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MutWPX__CRUK_Grand_Challenge_Mutographs_of_Cancer__Effects_of_Chemotherapy_on_the_Somatic_Mutational_Landscape_in_Normal_Human_Tissue___Matched_Normals

This study is investigating the effects of chemotherapy drugs used in cancer treatment on the somatic mutational landscape in normal human tissues. The samples used in this study have been taken from rapid autopsies of patients who have undergone chemotherapy using drugs thought to cause mutations in the DNA. Structures from a variety of tissues will be dissected using LCM and whole genome sequences will be produced in order to assess mutational burdens and signatures. This study contains the samples used as matched normals for each patient to remove germline mutations.

Type: Whole Genome Sequencing
Archive: European Genome-phenome Archive (EGA)

2 Datasets

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Dataset ID	Description	Technology	Samples
EGAD00001015828	Lifestyle, environmental and other exposures to exogenous mutagens generate somatic mutations in normal human cells in vivo and increase cancer risk. However, the global repertoire of exogenous mutagen exposures is uncertain. Using single-molecule duplex sequencing of normal kidney (n=319) and blood (n=272) samples from 10 countries, we show that kidney proximal tubule cells exhibit higher mutation rates than most normal cell types despite low cell division rates. Compared to cells from kidney glomeruli, medulla, distal tubules, or peripheral blood, proximal tubule cells show marked enrichment of mutational signatures due to the exogenous carcinogenic mutagens, aristolochic acids, and of several signatures of unknown causes. The results suggest the existence of multiple, common, systemically circulated mutagens affecting human populations and indicate that the genomes of kidney proximal tubule cells report such exposures with high sensitivity.	HiSeq X Ten Illumina NovaSeq 6000	333
EGAD00001016809	Mutations accumulate in normal human cells over the course of an individual’s lifetime. Early studies have shown differences in mutation rates and mutational signatures between cell types, but the range of tissues investigated has been constrained by limitations of DNA sequencing technologies. Here, we employ genome-wide NanoSeq single molecule duplex sequencing to survey the mutation landscapes of 53 normal cell types and tissue structures purified by laser-capture microdissection and flow sorting. Single base substitution mutation rates ranged from ~3/year in spermatogonia and sperm contributing to the male germline, to ~20/year in postmitotic neurons, ~50/year in mitotically active colorectal epithelial cells, ~60/year in kidney proximal tubule cells and hepatocytes, 100s/year in ultraviolet light exposed skin epidermis and from 10-50/year across the other cell types. At least 18 single base substitution and 9 small insertion and deletion mutational signatures contribute to mutation burdens, some to all cell types, some to subsets of cell types and others to a single cell type. Known exogenous mutagen exposures and endogenous mutational processes account for some mutational signatures but the origins and mechanisms underlying many are uncertain. This comprehensive survey of mutagenesis provides a foundation for understanding somatic evolution in human cell populations in health and disease.	HiSeq X Ten Illumina NovaSeq 6000	6