The mutational landscape of normal human endometrial epithelium

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

doi:10.1038/s41586-020-2214-z

Cited by 396 publications

(375 citation statements)

References 57 publications

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“…This hypothesis seems well supported by two recent studies wherein individual endometrial glands were laser-captured from different areas within the endometrium of the same patient. Both studies suggest that different glands harbored different mutations [34,35]. These studies and our own results are also consistent with the findings by Mutter et al (2014) [20],where PTEN-loss appears zonally in single, or small clusters of, glands (Supplementary Figure S1).…”

Section: Discussionsupporting

confidence: 92%

“…These studies and our own results are also consistent with the findings by Mutter et al (2014) [20],where PTEN-loss appears zonally in single, or small clusters of, glands (Supplementary Figure S1). Therefore, although our study represents broader sampling of the endometrium and mutations, our observations and those of others [34,35] are consistent with driver mutations, such as KRAS G12 mutations, occurring in small, clonal pockets throughout the uterus. Furthermore, it seems likely that acquisition of these mutations provides sufficient selective advantages to expand within an entire gland of affected endometrial cells, allowing this population to be detectable by our methods.…”

Section: Discussionsupporting

confidence: 89%

“…Although some of our normal endometrium specimens harbored multiple driver alterations within the same block, this was relatively uncommon and it remains unclear if mutations affected overlapping populations or independent subclones. The recent study by Moore et al found two or more driver mutations in single endometrial glands in 22% of specimens [35], suggesting an elevated probability, albeit still nonconclusive, that driver mutations may co-exist in the same non-cancerous cells.…”

Section: Discussionmentioning

confidence: 99%

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Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?

Lac

Nazeran

Tessier‐Cloutier

et al. 2019

Preprint

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The presence of somatic driver mutations in endometriosis has previously been believed to represent early events in transformation, however our group and others have described such mutations in roughly one-third of cases of deep infiltrating or iatrogenic endometriosis. These forms of endometriosis rarely progress to malignancy. Recent studies have also shown somatic driver mutations in normal skin, blood, peritoneal washings, and esophageal epithelium. Such findings prompt speculation on whether such mutations exist in the eutopic endometrium – the likely tissue of origin of endometriosis. In the current study we investigated the presence of somatic driver mutations in histologically normal endometrium from women lacking evidence of gynecologic malignancy or endometrial hyperplasia. Twenty-five women who underwent hysterectomies and 85 women who underwent endometrial biopsies were included in this study. Formalin-fixed, paraffin-embedded tissue specimens were analyzed by means of targeted sequencing followed by orthogonal validation with droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) was also performed as surrogates for inactivating mutations in the respective genes. Overall, we observed somatic driver-like events in over 50% of histologically normal endometrial samples analyzed, which included hotspot mutations in KRAS, PIK3CA, and FGFR2 as well as PTEN-loss by IHC. Analysis of anterior and posterior samplings collected from women who underwent hysterectomies is consistent with the presence of somatic driver mutations within clonal pockets spread throughout the uterus. The prevalence of such oncogenic mutations also increased with age (OR: 1.05 (95% CI: 1.00 – 1.10), p = 0.035). These findings have implications on our understanding of aging and so-called “normal tissues”, thereby necessitating caution in the utilization of mutation-based early detection tools for endometrial or other cancers.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?

Lac

Nazeran

Tessier‐Cloutier

et al. 2019

Preprint

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“…Cancers of the colorectum and endometrium are the predominant types associated with germline and somatic POLE/POLD1 mutations 16,17,45 . Similar to intestinal crypts, endometrial glands are clones derived from a single recent ancestral stem cell and whole genome sequencing of a gland reveals the mutations present in that ancestral cell 29,46 . Twelve endometrial glands dissected from a 60 year-old carrying a POLE L424V germline mutation showed elevated rates of SBS accumulation (177/year vs. 29/year in normal individuals) and ID (13/year vs. <1/year in normal individuals) (Fig 3a).…”

Section: Mutagenesis In Other Tissuesmentioning

confidence: 99%

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

Robinson

Coorens

Palles

et al. 2020

Preprint

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Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases Pol e and Pol d replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.POLE and POLD1 exonuclease domain mutations can also be inherited through the germline causing a rare autosomal dominant familial cancer predisposition syndrome, known as Polymerase Proofreading Associated Polyposis (PPAP), characterised primarily by early-onset colorectal and endometrial tumours 16,17 . It is plausible that an increased somatic mutation rate underlies this cancer predisposition and high somatic mutation loads have been reported in the small number of neoplasms analysed from such individuals 17 . However, whether the mutation rate is elevated in normal cells, or just in neoplastic cells, is not known. If elevated in normal cells, the magnitude of the increase, whether it is raised over the whole lifespan, the range of tissues and fraction of cells in each tissue it affects, and the impact of subsequent neoplastic change are important questions to address in elucidating the pathogenesis of neoplastic transformation.Accrual of somatic mutations has been proposed as the primary biological mechanism underlying ageing 18-21 . This hypothesis is based on the premises that a) mutations accumulate throughout life; and b) higher mutation loads cause widespread malfunction of cell biology. Recent reports have confirmed that the somatic mutation burden in normal cells does increase during life in a more or less linear manner 22-30 , compatible with a causal role for somatic mutations in ageing. However, somatic mutations could, in principle, accumulate without significant biological consequences. Thus, study of individuals with inherited POLE or POLD1 exonuclease domain mutations could provide insi...

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“…Structural variants were called using the BRASS algorithm (https://github.com/cancerit/BRASS) as previously described 1 . Calls were filtered using AnnotateBRASS (https://github.com/MathijsSanders/AnnotateBRASS) as previously described 5 .…”

Section: Structural Variantsmentioning

confidence: 99%

Somatic evolution in non-neoplastic IBD-affected colon

McIntyre

Coorens

Butler

et al. 2019

Preprint

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paragraph Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers 1-3 but our understanding of the effects of IBD on the mutational profile and clonal structure of the colon is limited. Here, we isolated and whole-genome sequenced 370 colonic crypts from 45 IBD patients, and compared these to 413 crypts from 41 non-IBD controls. We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon, and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeterscale clonal expansions. We also found that non-synonymous mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients. With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. Our results provide new insights into the consequences of chronic intestinal inflammation on the 2. Adami, H.-O. et al. The continuing uncertainty about cancer risk in inflammatory bowel disease. Gut 65, 889-893 (2016). 3. Lutgens, M. W. M. D. et al. Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm. Bowel Dis.

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The mutational landscape of normal human endometrial epithelium

Cited by 396 publications

References 57 publications

Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?

Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

Somatic evolution in non-neoplastic IBD-affected colon

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