CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution Journal Article
| Authors: | Dinh, K. N.; Vázquez-García, I.; Chan, A.; Malhotra, R.; Weiner, A.; McPherson, A. W.; Tavaré, S. |
| Article Title: | CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution |
| Abstract: | Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, n = 718). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas (n = 8207) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, n = 95). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation. © 2025 Dinh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| Keywords: | gene mutation; single nucleotide polymorphism; genetics; mutation; glioma; neoplasm; neoplasms; ovary adenocarcinoma; cell death; cell viability; cell division; genes; biological model; computational biology; prevalence; genotype; risk assessment; carcinogenesis; tumor suppressor gene; algorithm; probability; glioblastoma; chromosomal instability; genome; cell count; models, genetic; computer simulation; fitness; tumor growth; breast adenocarcinoma; chronic lymphatic leukemia; bioinformatics; karyotype; aneuploidy; phylogeny; chromosome 7; dna copy number variations; landscape; copy number variation; single cell analysis; single-cell analysis; chromosome 10; chromosome arm; population statistics; procedures; tumor progressions; copy-number alterations; genomic alterations; genome duplication; dna sequencing; humans; prognosis; human; article; whole genome sequencing; mean square error; cancer development; queueing theory; genes mutation; single cell resolution; model and simulation; selection parameters; cancer fitness; whole genome duplication |
| Journal Title: | PLoS Computational Biology |
| Volume: | 21 |
| Issue: | 4 |
| ISSN: | 1553-7358 |
| Publisher: | Public Library of Science |
| Date Published: | 2025-04-03 |
| Start Page: | e1012902 |
| Language: | English |
| DOI: | 10.1371/journal.pcbi.1012902 |
| PUBMED: | 40179124 |
| PROVIDER: | scopus |
| PMCID: | PMC11990800 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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