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Dataset ID
Description
Technology
Samples
EGAD00001004158
The extent to which cells in normal tissues accumulate mutations during life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors aged 20-75. Somatic mutations accumulate with age and are mainly caused by intrinsic mutational processes. We found strong Darwinian selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of such clones per square centimeter. By middle age, clones with cancer-associated mutations cover most of the epithelium, with NOTCH1 and TP53 mutations affecting 40% and 10% of all cells, respectively. Remarkably, the prevalence of NOTCH1 mutations in normal esophagus is several times higher than in esophageal cancers. The esophagus emerges as an evolving patchwork of mutant clones that colonize the majority of the epithelium, with implications for our understanding of cancer and ageing.
Illumina HiSeq 2500
-
EGAD00001006194
The risk of getting non-melanoma skin cancer varies over 40-fold across the body. Here we map mutations in normal skin in high and low risk sites in normal donors and those with an increased risk of skin cancer. The density of mutations varied widely, with evidence of positive and negative genetic selection. Regional differences in mutational signatures in high and low cancer risk sites and preferential selection of mutants of TP53 in high risk skin and FAT1 in lower risk skin were observed. 10% of clones had copy number changes in cancer associated genes and the largest had multiple driver mutations with loss of heterozygosity. In hair follicles, a proposed site of origin of skin cancers, mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. We conclude cancer risk reflects the efficiency of transformation of oncogenic mutants rather than the density of mutant clones.
HiSeq X Ten
Illumina HiSeq 2500
Illumina NovaSeq 6000
805
EGAD00001006969
NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age, but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations may promote clonal expansion but impede carcinogenesis. Here we test this hypothesis. Visualizing and sequencing NOTCH1 mutant clones in aging normal human esophagus, reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild type cells, an effect enhanced by loss of the second allele. Notch1 loss alters transcription but has minimal effects on epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. We conclude that Notch1 mutations in normal epithelium are beneficial as wild type Notch1 promotes tumor expansion. NOTCH1 blockade has therapeutic potential in esophageal squamous tumors.
Illumina HiSeq 2500
-
EGAD00001008281
Activating mutations in PIK3CA generate large clones in the aging human esophagus. Here we
investigate the underlying cellular mechanisms regulating their expansion by lineage tracing.
Expression of an activating heterozygous Pik3caH1047R mutation in single progenitor cells of the
mouse esophagus tilts cell fate towards proliferation, generating mutant clones that outcompete their
wild type neighbours. The mutation leads to increased aerobic glycolysis through the activation of
Hif1α transcriptional targets. In vitro and in vivo interventions that level out differences in activation
of the PI3K/HIF1α/aerobic glycolysis axis between wild type and Pik3caH1047R cells attenuate the
competitive advantage of the mutants. In contrast, metabolic conditions that alter Insulin/PI3K
signalling, such as type-1 diabetes or diet-induced insulin resistance, further increase Pik3caH1047R
mutant competitiveness in mice. Consistently, the density of activating PIK3CA mutations in human
esophagus is increased in overweight individuals. We conclude that the metabolic environment
influences the mutational landscape of normal epithelia. Clinically feasible interventions that even
out signalling imbalances between wild type and mutant cells may therefore limit the expansion of
oncogenic mutants in normal tissues.
Illumina HiSeq 2500
157
