Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies
Abstract
:1. Introduction
2. Material and Methods
2.1. Identification of Driver Regions in Cancer-Associated Proteins
2.2. Structural Categorization of Driver Regions
2.3. System-Level Analyses
3. Results
3.1. Disordered Protein Modules Are Targets for Tumorigenic Mutations
3.2. Disordered Drivers Function via Distinct Molecular Mechanisms
3.3. Disordered Driver Mutations Preferentially Modulate Receptor Tyrosine Kinases, DNA-Processing and The Degradation Machinery
3.4. Disordered Mutations Give Rise to Cancer Hallmarks by Targeting Central Elements of Biological Networks
3.5. Disordered Drivers Can Be the Dominant Players at The Patient Sample Level
3.6. Cancer Incidences Arising through Disordered Drivers Lack Effective Drugs
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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Tumor Type (Name) | Implicated Gene Product | Malignancy | Incidence | Reference |
---|---|---|---|---|
Diffuse large B-cell lymphoma (ABC subtype) | CARD11 | malignant | 9.6–10.8% (7/73, 4/37) | [72,73] |
Burkitt lymphoma | CCND3 | malignant | 14.6% (6/41) | [74] |
Diffuse large B-cell lymphoma (ABC subtype) | CCND3 | malignant | 10.7% (3/28) | [74] |
Diffuse large B-cell lymphoma (PCNS subtype) | CD79B | malignant | 31.6% (6/19) | [75] |
Acute myeloid leukaemia | CEBPA | malignant | 15% (16/104) | [76] |
Myelodysplasia and acute myeloblastic leukemia | CSF1R | malignant | 12.7% (14/110) | [77] |
Endometrioid endometrial carcinoma (low-grade) | CTNNB1 | malignant | 87.0% (47/54) | [78] |
Ovarian endometrioid carcinomas (low-grade) | CTNNB1 | malignant | 53.3% (16/30) | [79] |
Hepatocellular carcinoma (HBV/HCV related) | CTNNB1 | malignant | 26% (32/122) | [80] |
Desmoid tumor | CTNNB1 | benign | 73% (106/145) | [81] |
Juvenile nasopharyngeal angiofibroma | CTNNB1 | benign | 75% (12/16) | [82] |
Paraganglioma | EPAS1 | possibly malignant | 17% (7/41) | [83] |
Adult granulosa cell tumors of the ovary | FOXL2 | malignant | 93–97% (52/56, 86/89) | [84,85] |
Pediatric anaplastic astrocytoma/glioblastoma | H3F3A | malignant | 17.9–27.1% (5/28, 35/129) | [86] |
Giant cell tumor of bone (stromal cell) | H3F3A | benign | 92% (49/53) | [87] |
Chondroblastoma (stromal cell) | H3F3B | benign | 95% (73/77) | [87] |
GIST | KIT | malignant | 47% (57/121) | [88] |
Extrauterine leiomyoma and leiomyosarcoma | MED12 | (possibly) malignant | 19% (6/32) | [89] |
Phyllodes tumor of breast | MED12 | possibly malignant | 49% (41/83) | [90] |
Uterine leiomyoma | MED12 | benign | 70% (159/225) | [91] |
Rhabdomyosarcoma | MYOD1 | malignant | 20% (10/49) | [92] |
Esophageal squamous cell carcinoma | NFE2L2 | malignant | 9.6% (47/490) | [93] |
B-cell progenitor acute lymphoblastic leukemia | PAX5 | malignant | 34–39% (40/117, 94/242) | [94,95] |
Chronic myelomonocytic leukemia | SETBP1 | malignant | 25% (14/56) | [96] |
Atypical Chronic Myeloid Leukemia | SETBP1 | malignant | 24.3% (17/70) | [97] |
Chronic myelomonocytic leukaemia | SRSF2 | malignant | 47% (129/275) | [98] |
Pituitary adenoma | USP8 | possibly malignant | 14% (6/42) | [99] |
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Mészáros, B.; Hajdu-Soltész, B.; Zeke, A.; Dosztányi, Z. Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies. Biomolecules 2021, 11, 381. https://doi.org/10.3390/biom11030381
Mészáros B, Hajdu-Soltész B, Zeke A, Dosztányi Z. Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies. Biomolecules. 2021; 11(3):381. https://doi.org/10.3390/biom11030381
Chicago/Turabian StyleMészáros, Bálint, Borbála Hajdu-Soltész, András Zeke, and Zsuzsanna Dosztányi. 2021. "Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies" Biomolecules 11, no. 3: 381. https://doi.org/10.3390/biom11030381