Replicative Instability Drives Cancer Progression
Abstract
:1. Background
2. Methods
2.1. TCGA Pan-Cancer Analysis
2.2. Survival Analyses
2.3. DNA Repair Pathway WE Score
2.4. Catalogue of Somatic Mutations in Cancer (COSMIC) v3.2 Single Base Substitution (SBS) Analysis
2.5. RS Score
2.6. MPS
2.7. RSS Site Alteration Analysis
2.8. RSS Site Functional Analysis
2.9. Tumor Microenvironment Analysis
2.10. ORIEN Therapy Response
2.11. FUSED
2.12. ORIEN Metastatic Dissemination
2.13. Statistical Analyses
3. Results
3.1. Pan-Cancer Analysis Identifies MYBL2 Expression as a Robust Marker of Poor Patient Outcomes
3.2. MYBL2 High Tumors Are Characterized by Genomic Instability despite Containing Wildtype BRCA
3.3. Heterozygous Loss of Repair Effectors Underly Defective DNA Repair in MYBL2 High Tumors
3.4. Defective SSBR and TLS Are Linked to Increased Replication Stress and Distinct Genomic Footprints
3.5. Recurrent Copy Number Alterations at RSS Sites Rewire Transcriptional Programs and Impact Hallmark of Cancer Master Regulators
3.6. MYBL2 High Tumors Exhibit Immunosuppressive Microenvironments
3.7. Elevated MYBL2 Identifies Patients at Risk for Therapy Failure and Distant Metastases
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
RIN | replicative instability |
MYBL2 | Myb proto-oncogene like 2 |
TCGA | The Cancer Genome Atlas |
OS | overall survival |
PFS | progression free survival |
DSS | disease-specific survival |
LUAD | lung adenocarcinoma |
IDHMUT LGG | isocitrate dehydrogenase-mutant lower grade glioma |
PAAD | pancreatic adenocarcinoma |
UCEC | uterine corpus endometrial carcinoma |
SARC | sarcoma |
FGA | fraction of the genome altered |
MSI | microsatellite instability |
HR | homologous recombination |
RPS | repair proficiency score |
Combined-HRD score | combined homologous recombination deficiency score |
WE score | weighted expression score |
SSBR | single-strand break repair |
DSBR | double-strand break repair |
TLS | translesion synthesis |
NER | nucleotide excision repair |
NHEJ | non-homologous end-joining |
DR | direct reversal repair |
COSMIC | Catalog of Somatic Mutations in Cancer |
SBS | single-base substitution |
RS score | replication stress score |
MPS | mutational position score |
ERFS | early replicating fragile sites |
MiDAS | mitotic DNA synthesis sites |
RSS sites | replication stress sensitive sites |
MDSC | myeloid derived suppressor cell |
ORIEN | Oncology Research Information Exchange Network |
ID-BRE | invasive ductal breast cancer |
LRMM | late-relapse multiple myeloma |
FUSED | FUSion Error-prone repair Detection |
CIN | chromosomal instability |
MMEJ | microhomology mediated end-joining |
FA | Fanconi Anemia |
GO | Gene Ontology |
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Morris, B.B.; Smith, J.P.; Zhang, Q.; Jiang, Z.; Hampton, O.A.; Churchman, M.L.; Arnold, S.M.; Owen, D.H.; Gray, J.E.; Dillon, P.M.; et al. Replicative Instability Drives Cancer Progression. Biomolecules 2022, 12, 1570. https://doi.org/10.3390/biom12111570
Morris BB, Smith JP, Zhang Q, Jiang Z, Hampton OA, Churchman ML, Arnold SM, Owen DH, Gray JE, Dillon PM, et al. Replicative Instability Drives Cancer Progression. Biomolecules. 2022; 12(11):1570. https://doi.org/10.3390/biom12111570
Chicago/Turabian StyleMorris, Benjamin B., Jason P. Smith, Qi Zhang, Zhijie Jiang, Oliver A. Hampton, Michelle L. Churchman, Susanne M. Arnold, Dwight H. Owen, Jhanelle E. Gray, Patrick M. Dillon, and et al. 2022. "Replicative Instability Drives Cancer Progression" Biomolecules 12, no. 11: 1570. https://doi.org/10.3390/biom12111570
APA StyleMorris, B. B., Smith, J. P., Zhang, Q., Jiang, Z., Hampton, O. A., Churchman, M. L., Arnold, S. M., Owen, D. H., Gray, J. E., Dillon, P. M., Soliman, H. H., Stover, D. G., Colman, H., Chakravarti, A., Shain, K. H., Silva, A. S., Villano, J. L., Vogelbaum, M. A., Borges, V. F., ... Mayo, M. W. (2022). Replicative Instability Drives Cancer Progression. Biomolecules, 12(11), 1570. https://doi.org/10.3390/biom12111570