Computational Approaches to Study Interactions Between Mutagenic Processes and Cellular Processes

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Cancer mutational patterns are treated as quantitative traits and linked to expression, cell composition, and mutated subnetworks using concrete tools: 96 mutational categories and non-negative matrix factorization to extract signatures, correlation clustering and a sparse partial-correlation network to infer directed associations, and a custom deconvolution of damage vs repair model to capture non‑additive interactions. Results show smoking signature ties to cytokine signaling and increased goblet/reduced ciliated cells, homologous recombination deficiency associates with BRCA1/2 and TP53 and drives APOBEC activity, and additive models miss interacting damage–repair effects.

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" chapters (21)

1. 0:00Intro
2. 1:02Brief introduction to mutational processes
3. 2:43Specific mutational processes leave specific mutations patterns - mutational signatures
4. 4:48Deferent mutagenic processes have different signatures
5. 5:43Inferring Mutational Signatures using non-negative matrix factorization
6. 8:10Some mutagenic processes corresponding to the signatures are partially understood
7. 10:13Why study mutation signatures
8. 12:18Understanding mutational signatures by examining of their interactions with other processes
9. 13:08Study of mutational processes through interactions between signatures and other processes
10. 13:49EcoSigClust - a simple approach to uncover interaction between mutational processes and activity of molecular pathways
11. 16:18Interaction between mutagenic processes and molecular pathways in BRCA
12. 18:49Interaction between smoking and molecular processes in lung
13. 21:51Reprogramming of lung tissue composition
14. 22:45Refining expression - signature relation Gene-Signature-Network
15. 27:41Association with mutated pathways
16. 27:55Outline of the NETPHIX method to associate mutated subnetworks with continuous phenotype
17. 29:21Inetaraction between DNA damage and rapair
18. 29:51Two very different signatures associated with Mismatch Repair Deficiency (MMRd)
19. 30:15Modelling composition of DNA damage and repair Secondary/DNA repair mutational Primary mutational processes processes
20. 30:34Modeling regional activity of mutational processes
21. 31:43Summary • Mutation signatures provide a powerful formalism to study mutational processes in cancer • Joint analysis of mutational signatures, gene expression, and mutated subnetworks provides important insights to etiology and properties of mutational landscape in cancer