Exploring_the_landscape_of_somatic_mutations_in_normal_tissue_POL_WGS

Somatic mutations (burdens and signatures) and clonal dynamics in individuals with germline DNA polymerase mutations.

Type: Cancer Genomics
Archiver: EGA European Genome-Phenome Archive

2 Datasets 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001006212	Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases POLE and POLD1 replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.	Illumina HiSeq 4000 Illumina NovaSeq 6000	211
EGAD00001006595	This dataset contains 160 single-cell derived blood colonies from two neonates and 6 adults. It also contains 18 samples that were used as matched normals to call mutations in NanoSeq data (dataset EGAD00001006459).	HiSeq X Ten Illumina NovaSeq 6000	13

Publications	Citations
Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Robinson PS, Coorens THH, Palles C, Mitchell E, Abascal F, Olafsson S, Lee BCH, Lawson ARJ, Lee-Six H, Moore L, Sanders MA, Hewinson J, Martin L, Pinna CMA, Galavotti S, Rahbari R, Campbell PJ, Martincorena I, Tomlinson I, Stratton MR. Nat Genet 53: 2021 1434-1442	39

Exploring_the_landscape_of_somatic_mutations_in_normal_tissue___POL___WGS

Exploring_the_landscape_of_somatic_mutations_in_normal_tissue_POL_WGS