Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition
Circulating tumor DNA (ctDNA) monitoring, while sufficiently advanced to reflect tumor evolution in real time and inform cancer diagnosis, treatment, and prognosis, mainly relies on DNA that originates from cell death via apoptosis or necrosis. In solid tumors, chemotherapy and immune infiltration c...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/16/5/844 |
| _version_ | 1797264819583188992 |
|---|---|
| author | Thomas Rachman David Bartlett William LaFramboise Patrick Wagner Russell Schwartz Oana Carja |
| author_facet | Thomas Rachman David Bartlett William LaFramboise Patrick Wagner Russell Schwartz Oana Carja |
| author_sort | Thomas Rachman |
| collection | DOAJ |
| description | Circulating tumor DNA (ctDNA) monitoring, while sufficiently advanced to reflect tumor evolution in real time and inform cancer diagnosis, treatment, and prognosis, mainly relies on DNA that originates from cell death via apoptosis or necrosis. In solid tumors, chemotherapy and immune infiltration can induce spatially variable rates of cell death, with the potential to bias and distort the clonal composition of ctDNA. Using a stochastic evolutionary model of boundary-driven growth, we study how elevated cell death on the edge of a tumor can simultaneously impact driver mutation accumulation and the representation of tumor clones and mutation detectability in ctDNA. We describe conditions in which invasive clones are over-represented in ctDNA, clonal diversity can appear elevated in the blood, and spatial bias in shedding can inflate subclonal variant allele frequencies (VAFs). Additionally, we find that tumors that are mostly quiescent can display similar biases but are far less detectable, and the extent of perceptible spatial bias strongly depends on sequence detection limits. Overall, we show that spatially structured shedding might cause liquid biopsies to provide highly biased profiles of tumor state. While this may enable more sensitive detection of expanding clones, it could also increase the risk of targeting a subclonal variant for treatment. Our results indicate that the effects and clinical consequences of spatially variable cell death on ctDNA composition present an important area for future work. |
| first_indexed | 2024-04-25T00:34:58Z |
| format | Article |
| id | doaj.art-fa68bcff63db4f0a833e37d7c97d6aff |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-04-25T00:34:58Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fa68bcff63db4f0a833e37d7c97d6aff2024-03-12T16:40:33ZengMDPI AGCancers2072-66942024-02-0116584410.3390/cancers16050844Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA CompositionThomas Rachman0David Bartlett1William LaFramboise2Patrick Wagner3Russell Schwartz4Oana Carja5Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USAAllegheny Cancer Institute, Allegheny Health Network, Pittsburgh, PA 15224, USAAllegheny Cancer Institute, Allegheny Health Network, Pittsburgh, PA 15224, USAAllegheny Cancer Institute, Allegheny Health Network, Pittsburgh, PA 15224, USAComputational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USAComputational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USACirculating tumor DNA (ctDNA) monitoring, while sufficiently advanced to reflect tumor evolution in real time and inform cancer diagnosis, treatment, and prognosis, mainly relies on DNA that originates from cell death via apoptosis or necrosis. In solid tumors, chemotherapy and immune infiltration can induce spatially variable rates of cell death, with the potential to bias and distort the clonal composition of ctDNA. Using a stochastic evolutionary model of boundary-driven growth, we study how elevated cell death on the edge of a tumor can simultaneously impact driver mutation accumulation and the representation of tumor clones and mutation detectability in ctDNA. We describe conditions in which invasive clones are over-represented in ctDNA, clonal diversity can appear elevated in the blood, and spatial bias in shedding can inflate subclonal variant allele frequencies (VAFs). Additionally, we find that tumors that are mostly quiescent can display similar biases but are far less detectable, and the extent of perceptible spatial bias strongly depends on sequence detection limits. Overall, we show that spatially structured shedding might cause liquid biopsies to provide highly biased profiles of tumor state. While this may enable more sensitive detection of expanding clones, it could also increase the risk of targeting a subclonal variant for treatment. Our results indicate that the effects and clinical consequences of spatially variable cell death on ctDNA composition present an important area for future work.https://www.mdpi.com/2072-6694/16/5/844tumor growth modeltumor evolutionspatial evolutionctDNAtumor DNA shedding |
| spellingShingle | Thomas Rachman David Bartlett William LaFramboise Patrick Wagner Russell Schwartz Oana Carja Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition Cancers tumor growth model tumor evolution spatial evolution ctDNA tumor DNA shedding |
| title | Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition |
| title_full | Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition |
| title_fullStr | Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition |
| title_full_unstemmed | Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition |
| title_short | Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition |
| title_sort | modeling the effect of spatial structure on solid tumor evolution and circulating tumor dna composition |
| topic | tumor growth model tumor evolution spatial evolution ctDNA tumor DNA shedding |
| url | https://www.mdpi.com/2072-6694/16/5/844 |
| work_keys_str_mv | AT thomasrachman modelingtheeffectofspatialstructureonsolidtumorevolutionandcirculatingtumordnacomposition AT davidbartlett modelingtheeffectofspatialstructureonsolidtumorevolutionandcirculatingtumordnacomposition AT williamlaframboise modelingtheeffectofspatialstructureonsolidtumorevolutionandcirculatingtumordnacomposition AT patrickwagner modelingtheeffectofspatialstructureonsolidtumorevolutionandcirculatingtumordnacomposition AT russellschwartz modelingtheeffectofspatialstructureonsolidtumorevolutionandcirculatingtumordnacomposition AT oanacarja modelingtheeffectofspatialstructureonsolidtumorevolutionandcirculatingtumordnacomposition |