NEW YORK – Normal endometrial glands often contain cancer-driving mutations, some of which may arise early in life, a new whole-genome sequencing study has found.
Researchers from the Wellcome Sanger Institute isolated normal endometrial glands, found in the uterine lining where they secrete hormones, from about two dozen women for analysis. Endometrial cancer is the sixth most common cancer globally among women with more than 382,000 cases each year.
As they reported in Nature Wednesday, the researchers found that these tissues, though normal, were clonal and harbored a number of mutations associated with cancer. That mutational burden further increased with increasing age, though some alterations crop up quite early on in life.
"Human endometrium is a highly dynamic tissue that undergoes numerous cycles of remodeling during female reproductive years," first author Luiza Moore from the Wellcome Sanger Institute said in a statement. "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."
Moore and her colleagues isolated 292 histologically normal endometrial glands from 28 women between 19 and 81 years of age using laser-capture microdissection. The women in the cohort were, for instance, undergoing biopsies to investigate reproductive problems or having a hysterectomy for benign non-endometrial condition, or were sampled after death.
After sequencing each gland to a mean 28-fold coverage, the researchers compared the somatic mutations in each gland to sequencing data from other tissues from the same person.
Almost 90 percent of the women in the cohort had endometrial tissue that harbored cancer driver mutations. These alterations affected genes like PIK3CA, ERBB2, KRAS, and FOXA2. On their own, though, these mutations appeared insufficient to lead to cancer, the researchers noted.
Additionally, most of the glands appeared to be clonal and were likely derived from a single epithelial progenitor cell, regardless of whether any of those driver mutations were present.
The number of mutations in the endometrial tissue increased with age. In particular, there was an increase of 29 nucleotide substitutions per gland per year, though this mutation level remained below that of endometrial tumors.
Through a phylogenetic analysis, the researchers traced back the timing of when these driver mutations arose. Assuming a constant somatic mutation rate — an assumption they noted was unlikely — the researchers estimated that some driver mutations emerged early in life. In particular, they noted that a KRAS mutation identified in three glands from a 35-year-old woman and a PIK3CA mutation found in two glands from a 34-year-old woman likely arose during their first decade of life.
This is a key finding, the University of North Carolina at Chapel Hill's Victoria Bae-Jump and NYU Langone Health's Douglas Levine wrote in a related commentary, also appearing in Nature. "This insight is important because the typical timeline between developing driver mutations and cancer is not yet well defined," they added.
They noted, though, that the study comes with a few caveats. For instance, the researchers collected samples from women undergoing evaluation for infertility, which is an independent risk factor for endometrial cancer. They suggested that future work might include samples from a cross-sectional population.
Still, the study hinted that the alterations leading to cancer later in life might be acquired young. "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," added senior author Michael Stratton from the Wellcome Sanger Institute in a statement.