Click on a Dataset ID in the table below to learn more, and to find
out who to contact about access to these data
Dataset ID
Description
Technology
Samples
EGAD00001008764
The single base substitution mutational signatures SBS2 and SBS13, likely caused by APOBEC cytosine deaminases, are common in many human cancer types. However, the stimulus activating APOBEC mutagenesis is unknown and understanding of when it occurs in the progression from normal to cancer cell is limited. Here, as part of a wider survey of human tissues, we whole genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals. SBS2/13 mutations were present in 17% normal small intestine crypts and were likely due to APOBEC3A activity. Localised clusters of SBS2/13 mutations (kataegis) were also commonly found. APOBEC mutation burdens were variable between individuals and between crypts from the same individual. Crypts with SBS2/13 often had immediate crypt neighbours without SBS2/13, suggesting that the underlying cause of SBS2/13 is cell-intrinsic rather than a widely distributed microenvironmental exposure, or needs to be permitted by cell-intrinsic conditions. APOBEC mutagenesis occurred throughout the human lifespan, including in young children, and was episodic with a small number of episodes occurring during the life history of a single cell. The results indicate that APOBEC mutagenesis is more common in the small intestine epithelium than in many other cell types, and is an episodic process in vivo initiated or permitted by cell intrinsic factors.
HiSeq X Ten
Illumina NovaSeq 6000
31
EGAD00001015471
The succession of somatic genetic events associated with the conversion of a normal colorectal epithelial cell into a colorectal carcinoma constitutes a paradigmatic model of cancer development. To investigate the earliest stages of the progression, we microdissected and individually whole genome sequenced 279 histologically normal and abnormal colorectal crypts from 15 individuals with Familial Adenomatous Polyposis in whom one inherited APC gene allele carries an inactivating mutation. Histologically normal crypts generally exhibited similar mutation burdens and mutational signatures to normal crypts from wild-type individuals of the same age, and 1/110 such crypts carried a somatic inactivating APC mutation. By contrast, 9/17 aberrant crypt foci carried somatic APC mutations and these showed modestly increased burdens of some mutational signatures found in normal crypts. 16/16 diminutive adenomatous polyps (<5mm diameter) showed somatic APC mutations and carried substantially increased mutation loads of most mutational signatures present in normal crypts. Phylogenetic trees of crypts from aberrant crypt foci and adenomatous polyps revealed that some had acquired their initiating somatic APC mutations decades previously during the first few years of life. The results catalogue the changes in somatic mutation rates, mutational processes and “driver” mutations in cancer genes during very early stages of colorectal neoplastic transformation and highlight the long periods of clonal evolution required for a cancer to develop.
HiSeq X Ten
Illumina NovaSeq 6000
-
