title: Deep sequencing of the X chromosome reveals the proliferation history of colorectal adenomas.
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.
authors.forename: Anna
authors.initials: A
authors.lastname: De Grassi
authors.forename: Fabio
authors.initials: F
authors.lastname: Iannelli
authors.forename: Matteo
authors.initials: M
authors.lastname: Cereda
authors.forename: Sara
authors.initials: S
authors.lastname: Volorio
authors.forename: Valentina
authors.initials: V
authors.lastname: Melocchi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.forename: Gianluca
authors.initials: G
authors.lastname: Basso
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.forename: Michele
authors.initials: M
authors.lastname: Caselle
authors.forename: Francesca D
authors.initials: FD
authors.lastname: Ciccarelli
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000465:Algorithms; D041321:Chromosomes, Human, X / Q000235:genetics*; D060965:Clonal Evolution; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D059645:Mutation Rate; D017422:Sequence Analysis, DNA / Q000379:methods*