Early culprits

Multi-institution research team finds that cancer-driving mutations can arise in endometrial cells early in life

Kelsey Kaustinen
LONDON—While endometrial, or uterine, cancer most commonly appears in older, post-menopausal women, new research has shown that driving mutations for this cancer subtype can arise at a much younger age.
By applying whole-genome sequencing to healthy human cells from glands in the endometrial epithelium (the lining of the uterus that is shed during menstruation), a team comprised of researchers from the Wellcome Sanger Institute, the University of Cambridge and collaborators generated an overview of patterns and rates of DNA change in endometrial cells. Their results, published in Nature, appeared in a paper titled “The mutational landscape of normal human endometrial epithelium.”
A total of 292 endometrial glands from uterine tissue samples—donated by 28 women, whose ages ranged from 19 to 81 years—underwent whole-genome sequencing. Somatic mutations were identified by comparing the endometrial samples with whole-genome sequencing results for other tissues from the same individual.
Of the sequenced endometrial cells, a high proportion presented with driver mutations despite appearing normal during microscopic evaluation. Cancer-driving mutations are somatic mutations that occur in known oncogenic genes and can cause a healthy cell to turn cancerous. Even more surprisingly, many of the mutations seemed to have arisen early in life, even as early as childhood.
“Human endometrium is a highly dynamic tissue that undergoes numerous cycles of remodeling during female reproductive years. We identified frequent cancer driver mutations in normal endometrium and showed that many such events had occurred early in life, in some cases even before adolescence. Over time, these mutant stem cells accumulate further driver mutations,” said Dr. Luiza Moore, the lead researcher based at the Wellcome Sanger Institute.
Even if a cell has a cancer-driving mutation, three to six such mutations are generally needed for cancer to result, and developing those additional mutations can take decades.
“New technologies and approaches to investigating DNA mutations in normal tissues are providing profound insights into the procession of genetic changes that convert a normal cell into a cancer cell,” commented Prof. Mike Stratton, director of the Wellcome Sanger Institute. “The results indicate that, 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.”
“Incidence of uterine cancers have been steadily rising in the U.K. for several decades, so knowing when and why genetic changes linked to cancer occur will be vital in helping to reverse this trend. This research is an important step and wouldn’t have been possible without the individuals who gifted precious samples for this study, including transplant donors and their families,” added Dr. Kourosh Saeb-Parsy, University of Cambridge and director of the Cambridge Biorepository for Translational Medicine (CBTM). The CBTM provided the tissue samples for this research, which came from post-mortem or transplant donors.
Victoria L. Bae-Jump of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and Douglas A. Levine of the Perlmutter Cancer Center at NYU Langone Health authored a Nature commentary piece centered on this research, titled “A catalogue of cancer-driving mutations in healthy tissue.” They noted that “A remarkable finding is that each endometrial gland seems to be clonal—that is, all the cells in the gland are derived from a single epithelial progenitor cell. It might be expected that each gland could develop multiple independent mutations, but the authors’ discovery of clonality indicates that there is instead a uniformity to the mutational process … They report that many glands that were located in close physical proximity in the uterine wall displayed distant phylogeny. This suggests that the cellular populations in each gland remain genetically isolated, providing many separate opportunities for cancer to develop.”
“Knowing that the compilation of driver mutations in normal endometrial glands is different from those found in established endometrial cancers might change the approach for further research into the prevention and early detection of this disease. Determining the role of these mutations in concert with other known risk factors, such as nulliparity [never having given birth], obesity, race and genetic predisposition, will help to better identify women who are at risk of endometrial cancer,” Bae-Jump and Levine added.
According to Cancer Research UK, uterine cancer is the fourth most common cancer for women in the U.K., comprising 5 percent of all new cancer cases for women. Worldwide, the World Cancer Research Fund reports that uterine/endometrial cancer is the sixth most common cancer in women, and the 14th most common overall. Global incidence and mortality rates for this cancer type have been increasing in recent years.
SOURCE: Wellcome Sanger Institute press release
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