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A clinically annotated post-mortem approach to study multi-organ somatic mutational clonality in normal tissues.

Tom Luijts1,2,3, Kerryn Elliott3, Joachim Tetteh Siaw1,2,3

  • 1Department of Human Structure and Repair, Ghent University, Ghent, Belgium.

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|June 21, 2022
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Summary

Researchers discovered widespread cell clones with cancer-driving mutations in healthy tissues using post-mortem samples. This whole-body donor approach offers a new resource for studying early cancer evolution and mutagenic insights.

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Area of Science:

  • Genomics
  • Oncology
  • Human Pathology

Background:

  • Normal human tissues harbor cell clones with cancer-associated somatic mutations (e.g., TP53, NOTCH1).
  • Existing studies often rely on surgical tissues, limiting pan-organ analysis and access to diverse tissues.
  • Tumor evolution models are being revised due to these findings.

Purpose of the Study:

  • To establish and validate a post-mortem tissue approach for studying clonal dynamics in healthy human organs.
  • To investigate the presence and selection of somatic mutations in various tissues using whole-body donor samples.
  • To explore the impact of environmental factors like smoking on clonal evolution in oral epithelia.

Main Methods:

  • Utilized clinically annotated post-mortem whole-body donor tissues from human anatomy units.
  • Validated the approach with UV-exposed and unexposed epidermal skin tissues.
  • Analyzed gene selection signals in TP53, NOTCH1/2, FAT1, immune genes, and housekeeping genes.

Main Results:

  • Confirmed the presence of positively selected NOTCH1/2-, TP53-, and FAT1-driven clones in skin tissues.
  • Observed no selection signals in immune or housekeeping genes, indicating specific clonal selection.
  • Provided evidence of smoking-induced clonal changes in oral epithelia, potentially linked to head and neck cancer origins.

Conclusions:

  • The whole-body donor approach provides an extensive resource for studying mutational clonality in healthy tissues.
  • This method enables fundamental insights into the earliest stages of tumor evolution.
  • Findings highlight the potential of post-mortem tissues for understanding pre-cancerous clonal dynamics and carcinogenesis.