Post-Transcriptional Modifications to miRNAs Undergo Widespread Alterations, Creating a Unique Lung Adenocarcinoma IsomiRome
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Sample Collection, Sequencing, and Data Processing
2.2. Processing of Small RNA Sequencing Data
2.3. IsomiR and miRNA Quantification and Nomenclature
2.4. Identification of High-Confidence miRNAs and isomiRs
2.5. Computation of Sample-Wide miRNA Editing/Adenylation/Uridylation Rates
2.6. Determination of Significant Differences between ANL and LUAD Samples
2.7. Analysis of Correlations between Variables
2.8. Survival Analyses
2.9. Support Vector Machine and Random Forest Classifiers
2.10. Statistical and Graphical Software
3. Results
3.1. Characterization of the Lung isomiRome
3.2. The Lung isomiRome Is Widely Altered in LUAD
3.3. miRNA-Modifying Enzymes Are Dysregulated in LUAD
3.4. Individual miRNAs Are Modified in Distinct Fashions in LUAD
3.5. IsomiR-Based Biomarkers Distinguish ANL and LUAD Samples
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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Characteristic | EWU (n = 48) | TCGA (n = 389) | BCCA (n = 63) |
---|---|---|---|
Median Age (Range) | 59.5 (37–78) | 66 (39–88) | 70 (45–86) |
Sex | |||
Male | 0 (0%) | 173 (44%) | 19 (30%) |
Female | 48 (100%) | 216 (56%) | 44 (70%) |
Smoking History | |||
Current or Former | 7 (15%) | 307 (79%) | 40 (63%) |
Never | 41 (85%) | 64 (16%) | 23 (37%) |
Stage | |||
IA | 23 (48%) | 102 (26%) | 23 (37%) |
IB | 7 (15%) | 103 (26%) | 18 (29%) |
IIA | 5 (10%) | 43 (11%) | 2 (3%) |
IIB | 1 (2%) | 52 (13%) | 11 (17%) |
IIIA | 12 (25%) | 57 (15%) | 4 (6%) |
IIIB | 0 (0%) | 6 (2%) | 1 (2%) |
IV | 0 (0%) | 17 (4%) | 1 (2%) |
miRNA | 5′ Shift | Edited Position | Adjacent Nucleotides * |
---|---|---|---|
hsa-let-7d-3p | 0 | 4 | UAC |
hsa-miR-151a-3p | −2 | 2 | UAG |
hsa-miR-200b-3p | 0 | 4 | UAC |
hsa-miR-376c-3p | 0 | 5 | UAG |
hsa-miR-379-5p | 0 | 4 | UAG |
hsa-miR-381-3p | −1 | 3 | UAC |
hsa-miR-381-3p | 0 | 3 | UAC |
hsa-miR-411-5p | −1 | 4 | UAG |
hsa-miR-411-5p | 0 | 4 | UAG |
hsa-miR-455-5p | 0 | 16 | UAC |
hsa-miR-4662a-5p | 0 | 2 | UAG |
hsa-miR-497-5p | 0 | 1 | CAG |
hsa-miR-589-3p | 0 | 5 | AAC |
hsa-miR-9903 | 0 | 2 | UAU |
hsa-miR-99a-5p | −1 | 0 | AAA |
hsa-miR-99a-5p | 0 | 0 | AAA |
Edited isomiR | ADAR ρ Value | ADAR p-Value | ADARB1 ρ Value | ADARB1 p-Value | Group * |
---|---|---|---|---|---|
hsa-let-7d-3p 0 4 AI | 0.079 | 0.124 | 0.198 | 9.38 × 10−5 | ADARB1 |
hsa-miR-151a-3p -2 2 AI | 0.267 | 1.12 × 10−7 | 0.067 | 0.192 | ADAR |
hsa-miR-200b-3p 0 4 AI | 0.452 | 9.65 × 10−21 | −0.040 | 0.436 | ADAR |
hsa-miR-376c-3p 0 5 AI | −0.031 | 0.547 | 0.030 | 0.559 | Neither |
hsa-miR-379-5p 0 4 AI | −0.030 | 0.561 | 0.249 | 7.63 × 10−7 | ADARB1 |
hsa-miR-381-3p -1 3 AI | −0.070 | 0.170 | 0.006 | 0.904 | Neither |
hsa-miR-381-3p 0 3 AI | 0.061 | 0.233 | −0.118 | 0.021 | Neither |
hsa-miR-411-5p -1 4 AI | −0.047 | 0.357 | 0.103 | 0.044 | Neither |
hsa-miR-411-5p 0 4 AI | 0.008 | 0.874 | 0.171 | 7.97 × 10−4 | ADARB1 |
hsa-miR-455-5p 0 16 AI | −0.030 | 0.559 | 0.268 | 9.75 × 10−8 | ADARB1 |
hsa-miR-4662a-5p 0 2 AI | −0.017 | 0.745 | 0.224 | 9.28 × 10−6 | ADARB1 |
hsa-miR-497-5p 0 1 AI | −0.046 | 0.374 | 0.233 | 3.80 × 10−6 | ADARB1 |
hsa-miR-589-3p 0 5 AI | 0.319 | 1.52 × 10−10 | −0.027 | 0.592 | ADAR |
hsa-miR-9903 0 2 AI | −0.052 | 0.343 | −0.095 | 0.081 | Neither |
hsa-miR-99a-5p -1 0 AI | −0.135 | 0.008 | 0.116 | 0.023 | ADARB1 |
hsa-miR-99a-5p 0 0 AI | −0.081 | 0.114 | 0.310 | 5.48 × 10−10 | ADARB1 |
RPM-Based Classifiers | Frequency-Based Classifiers | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
miRNA | 3′ U | 3′ A | A-to-I | 5′ | 3′ U | 3′ A | A-to-I | 5′ | ||
Mean classification error in 10-fold CV | BCCA SVM | 1.56% | 1.56% | 0.78% | 3.13% | 2.34% | 0.78% | 0.00% | 4.69% | 3.13% |
TCGA SVM | 1.45% | 1.16% | 2.03% | 1.45% | 0.58% | 1.16% | 2.62% | 1.74% | 1.16% | |
EWU SVM | 2.38% | 2.38% | 2.38% | 2.38% | 2.38% | 1.19% | 3.57% | 11.90% | 3.57% | |
Mean | 1.80% | 1.70% | 1.73% | 2.32% | 1.77% | 1.04% | 2.06% | 6.11% | 2.62% | |
Out of bag error | BCCA RF | 0.78% | 0.78% | 0.00% | 1.56% | 0.78% | 4.69% | 1.56% | 3.91% | 4.69% |
TCGA RF | 1.45% | 0.58% | 0.87% | 1.16% | 0.87% | 1.45% | 2.62% | 2.62% | 1.74% | |
EWU RF | 1.19% | 0.00% | 0.00% | 1.19% | 0.00% | 8.33% | 14.29% | 3.57% | 5.95% | |
Mean | 1.14% | 0.45% | 0.29% | 1.30% | 0.55% | 4.82% | 6.16% | 3.37% | 4.13% |
RPM-Based Classifiers | Frequency-Based Classifiers | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
miRNA | 3′ U | 3′ A | A-to-I | 5′ | 3′ U | 3′ A | A-to-I | 5′ | ||
Test Cohort AUCs | Features | 368 | 37 | 41 | 7 | 115 | 17 | 34 | 7 | 36 |
BCCA SVM | 0.944 | 0.998 | 0.962 | 0.997 | 0.992 | 0.663 | 0.476 | 0.985 | 0.716 | |
EWU SVM | 0.951 | 0.995 | 0.884 | 0.934 | 0.982 | 0.582 | 0.752 | 0.968 | 0.893 | |
BCCA RF | 0.901 | 0.891 | 0.855 | 0.990 | 0.894 | 0.634 | 0.756 | 0.981 | 0.889 | |
EWU RF | 0.988 | 0.910 | 0.995 | 0.988 | 0.973 | 0.572 | 0.704 | 0.955 | 0.606 | |
Mean | 0.946 | 0.949 | 0.924 | 0.977 | 0.960 | 0.613 | 0.672 | 0.972 | 0.776 |
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Cohn, D.E.; Souza, V.G.P.; Forder, A.; Telkar, N.; Stewart, G.L.; Lam, W.L. Post-Transcriptional Modifications to miRNAs Undergo Widespread Alterations, Creating a Unique Lung Adenocarcinoma IsomiRome. Cancers 2024, 16, 3322. https://doi.org/10.3390/cancers16193322
Cohn DE, Souza VGP, Forder A, Telkar N, Stewart GL, Lam WL. Post-Transcriptional Modifications to miRNAs Undergo Widespread Alterations, Creating a Unique Lung Adenocarcinoma IsomiRome. Cancers. 2024; 16(19):3322. https://doi.org/10.3390/cancers16193322
Chicago/Turabian StyleCohn, David E., Vanessa G. P. Souza, Aisling Forder, Nikita Telkar, Greg L. Stewart, and Wan L. Lam. 2024. "Post-Transcriptional Modifications to miRNAs Undergo Widespread Alterations, Creating a Unique Lung Adenocarcinoma IsomiRome" Cancers 16, no. 19: 3322. https://doi.org/10.3390/cancers16193322