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Researchers at the Wellcome Sanger Institute and the University of Cambridge have found that ‘cancer-driving’ mutations occur commonly in cells of the uterine inner lining, often arising early in life. Using whole-genome sequencing, the research team was able to search for mutations in the cells of healthy uterine endometrium by comparing their genomes with those of tissues from other parts of the body. The findings, published in Nature, show that the mutations leading to uterine cancer can occur decades before they manifest as an invasive cancer, shedding light on the earliest stages of this developmental process.

Uterine cancer is the fourth most common cancer in women in the UK, accounting for five per cent of all new female cancer cases. Dr Kourosh Saeb-Parsy, of the University of Cambridge and Director of the Cambridge Biorepository for Translational Medicine (CBTM), says: “Incidence of uterine cancers have been steadily rising in the UK for several decades, so knowing when and why genetic changes linked to cancer occur will be vital in helping to reverse this trend.”

The endometrium, more commonly known as the womb lining, is the inner part of the uterus. It adopts multiple physiological states over a lifetime, regulated by levels of hormones such as oestrogen and progesterone. It is lined by a gland-forming epithelium, the layer that sheds during menstruation. Most somatic mutations (changes in DNA that do not occur in the sperm or egg) in the cells of this epithelial layer are harmless, but a tiny fraction can result in a cell becoming cancerous. These mutations are called ‘driver’ mutations, and they take place within a subset of cancer genes.

The researchers used laser-capture microscopy to isolate 292 endometrial glands from womb tissue samples donated by 28 different women, before sequencing the DNA in each gland. They found that a high proportion of cells carried driver mutations in cancer genes, even though they appeared normal under the microscope. These mutations often originate during the first decades of life, and then progressively colonize the epithelial lining of the endometrium. The timing of the driver mutations was calculated by constructing phylogenetic trees for the sampled glands and assuming a constant somatic mutation rate, allowing the researchers to model genetic change over time.

Although the first driver mutation may occur early, it takes multiple such mutations in a given cell before an invasive cancer develops. This means that the majority of cells with driver mutations never become cancerous, but when a cancer does develop it can be the result of a process occurring over many years, sometimes even starting before adolescence. As Professor Sir Mike Stratton, Director of the Welcome Sanger Institute, explains, “Although most cancers occur at relatively advanced ages, the genetic changes that underlie them may have started early in life and we may have been incubating the developing cancer for most of our lifetime.”

This research serves as a valuable insight into the process by which normal cells evolve into malignant ones over the course of a lifetime. Indeed, the findings may have implications beyond the specific case of uterine cancer. The authors of the paper note that “this perspective on the long duration of neoplastic evolution of invasive endometrial cancer has resonance with previous observations of leukaemia ... and may be a common feature of the development of human cancers.”

Publication: Luiza Moore, Daniel Leongamornlert and Tim H. H. Coorens et. al. (2020). The mutational landscape of normal human endometrial epithelium. Nature. DOI: 10.1038/s41586-020-2214-z

Zak Lakota-Baldwin is a news editor at Bluesci