Many private mutations originate from the first few divisions of a human colorectal adenoma.
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Date
2015-11-01ICR Author
Author
Kang, H
Salomon, MP
Sottoriva, A
Zhao, J
Toy, M
Press, MF
Curtis, C
Marjoram, P
Siegmund, K
Shibata, D
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Humans
Adenoma
Colorectal Neoplasms
Genetic Predisposition to Disease
Oligonucleotide Array Sequence Analysis
Gene Expression Profiling
DNA Mutational Analysis
Cell Division
DNA Methylation
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Gene Dosage
Phenotype
Point Mutation
Polymorphism, Single Nucleotide
Clonal Evolution
Biomarkers, Tumor
Language
eng
Date accepted
2015-06-24
License start date
2015-11
Citation
The Journal of pathology, 2015, 237 (3), pp. 355 - 362
Publisher
WILEY