Journal Article

The mutational landscape of normal human endometrial epithelium

Sanders, Mathijs A., Iacobuzio-Donahue, Christine A., Butler, Tim, Dentro, Stefan C., Tarpey, Patrick S., Coorens, Tim H. H., Lee-Six, Henry, Mitchell, Thomas J., Martincorena, Inigo, Nangalia, Jyoti, Moore, Luiza, Leongamornlert, Daniel, Brunner, Simon F., Hooks, Yvette, Mahbubani, Krishnaa T., Saeb-Parsy, Kourosh, Jimenez-Linan, Mercedes, Campbell, Peter J., Moody, Sarah, Brosens, Jan J., Maura, Francesco, Ellis, Peter, Dawson, Kevin J., Rahbari, Raheleh, Stratton, Michael R.

2020

Overview

All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium 1 , 2 . Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry ‘driver’ mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues—perhaps shaped by differences in their structure and physiology—and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life. Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14 / 14/63 / 45 / 45/23 / 631/208/737 / 631/67/69 / 692/308/2056 / Acquisitions & mergers / Adult / Age / Age of Onset / Aged / Aged, 80 and over / Aging - genetics / Analysis / Biopsy / Cancer / Carcinogenesis - genetics / Clone Cells - cytology / Cloning / Confidence intervals / Deoxyribonucleic acid / DNA / DNA Mutational Analysis / DNA sequencing / Endometrial cancer / Endometrial Neoplasms - genetics / Endometrium / Endometrium - cytology / Endometrium - metabolism / Endometrium - pathology / Epithelial cells / Epithelial Cells - cytology / Epithelial Cells - metabolism / Epithelial Cells - pathology / Epithelium / Epithelium - metabolism / Epithelium - pathology / Female / Gene sequencing / Genetic aspects / Genomes / Glands / Health / Humanities and Social Sciences / Humans / Middle Aged / multidisciplinary / Mutation / Mutation (Biology) / Nucleotide sequencing / Parity - genetics / Physiological aspects / Physiology / Science / Science (multidisciplinary) / Signatures / Somatic cells / Statistical analysis / Stem cells / Time Factors / Uterine cancer / Uterus / Whole genome sequencing / Womens health / Young Adult