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Detection of Copy Number Alterations Using Single Cell Sequencing
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Cancer subclone detection based on DNA copy number in single-cell and spatial omic sequencing data.

Chi-Yun Wu1,2, Jiazhen Rong1,2, Anuja Sathe3

  • 1Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA, USA.

Nature Methods
|September 15, 2025
PubMed
Summary

Clonalscope identifies distinct cancer subclones using copy number profiles in single-cell and spatial transcriptomics data. This method aids in understanding tumor evolution and improving cancer therapy by revealing subclone characteristics and spatial distribution.

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Area of Science:

  • Genomics
  • Computational Biology
  • Cancer Research

Background:

  • Somatic mutations, including copy number alterations, drive cancer progression and intratumor heterogeneity.
  • Understanding the genetic makeup and spatial arrangement of tumor subclones is crucial for effective cancer treatment and unraveling tumor evolution.

Purpose of the Study:

  • To introduce Clonalscope, a novel computational method for detecting and characterizing tumor subclones.
  • To apply Clonalscope to spatial transcriptomics and single-cell sequencing data for comprehensive subclone analysis.

Main Methods:

  • Clonalscope utilizes copy number profiles and a nested Chinese Restaurant Process for de novo subclone identification.
  • The method can integrate prior information from bulk DNA sequencing for enhanced subclone detection and malignant cell labeling.
  • It is applicable to single-cell RNA sequencing (scRNA-seq), single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq), and spatial transcriptomics data.

Main Results:

  • Clonalscope successfully labeled malignant cells and identified distinct subclones in gastrointestinal tumors using scRNA-seq and scATAC-seq data.
  • In spatial transcriptomics data from various tumors, Clonalscope identified spatially segregated subclones with varying differentiation levels.
  • The method revealed subclones expressing genes linked to drug resistance and survival in both primary and metastatic tumors.

Conclusions:

  • Clonalscope is an effective tool for dissecting intratumor heterogeneity using copy number profiles.
  • The method provides insights into tumor evolution, spatial architecture, and potential therapeutic vulnerabilities.
  • Clonalscope's ability to analyze diverse single-cell and spatial data enhances its utility in cancer research and precision medicine.