title: Many private mutations originate from the first few divisions of a human colorectal adenoma.
abstract: Intratumoural mutational heterogeneity (ITH) or the presence of different private mutations in different parts of the same tumour is commonly observed in human tumours. The mechanisms generating such ITH are uncertain. Here we find that ITH can be remarkably well structured by measuring point mutations, chromosome copy numbers, and DNA passenger methylation from opposite sides and individual glands of a 6 cm human colorectal adenoma. ITH was present between tumour sides and individual glands, but the private mutations were side-specific and subdivided the adenoma into two major subclones. Furthermore, ITH disappeared within individual glands because the glands were clonal populations composed of cells with identical mutant genotypes. Despite mutation clonality, the glands were relatively old, diverse populations when their individual cells were compared for passenger methylation and by FISH. These observations can be organized into an expanding star-like ancestral tree with co-clonal expansion, where many private mutations and multiple related clones arise during the first few divisions. As a consequence, most detectable mutational ITH in the final tumour originates from the first few divisions. Much of the early history of a tumour, especially the first few divisions, may be embedded within the detectable ITH of tumour genomes.
authors.affiliation: Department of Pathology, CHA University, Seongnam-si, South Korea.
authors.forename: Haeyoun
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Salomon
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sottoriva
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Junsong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Toy
authors.affiliation: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
authors.affiliation: Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Curtis
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Marjoram
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Siegmund
authors.affiliation: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Darryl
authors.initials: D
authors.lastname: Shibata
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D002455:Cell Division; D060965:Clonal Evolution; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D014408:Biomarkers, Tumor
keywords: Big Bang tumourigenesis; adenoma; colorectal; intratumoural heterogeneity; mutation topography