Bootstrap confidence for molecular evolutionary estimates from tumor bulk sequencing data

Bulk sequencing is commonly used to characterize the genetic diversity of cancer cell populations in tumors and the evolutionary relationships of cancer clones. However, bulk sequencing produces aggregate information on nucleotide variants and their sample frequencies, necessitating computational methods to predict distinct clone sequences and their frequencies within a sample. Interestingly, no methods are available to measure the statistical confidence in the variants assigned to inferred clones. We introduce a bootstrap resampling approach that combines clone prediction and statistical confidence calculation for every variant assignment. Analysis of computer-simulated datasets showed the bootstrap approach to work well in assessing the reliability of predicted clones as well downstream inferences using the predicted clones (e.g., mapping metastatic migration paths). We found that only a fraction of inferences have good bootstrap support, which means that many inferences are tentative for real data. Using the bootstrap approach, we analyzed empirical datasets from metastatic cancers and placed bootstrap confidence on the estimated number of mutations involved in cell migration events. We found that the numbers of driver mutations involved in metastatic cell migration events sourced from primary tumors are similar to those where metastatic tumors are the source of new metastases. So, mutations with driver potential seem to keep arising during metastasis. The bootstrap approach developed in this study is implemented in software available at https://github.com/SayakaMiura/CloneFinderPlus.

• Publication year

  2023

• Venue

  Frontiers in Bioinformatics

• Publication date

  2023-05-16

• Fields of study

  Biology, Medicine, Computer Science

• Identifiers
  DOI 10.3389/fbinf.2023.1090730PMID 37261293PMCID 10228696
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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