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Somatic mutant selection is altered by prior NOTCH1 mutation in ageing esophageal epithelium

Authors: Charlotte King1, Emilie Abbie1, Joanna C. Fowler1, Irina Abnizova1, Roshan K. Sood1, Swee Hoe Ong1, Michael W. J. Hall1,2, Faye Lynch-Williams3, Benjamin A. Hall4, Philip H. Jones1,2,5 Abstract: In cancer evolution, genome alterations often occur in a specific order, implying selection depends on the prior clonal genotype 1-3. It is unknown if similar constraints operate in normal epithelia. Here, we mapped mutations in normal mid-esophagus of aged UK subjects. Mutant NOTCH1 clones colonized most of the epithelium by age 60 and above 70 tissue was saturated with mutants under strong competitive selection. Mutant TP53 was more strongly selected in donors over 60 years of age. Samples predominantly mutant for NOTCH1 showed increased selection of NOTCH2 mutants and weaker selection of mutant TP53 compared with samples that were mostly NOTCH1 wild type. In mouse esophagus lacking Notch1 we observed strong selection of mutant Notch2 and other genes not selected in wild type esophagus. In normal ageing esophagus, the first driver mutation may change the trajectory of subsequent somatic evolution by altering mutant selection.

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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001007695 Other

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ID File Type Size Located in
EGAF00008374604 cram 10.0 GB
EGAF00008374605 cram 9.9 GB
EGAF00008374606 cram 8.7 GB
EGAF00008374607 cram 9.5 GB
EGAF00008374608 cram 9.3 GB
EGAF00008374609 cram 9.4 GB
EGAF00008374610 cram 8.7 GB
EGAF00008374611 cram 9.6 GB
EGAF00008374612 cram 11.1 GB
EGAF00008374613 cram 8.4 GB
EGAF00008374614 cram 10.2 GB
EGAF00008374615 cram 8.3 GB
EGAF00008374616 cram 9.5 GB
EGAF00008374617 cram 9.2 GB
EGAF00008374618 cram 8.7 GB
EGAF00008374619 cram 8.6 GB
EGAF00008374620 cram 7.7 GB
EGAF00008374621 cram 9.0 GB
EGAF00008374622 cram 9.9 GB
EGAF00008374623 cram 8.6 GB
EGAF00008374624 cram 9.3 GB
EGAF00008374625 cram 9.0 GB
EGAF00008374626 cram 8.6 GB
EGAF00008374627 cram 8.3 GB
EGAF00008374628 cram 8.6 GB
EGAF00008374629 cram 8.3 GB
EGAF00008374630 cram 9.0 GB
EGAF00008374631 cram 8.3 GB
EGAF00008374632 cram 9.8 GB
EGAF00008374633 cram 8.3 GB
EGAF00008374634 cram 8.9 GB
31 Files (280.7 GB)