Nature: The endometrial begins to produce cancer-causing mutations early in life!

April 23, 2020 /PRNewswire/ -- Understanding how normal tissues cause cancer is critical to improving prevention and early detection of this deadly disease Over the past two decades, the genome mapping of most types of invasive cancers has been mapped; however, similar analyses of normal tissue face a unique set of challenges Cancer tissue is usually obtained through biopsies or surgery, but samples of normal tissue tend to be much smaller and samples are not well collected, making it difficult to collect high-quality materials In a recent study published in the journal Nature, Moore, from the William Sanger Institute at the University of Cambridge, and his co-working partner, overcame these challenges and successfully discovered cancer-causing mutations in the normal endometrial glands study showed that many cells in the endometrium carry "carcinogenic" mutations, which usually occur early in life The team sequenced the whole genome of the endometrium in healthy humans to gain a comprehensive picture of the speed and pattern of changes in endometriosis DNA This study provides new ideas for the early development of uterine cancer the endometrium is located inside the uterus It is regulated by hormones such as estrogen and progesterone and enters different states during childhood, reproduction, pregnancy and menopause uterine cancer is the fourth most common female cancer in the UK, accounting for 5% of all new female cancer cases About 9,400 new cases are diagnosed each year, resulting in 2,300 deaths of women Most cases occurred in the 1970s and 1980s The incidence of uterine cancer in the UK has risen by 55% since the early 1990s image source: NIH All cancers occur due to changes in DNA, known as somatic cell mutations, which last a lifetime in all of our cells A small fraction of these somatic cell mutations help normal cells turn into cancer cells, and they are called "drive" mutations that occur in a class of "cancer" genes this study uses genome-wide sequencing to better understand genetic changes in healthy endometrial tissue The team developed a technique that can sort the genomes of small numbers of cells in individual glands in the epithelial tissue of the endometrial cortex The epithelial tissue of the endometrial membrane is the layer of tissue that falls off and regenerates during the female menstrual cycle researchers used laser-capture microscopes to separate 292 endometrial glands from uterine tissue samples donated by 28 women between the ages of 19 and 81, and then sequenced the DNA of each gland genome The team then looked for somatic cell mutations in each gland by comparing genome-wide sequences from other tissues from the same individual researchers found that although they appeared perfectly normal under the microscope, a large proportion of cells still had drive mutations Many of these drive mutations seem to occur early in life, in many cases in childhood Lead researcher Dr Luiza Moore, of the 's Wellcome Sanginstitute Institute, said: "The human endometrium is a highly dynamic tissue that has undergone numerous remodeling cycles at the female reproductive age We have found frequent cancer-driven mutations in the normal endometrium and found that many of these events occur early in life, some even before puberty Over time, these mutated stem cells accumulate more drive mutations "
Although the first cancer-driven mutation occurred early, it took decades for a cell to accumulate the remaining drivers, leading to invasive cancer Typically, three to six drive mutations are needed in the same cell to develop cancer As a result, the vast majority of normal cells with drive mutations never translate into invasive cancers As an invasive cancer develops, it may evolve quietly in our bodies for most of our lives image source: Dr Kouroh Saeb-Pary, director of the Transformative Medicine Bioincubation Programme (CBTM) at the University of Cambridge, said: "The incidence of uterine cancer has been rising steadily in the UK for decades and knowing when and why the genetic changes that cause cancer are crucial to helping reverse this trend The study is an important step, and it would not have been possible without those who donated valuable samples to the study, including transplant donors and their families Professor Mike Stratton, director of the Wellcome Sanger Institute at , said: "New techniques and methods for studying DNA mutations in normal tissues provide insightinto into the process of genetic change that converts normal cells into cancer cells The results suggest that although most cancers occur at a relatively late age, the genetic changes behind them may begin early in life, and we may have developing cancers for most of our lives "
understanding that the drive mutations of normal endometrial glands are different from those found in established endometrial cancers may change the way further research is used to prevent and detect the disease at an early stage." Determining these mutations and other known risk factors, such as ineffective fertility, obesity, race and genetic susceptibility, will help better determine the risk of endometrial cancer in women Even before we get this information, Moore and his colleagues' findings should be useful for ongoing research on early endometrial cancer testing, including analysis of cellless DNA circulating in the blood, collection of vaginal secretions and fluid examination of cervical tissue More broadly, a better understanding of the normal mutation spectrum in the tissue will give us a clearer picture of the consequences of specific cancer drivers for many solid tumors (BioValleyBioon.com) References: 1, Human uteru colonized by clone with with-driving the mutation arie early in life .
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, Nature (2020) DOI: 10.1038/41586-020-2214-z 3 A-a-ring of cancer-driving mutation in health tiue