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Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition

  • 0Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Cancers +

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March 13, 2024

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March 13, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Spatially variable cell death in tumors can distort circulating tumor DNA (ctDNA) profiles. This bias in ctDNA may lead to inaccurate cancer assessments and treatment decisions, highlighting a critical area for future research.

Area Of Science

  • Oncology
  • Genomics
  • Computational Biology

Background

  • Circulating tumor DNA (ctDNA) monitoring is crucial for real-time tumor evolution tracking, diagnosis, treatment guidance, and prognosis.
  • Current ctDNA analysis primarily relies on DNA from apoptotic or necrotic cells, which can be influenced by tumor microenvironment factors like chemotherapy and immune infiltration.

Purpose Of The Study

  • To investigate how spatially variable cell death rates at tumor boundaries impact driver mutation accumulation and ctDNA representation.
  • To model the effects of biased cell shedding on clonal composition, mutation detectability, and variant allele frequencies (VAFs) in ctDNA.

Main Methods

  • Utilized a stochastic evolutionary model of boundary-driven tumor growth.
  • Simulated conditions with elevated cell death rates on the tumor periphery.
  • Analyzed the impact on driver mutation accumulation, clonal representation, and VAFs in ctDNA.

Main Results

  • Spatially variable cell death can lead to over-representation of invasive clones in ctDNA.
  • Observed potential inflation of subclonal VAFs and apparent elevation of clonal diversity in blood samples.
  • Demonstrated that quiescent tumors with spatial shedding bias are less detectable, and detection limits influence perceived bias.

Conclusions

  • Spatially structured cell death can significantly bias ctDNA profiles, potentially misrepresenting the true tumor state.
  • While biased shedding may enhance detection of expanding clones, it risks guiding treatment towards subclonal variants.
  • Further research is needed to understand the clinical implications of spatially variable cell death on ctDNA composition and its impact on cancer management.

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