Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice
Abstract
:1. Introduction
2. Results
2.1. In Vivo and Ex Vivo Data
2.2. Mutational Landscape of MLH1−/− Tumors
2.3. Mutation Types and Shared Mutations
2.4. Mutational Frequencies and Types of Alterations for Selected Gene Sets Based on Prior Knowledge in Mouse and Human
2.5. Pairwise Exclusively SNV in GIT and Lymphomas
2.6. Prevalence and Hotspot Regions of GIT and Lymphomas in ARID1A, POLE, and SMAD4
2.7. Somatic Mutation Distribution and Nucleotide Changes in Chromosome X
2.8. Microsatellite Instability (MSI) Pathway—Prognostic, Predictive and Therapeutic Implications
2.9. Ongoing Mutations in MLH1−/− Tumors
2.10. In Vivo Vaccination Approach
3. Discussion
4. Critical Limitation of the Study
5. Materials and Methods
5.1. In Vivo Mouse Model and Sample Acquisition
5.2. Whole-Exome Sequencing (WES) Analysis
5.3. Data Visualization
5.4. Hypermutation and TMB Calculation
5.5. Coding Microsatellite (cMS) Frameshift Mutation Analysis
5.6. In Vivo Vaccination with MLH1−/− Tumor Lysates
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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MLH1−/− Number | Sex | Sample Type/Origin | Time of Onset [Weeks] |
---|---|---|---|
328 | ♂ | GIT/duodenum | 29.5 |
7450 | ♀ | GIT/duodenum | 41.0 |
1351 | ♀ | Lymphoma/spleen | 17.4 |
1444 | ♀ | Lymphoma/skin | 36.0 |
Gene | 7450-GIT | 328-GIT | Splenic Lymphoma | Skin Lymphoma | Survival | ||
---|---|---|---|---|---|---|---|
ARID1A | SILENT/MISSENSE | MISSENSE | MISSENSE | MISSENSE | OS | DFS | DSS |
BCL2 | NONE | SILENT/MISSENSE | SILENT | SILENT/MISSENSE | |||
PIK3CA | SILENT | SILENT/MISSENSE | SILENT/MISSENSE | SILENT/MISSENSE | DFS | ||
SMAD4 | SILENT | SILENT | SILENT | SILENT/MISSENSE | OS | DSS |
Gene | Splenic Lymphoma | Skin Lymphoma | Survival | ||
---|---|---|---|---|---|
AKT2 | SILENT/MISSENSE | SILENT/MISSENSE | OS | DFS | DSS |
CASP4 | NA | NA | |||
CASP9 | MISSENSE | NA | |||
CERS1 | NA | NA | DFS | ||
ECHS1 | SILENT | NA | |||
EGR1 | SILENT | SILENT | OS | DFS | DSS |
INADL | NA | NA | |||
MAPK1 | SILENT | SILENT | |||
RAC1 | SILENT | SILENT | DSS | ||
RHOA | SILENT | SILENT |
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Gladbach, Y.S.; Wiegele, L.; Hamed, M.; Merkenschläger, A.-M.; Fuellen, G.; Junghanss, C.; Maletzki, C. Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice. Cancers 2019, 11, 1485. https://doi.org/10.3390/cancers11101485
Gladbach YS, Wiegele L, Hamed M, Merkenschläger A-M, Fuellen G, Junghanss C, Maletzki C. Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice. Cancers. 2019; 11(10):1485. https://doi.org/10.3390/cancers11101485
Chicago/Turabian StyleGladbach, Yvonne Saara, Leonie Wiegele, Mohamed Hamed, Anna-Marie Merkenschläger, Georg Fuellen, Christian Junghanss, and Claudia Maletzki. 2019. "Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice" Cancers 11, no. 10: 1485. https://doi.org/10.3390/cancers11101485