p-Value |
All patients | |||||
Chromosome 3 | |||||
D3 | 20 (37) | 7.02 | 0.001 * | 8.23 | <0.001 * |
M3 | 34 (63) | 7.24 | 7.69 | ||
Chromosome 8q | |||||
Normal | 13 (24) | 7.01 | 0.003 * | 8.22 | 0.001 * |
Gain | 41 (76) | 7.24 | 7.74 | ||
BAP1 IHC | |||||
Negative | 30 (56) | 7.28 | <0.001 * | 7.71 | 0.003 * |
Positive | 24 (54) | 7.02 | 8.17 | ||
Sub-group analysis | |||||
Within D3 Lesions | |||||
D3/BAP1− | 3 | 7.30 | 0.028 * | 8.23 | 0.921 |
D3/BAP1+ | 17 | 7.01 | 8.23 | ||
Within M3 Lesions | |||||
M3/BAP1− | 27 | 7.25 | 0.015 * | 7.70 | 0.647 |
M3/BAP1+ | 7 | 7.10 | 7.56 | ||
Within D3/BAP1+ Lesions | |||||
D3/BAP1+/n8q | 9 | 6.98 | 0.200 | 8.22 | 1.000 |
D3/BAP1+/8qgain | 8 | 7.07 | 8.32 |
HIF1a | VHL | |||
---|---|---|---|---|
Variables | B (95% CI) | p-Value | B (95% CI) | p-Value |
Univariate Regression | ||||
Chr. 3 (M3 vs. D3) | 0.17 (0.03; 0.32) | 0.019 * | −0.51 (−0.65; −0.37) | <0.001 * |
BAP1 (BAP1− vs. BAP1+) | −0.26 (−0.39; −0.14) | <0.001 * | 0.31 (0.13; 0.48) | 0.001 * |
LBD (per mm increase) | −0.01 (−0.03; 0.01) | 0.208 | −0.03 (−0.05; −0.002) | 0.034 * |
Multivariate Regression | ||||
Model 1 | ||||
Chr. 3 | 0.01 (−0.16; 0.17) | 0.952 | −0.51 (−0.70; −0.33) | <0.001 * |
BAP1 | −0.26 (−0.43; −0.10) | 0.002 * | −0.01 (−0.18; 0.17) | 0.957 |
Model 2 | ||||
LBD | −0.02 (−0.03; 0.002) | 0.086 | −0.03 (−0.05; −0.002) | 0.034 * |
BAP1 | −0.27 (−0.40; −0.15) | <0.001 * | 0.30 (0.13; 0.47) | 0.001 * |
Model 3 | ||||
LBD | −0.02 (−0.04; 0.00) | 0.055 | −0.01 (−0.03; 0.006) | 0.173 |
Chr. 3 | 0.20 (0.06; 0.35) | 0.006 * | −0.49 (−0.63; −0.34) | <0.001 * |
Univariate Regression | ||||
Within D3 (n = 20) | ||||
LBD | −0.05 (−0.10; 0.004) | 0.067 | −0.04 (−0.08; −0.004) | 0.033 * |
Within M3 (n = 34) | ||||
LBD | −0.01 (−0.03; 0.008) | 0.230 | −0.006 (−0.03; 0.02) | 0.605 |
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Share and Cite
Brouwer, N.J.; Wierenga, A.P.A.; Gezgin, G.; Marinkovic, M.; Luyten, G.P.M.; Kroes, W.G.M.; Versluis, M.; van der Velden, P.A.; Verdijk, R.M.; Jager, M.J. Ischemia Is Related to Tumour Genetics in Uveal Melanoma. Cancers 2019, 11, 1004. https://doi.org/10.3390/cancers11071004
Brouwer NJ, Wierenga APA, Gezgin G, Marinkovic M, Luyten GPM, Kroes WGM, Versluis M, van der Velden PA, Verdijk RM, Jager MJ. Ischemia Is Related to Tumour Genetics in Uveal Melanoma. Cancers. 2019; 11(7):1004. https://doi.org/10.3390/cancers11071004
Chicago/Turabian StyleBrouwer, Niels J., Annemijn P. A. Wierenga, Gülçin Gezgin, Marina Marinkovic, Gregorius P. M. Luyten, Wilma G. M. Kroes, Mieke Versluis, Pieter A. van der Velden, Robert M. Verdijk, and Martine J. Jager. 2019. "Ischemia Is Related to Tumour Genetics in Uveal Melanoma" Cancers 11, no. 7: 1004. https://doi.org/10.3390/cancers11071004