Deep sequencing of the X chromosome reveals the proliferation history of colorectal adenomas

Anna De Grassi, Fabio Iannelli, Matteo Cereda, Sara Volorio, Valentina Melocchi, Alessandra Viel, Gianluca Basso, Luigi Laghi, Michele Caselle, Francesca D. Ciccarelli

Research output: Contribution to journalArticle

Abstract

Background: Mismatch repair deficient colorectal adenomas are composed of transformed cells that descend from a common founder and progressively accumulate genomic alterations. The proliferation history of these tumors is still largely unknown. Here we present a novel approach to rebuild the proliferation trees that recapitulate the history of individual colorectal adenomas by mapping the progressive acquisition of somatic point mutations during tumor growth. Results: Using our approach, we called high and low frequency mutations acquired in the X chromosome of four mismatch repair deficient colorectal adenomas deriving from male individuals. We clustered these mutations according to their frequencies and rebuilt the proliferation trees directly from the mutation clusters using a recursive algorithm. The trees of all four lesions were formed of a dominant subclone that co-existed with other genetically heterogeneous subpopulations of cells. However, despite this similar hierarchical organization, the growth dynamics varied among and within tumors, likely depending on a combination of tumor-specific genetic and environmental factors. Conclusions: Our study provides insights into the biological properties of individual mismatch repair deficient colorectal adenomas that may influence their growth and also the response to therapy. Extended to other solid tumors, our novel approach could inform on the mechanisms of cancer progression and on the best treatment choice.

Original languageEnglish
Article number437
JournalGenome Biology
Volume15
Issue number8
DOIs
Publication statusPublished - Aug 30 2014

Keywords

  • Cancer genomics
  • Clonal evolution
  • Colorectal cancer
  • Tumor proliferation history

ASJC Scopus subject areas

  • Cell Biology
  • Ecology, Evolution, Behavior and Systematics
  • Genetics

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  • Cite this

    De Grassi, A., Iannelli, F., Cereda, M., Volorio, S., Melocchi, V., Viel, A., Basso, G., Laghi, L., Caselle, M., & Ciccarelli, F. D. (2014). Deep sequencing of the X chromosome reveals the proliferation history of colorectal adenomas. Genome Biology, 15(8), [437]. https://doi.org/10.1186/s13059-014-0437-8