A Novel Ferroptosis-Associated Gene Signature to Predict Prognosis in Patients with Uveal Melanoma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cohorts and Ferroptosis-Related Genes
2.2. Identification and Validation of the Prognostic Ferroptosis-Related Gene Signature
2.3. Correlation between Gene Signature and UM Common Mutations
2.4. Relationships between Gene Signature and Autophagy in UM
2.5. Gene Set Enrichment Analysis
2.6. Relationship of Gene Signature and the 22 Tumor-Infiltrating Immune Cells (TICs)
2.7. Statistical Analysis
3. Results
3.1. Characteristics of UMs
3.2. Identification of Prognostic Ferroptosis-Related Gene Signature
3.3. The Prognostic Capacity of the Seven-Gene Signature
3.4. Identification of the Correlation between Seven-Gene Signature and UM Common Mutations
3.5. Identification of the Autophagy Correlation with the Seven-Gene Signature
3.6. Gene Set Enrichment Analysis
3.7. Identification of the Relationship between the Seven-Gene Signature and 22 TICs
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | Training Cohort (TCGA-UVM, 80 Cases) | Validation Cohort (GSE22138, 63 Cases) | |
---|---|---|---|
age | |||
<65 | 45(56.25%) | 36(57.14%) | |
≥65 | 35(43.75%) | 27(42.86%) | |
gender | |||
female | 35(43.75%) | 24(38.1%) | |
male | 45(56.25%) | 39(61.9%) | |
T classification | |||
T1 | 0 | NA | |
T2 | 4(5%) | NA | |
T3 | 36(45%) | NA | |
T4 | 38(47.5%) | NA | |
unknown | 2(2.5%) | NA | |
M classification | |||
M0 | 73(91.25%) | 28(44.44%) | |
M1 | 3(3.75%) | 35(55.56%) | |
unknown | 4(5%) | 0 | |
tumor stage | |||
stage I | 0 | NA | |
stage II | 36(45%) | NA | |
stage III | 40(50%) | NA | |
stage IV | 4(5%) | NA | |
extrascleral extension | |||
yes | 7(8.75%) | 5(7.94%) | |
no | 68(85%) | 48(76.19%) | |
unknown | 5(6.25%) | 10(15.87%) | |
tumor diameter, mm | |||
<20 | 60(75%) | 44(69.84%) | |
≥20 | 19(23.75%) | 9(14.29%) | |
unknown | 1(1.25%) | 10(15.87%) | |
tumor thickness, mm | |||
<10 | 29(36.25%) | 10(15.87%) | |
≥10 | 51(63.75%) | 53(84.13%) | |
tumor eye side | |||
left | NA | 33(52.38%) | |
right | NA | 30(47.62%) | |
tumor location | |||
all over the eye | NA | 1(1.59%) | |
anterior to equator | NA | 3(4.76%) | |
on equator | NA | 42(66.67%) | |
posterior and on equator | NA | 3(4.76%) | |
posterior to equator | NA | 9(14.29%) | |
unknown | NA | 5(7.94%) | |
tumor cell type | |||
epithelioid | NA | 21(33.33%) | |
mixed | NA | 23(36.51%) | |
unknown | NA | 19(30.16%) | |
eye color | |||
blue | 9(11.25%) | NA | |
brown | 15(18.75%) | NA | |
green | 6(7.5%) | NA | |
unknown | 50(62.5%) | NA | |
person neoplasm cancer status | |||
with tumor | 9(11.25%) | NA | |
tumor free | 56(70%) | NA | |
unknown | 15(18.75%) | NA | |
radiation therapy | |||
yes | 3(3.75%) | NA | |
no | 63(78.75%) | NA | |
unknown | 14(17.5%) | NA | |
ethnicity | |||
hispanic or latino | 1(1.25%) | NA | |
not hispanic or latino | 52(65%) | NA | |
unknown | 27(33.75%) | NA | |
tissue or organ of origin diagnosis | |||
choroid | 67(83.75%) | NA | |
ciliary body | 5(6.25%) | NA | |
overlapping lesion of eye and adnexa | 8(10%) | NA | |
retinal detachment | |||
yes | NA | 36(57.14%) | |
no | NA | 22(34.92%) | |
unknown | NA | 5(7.94%) | |
mitotic count | |||
<20 | 42(52.5%) | NA | |
≥20 | 11(13.75%) | NA | |
unknown | 27(33.75%) | NA | |
chromosome 3 status | |||
disomy | NA | 18(28.57%) | |
monosomy | NA | 37(58.73%) | |
unknown | NA | 8(12.7%) |
Gene Symbol | Description | Category | Genomic Location | Kaplan–Meier Analysis (p-Value) | Univariate Cox Regression Analysis | |||
---|---|---|---|---|---|---|---|---|
HR | HR_95L | HR_95H | p-Value | |||||
VDAC1 | Voltage Dependent Anion Channel 1 | Protein Coding | chr5 | 7.12 × 10−6 | 5.291343594 | 1.781142996 | 15.71929771 | 2.71 × 10−3 |
STEAP3 | STEAP3 Metalloreductase | Protein Coding | chr2 | 3.19 × 10−3 | 4.206162616 | 2.092921898 | 8.453160136 | 5.49 × 10−5 |
SLC39A8 | Solute Carrier Family 39 Member 8 | Protein Coding | chr4 | 3.77 × 10−2 | 3.869852511 | 1.326333156 | 11.29109861 | 1.33 × 10−2 |
SLC11A2 | Solute Carrier Family 11 Member 2 | Protein Coding | chr12 | 4.76 × 10−3 | 3.094601274 | 1.570769273 | 6.096730571 | 1.09 × 10−3 |
PEBP1 | Phosphatidylethanolamine Binding Protein 1 | Protein Coding | chr12 | 4.86 × 10−2 | 0.234529606 | 0.075635069 | 0.727230595 | 1.20 × 10−2 |
MAPK1 | Mitogen−Activated Protein Kinase 1 | Protein Coding | chr22 | 9.03 × 10−3 | 2.895607401 | 1.163501743 | 7.206299663 | 2.23 × 10−2 |
MAP1LC3C | Microtubule Associated Protein 1 Light Chain 3 Gamma | Protein Coding | chr1 | 1.31 × 10−2 | 0.459748503 | 0.271733125 | 0.777853955 | 3.78 × 10−3 |
LINC00472 | Long Intergenic Non-Protein Coding RNA 472 | RNA Gene | chr6 | 6.36 × 10−3 | 0.043258919 | 0.003322917 | 0.563160037 | 1.65 × 10−2 |
ITGA6 | Integrin Subunit Alpha 6 | Protein Coding | chr2 | 1.13 × 10−3 | 4.613594536 | 2.148024539 | 9.909223176 | 8.85 × 10−5 |
HSPA5 | Heat Shock Protein Family A (Hsp70) Member 5 | Protein Coding | chr9 | 8.91 × 10−3 | 2.25326069 | 1.228917946 | 4.131426149 | 8.63 × 10−3 |
HMOX1 | Heme Oxygenase 1 | Protein Coding | chr22 | 2.19 × 10−3 | 2.334473768 | 1.59857086 | 3.409149952 | 1.14 × 10−5 |
GSS | Glutathione Synthetase | Protein Coding | chr20 | 3.31 × 10−3 | 3.851728269 | 1.85357871 | 8.003874117 | 3.02 × 10−4 |
FTH1 | Ferritin Heavy Chain 1 | Protein Coding | chr11 | 4.64 × 10− 3 | 4.040699109 | 1.10619952 | 14.75976891 | 3.46 × 10−2 |
CD44 | CD44 Molecule (Indian Blood Group) | Protein Coding | chr11 | 6.66 × 10− 3 | 0.304760194 | 0.142947413 | 0.649740862 | 2.10 × 10−3 |
CASP8 | Caspase 8 | Protein Coding | chr2 | 3.91 × 10−2 | 2.604965341 | 1.209052632 | 5.612530215 | 1.45 × 10−2 |
BAP1 | BRCA1 Associated Protein 1 | Protein Coding | chr3 | 1.40 × 10−6 | 0.561778701 | 0.412394493 | 0.765275275 | 2.56 × 10−4 |
AURKA | Aurora Kinase A | Protein Coding | chr20 | 2.54 × 10−2 | 3.390492663 | 1.565174215 | 7.344511806 | 1.96 × 10−3 |
ANO6 | Anoctamin 6 | Protein Coding | chr12 | 2.56 × 10−2 | 2.263254914 | 1.292723147 | 3.962428319 | 4.26 × 10−3 |
ALOX12 | Arachidonate 12-Lipoxygenase, 12S Type | Protein Coding | chr17 | 1.48 × 10−3 | 0.022909689 | 0.002539428 | 0.20668188 | 7.66 × 10−4 |
AIFM2/FSP1 | Apoptosis Inducing Factor Mitochondria Associated 2 | Protein Coding | chr10 | 6.03 × 10−6 | 6.104896507 | 2.780109603 | 13.40586045 | 6.55 × 10−6 |
ACSL6 | Acyl-CoA Synthetase Long Chain Family Member 6 | Protein Coding | chr5 | 4.56 × 10−4 | 2.283441779 | 1.099533069 | 4.742109633 | 2.68 × 10−2 |
ACSL1 | Acyl-CoA Synthetase Long Chain Family Member 1 | Protein Coding | chr4 | 6.64 × 10−3 | 1.873686292 | 1.236619189 | 2.838950221 | 3.06 × 10−3 |
Gene Symbol | Description | Role | Risk Coefficient |
---|---|---|---|
STEAP3 | STEAP3 Metalloreductase | Marker [26] | 0.055060532 |
MAP1LC3C | Microtubule Associated Protein 1 Light Chain 3 Gamma | Driver [27] | −0.202884346 |
ITGA6 | Integrin Subunit Alpha 6 | Suppressor [28] | 0.34461317 |
HMOX1 | Heme Oxygenase 1 | Driver [29,30,31,32], Suppressor [33,34], Marker [35,36] | 0.125266141 |
CD44 | CD44 Molecule (Indian Blood Group) | Suppressor [37] | −0.316011897 |
ALOX12 | Arachidonate 12-Lipoxygenase, 12S Type | Driver [38,39,40], Marker [41] | −1.311120914 |
AIFM2/FSP1 | Apoptosis Inducing Factor Mitochondria Associated 2 | Suppressor [42,43] | 0.710789029 |
Variable | Univariate Cox Analysis | Multivariate Cox Analysis | ||||||
---|---|---|---|---|---|---|---|---|
Coef | HR (95% CI) | z | p-Value | Coef | HR (95% CI) | z | p-Value | |
TCGA-UVM (overall survival) * | ||||||||
age | 0.0447 | 1.05 (1.01–1.09) | 2.35 | 0.0186 | 0.101 | 1.11 (0.976–1.25) | 1.57 | 0.115 |
gender (male vs. female) | 0.433 | 1.54 (0.651–3.65) | 0.984 | 0.325 | ||||
tumor stage (stage III vs. stage II) | 0.336 | 1.4 (0.556–3.52) | 0.713 | 0.476 | −3.06 | 0.047 (0.00199–1.11) | −1.9 | 0.0579 |
tumor stage (stage IV vs. stage II) | 4.37 | 79.3 (7.55–834) | 3.64 | 0.000269 | NA | NA | NA | NA |
extrascleral extension (yes vs. no) | 1.54 | 4.64 (1.5–14.4) | 2.66 | 0.00774 | −4.25 | 0.0142 (3.98× 10−13–5.1× 10 8) | −0.343 | 0.732 |
tumor diameter | 0.155 | 1.17 (1.01–1.35) | 2.12 | 0.0344 | 0.723 | 2.06 (1.11–3.83) | 2.29 | 0.0221 |
tumor thickness | 0.111 | 1.12 (0.949–1.32) | 1.33 | 0.183 | ||||
radiation therapy (yes vs. no) | 1.68 | 5.35 (1.09–26.3) | 2.07 | 0.0389 | 7.79 | 2410 (4.34 × 10−8–1.33 × 10 14) | 0.617 | 0.537 |
ethnicity (hispanic or latino vs. not hispanic or latino) | −16 | 1.09 × 10−7 (0-Inf) | −0.00205 | 0.998 | ||||
tissue or organ of origin diagnosis (choroid vs. not choroid) | −0.286 | 0.751 (0.254–2.22) | −0.517 | 0.605 | ||||
mitotic count | −0.0119 | 0.988 (0.931–1.05) | −0.394 | 0.693 | ||||
chromosome 3 copy number | −1.86 | 0.156 (0.0574–0.422) | −3.65 | 0.00026 | 2.76 | 15.9 (0.894–281) | 1.88 | 0.0597 |
chromosome 6p copy number | −1.06 | 0.348 (0.176–0.687) | −3.04 | 0.00237 | −0.874 | 0.417 (0.0559–3.11) | −0.852 | 0.394 |
chromosome 8q copy number | 0.516 | 1.67 (1.27–2.2) | 3.68 | 0.000235 | −0.88 | 0.415 (0.126–1.37) | −1.44 | 0.149 |
risk score | 1.65 | 5.22 (2.59–10.5) | 4.61 | 3.99 × 10−6 | 4.23 | 68.6 (3.36–1400) | 2.75 | 0.00598 |
TCGA-UVM (progression-free survival) # | ||||||||
age | 0.0271 | 1.03 (0.996–1.06) | 1.7 | 0.0886 | ||||
gender (male vs. female) | −0.139 | 0.87 (0.422–1.8) | −0.376 | 0.707 | ||||
tumor stage (stage III vs. stage II) | 0.381 | 1.46 (0.665–3.22) | 0.946 | 0.344 | −0.959 | 0.383 (0.094–1.56) | −1.34 | 0.181 |
tumor stage (stage IV vs. stage II) | 3.31 | 27.4 (5.06–149) | 3.84 | 0.000124 | 2.87 | 17.6 (0.677–455) | 1.73 | 0.0845 |
extrascleral extension (yes vs. no) | 1.45 | 4.26 (1.57–11.5) | 2.85 | 0.0044 | −0.682 | 0.506 (0.00917–27.9) | −0.333 | 0.739 |
tumor diameter | 0.113 | 1.12 (0.999–1.25) | 1.94 | 0.0527 | ||||
tumor thickness | 0.00859 | 1.01 (0.875–1.16) | 0.119 | 0.905 | ||||
radiation therapy (yes vs. no) | 0.0846 | 1.09 (0.142–8.33) | 0.0814 | 0.935 | ||||
ethnicity (hispanic or latino vs. not hispanic or latino) | −17 | 3.98 × 10−8 (0-Inf) | −0.00217 | 0.998 | ||||
tissue or organ of origin diagnosis (choroid vs. not choroid) | 0.0872 | 1.09 (0.377–3.16) | 0.161 | 0.872 | ||||
mitotic count | 0.0545 | 1.06 (1.01–1.1) | 2.64 | 0.00829 | 0.0575 | 1.06 (0.976–1.15) | 1.37 | 0.17 |
chromosome 3 copy number | −1.86 | 0.156 (0.0631–0.386) | −4.02 | 5.88 × 10−5 | −1.3 | 0.272 (0.0293–2.52) | −1.15 | 0.252 |
chromosome 6p copy number | −0.628 | 0.534 (0.321–0.888) | −2.42 | 0.0155 | 0.709 | 2.03 (0.611–6.75) | 1.16 | 0.247 |
chromosome 8q copy number | 0.521 | 1.68 (1.31–2.16) | 4.08 | 4.56 × 10−5 | 0.146 | 1.16 (0.546–2.45) | 0.381 | 0.703 |
risk score | 0.933 | 2.54 (1.65–3.91) | 4.25 | 2.13 × 10−5 | 0.703 | 2.02 (0.486–8.39) | 0.967 | 0.0334 |
GSE22138 (metastasis-free survival) & | ||||||||
age | 0.0213 | 1.02 (0.995–1.05) | 1.59 | 0.113 | ||||
gender (male vs. female) | 0.353 | 1.42 (0.714–2.84) | 1 | 0.316 | ||||
tumor eye side (left vs. right) | −0.193 | 0.824 (0.424–1.6) | −0.57 | 0.569 | ||||
tumor location (on equator vs. others) | −0.325 | 0.723 (0.357–1.46) | −0.903 | 0.366 | ||||
tumor diameter | −0.0165 | 0.984 (0.893–1.08) | −0.336 | 0.737 | ||||
tumor thickness | 0.116 | 1.12 (0.951–1.33) | 1.37 | 0.171 | ||||
tumor cell type (epithelioid vs. mixed) | 0.753 | 2.12 (0.954–4.72) | 1.85 | 0.0649 | ||||
retinal detachment (yes vs. no) | 1.06 | 2.87 (1.24–6.68) | 2.45 | 0.0142 | 0.857 | 2.36 (0.981–5.66) | 1.92 | 0.0553 |
extrascleral extension (yes vs. no) | 0.563 | 1.76 (0.668–4.62) | 1.14 | 0.253 | ||||
chromosome 3 status (monosomy vs. disomy) | 1.67 | 5.29 (1.82–15.3) | 3.07 | 0.00217 | 1.24 | 3.45 (1.04–11.5) | 2.02 | 0.0435 |
risk score | 0.646 | 1.91 (1.31–2.78) | 3.37 | 0.000745 | 0.523 | 1.69 (1.03–2.77) | 2.07 | 0.0388 |
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Luo, H.; Ma, C. A Novel Ferroptosis-Associated Gene Signature to Predict Prognosis in Patients with Uveal Melanoma. Diagnostics 2021, 11, 219. https://doi.org/10.3390/diagnostics11020219
Luo H, Ma C. A Novel Ferroptosis-Associated Gene Signature to Predict Prognosis in Patients with Uveal Melanoma. Diagnostics. 2021; 11(2):219. https://doi.org/10.3390/diagnostics11020219
Chicago/Turabian StyleLuo, Huan, and Chao Ma. 2021. "A Novel Ferroptosis-Associated Gene Signature to Predict Prognosis in Patients with Uveal Melanoma" Diagnostics 11, no. 2: 219. https://doi.org/10.3390/diagnostics11020219