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Cited by 54Cancer Genomics and DiagnosticsEvolution and Genetic DynamicsSingle-cell and spatial transcriptomics

Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium

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Yamaguchi, Manako, Nakaoka, Hirofumi, Suda, Kazuaki, Yoshihara, Kosuke, Ishiguro, Tatsuya, Yachida, Nozomi, Saito, Kyota, Ueda, Haruka +10 more·2022·Nature Communications
DOI 10.1038/s41467-022-28568-2PMC PMC8854701
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Abstract

It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that “rhizome structures”, in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases.

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  • The toolkit has a significant advantage to generate isogenic models of novel mutations in early tumorigenesis.

    “Taken together, these results demonstrate the significant advantage the toolkit we have developed in this study has to generate isogenic models of novel mutations in early tumorigenesis48,50–52.”

    From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [52]

    The Results section ('Cancer-associated gene mutations in normal endometrial glands'; page unavailable) identifies cancer-associated mutations in normal tissue, and the Discussion suggests that some mutations in endometrial cancers are inherited from normal endometrium. The paper does not assess a toolkit’s ability or advantage in generating isogenic models; the citing sentence describes that toolkit as the citing authors’ own work. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • This hypothesis had never before been tested in an isogenic model.

    “While this hypothesis has been previously proposed48,50–52, it had never before been tested in an isogenic model.”

    From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [52]

    The Results section describes sequencing naturally occurring endometrial glands, and the Discussion describes their clonal origins. Neither passage addresses whether the hypothesis had previously been tested in an isogenic model; a search for “isogenic model” found no such statement in our copy. (LLM, conf=0.72)

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Research works printed but not linked: 78

  1. [1]Stratton MR Campbell PJ Futreal PA The cancer genome Nature 2009 458 719 724 19360079 PMC2821689
  2. [2]Stratton MR Exploring the genomes of cancer cells: progress and promise Science 2011 331 1553 1558 21436442
  3. [3]Vogelstein B Cancer genome landscapes Science 2013 339 1546 1558 23539594 PMC3749880
  4. [6]Tomasetti C Li L Vogelstein B Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention Science 2017 355 1330 1334 28336671 PMC5852673
  5. [7]Tomasetti C Vogelstein B Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions Science 2015 347 78 81 25554788 PMC4446723
  6. [8]Wijewardhane N Dressler L Ciccarelli FD Normal somatic mutations in cancer transformation Cancer Cell 2021 39 125 129 33220180
  7. [11]Lee-Six H The landscape of somatic mutation in normal colorectal epithelial cells Nature 2019 574 532 537 31645730
  8. [12]Kakiuchi N Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis Nature 2020 577 260 265 31853061
  9. [13]Olafsson S Somatic evolution in non-neoplastic IBD-affected colon Cell 2020 182 672 684.e11 32697969 PMC7427325
  10. [16]Lac V Oncogenic mutations in histologically normal endometrium: the new normal? J. Pathol. 2019 249 173 181 31187483
  11. [18]Weaver JMJ Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis Nat. Genet. 2014 46 837 843 24952744 PMC4116294
  12. [19]Martincorena I Somatic mutant clones colonize the human esophagus with age Science 2018 362 911 917 30337457 PMC6298579
  13. [21]Brunner SF Somatic mutations and clonal dynamics in healthy and cirrhotic human liver Nature 2019 574 538 542 31645727 PMC6837891
  14. [22]Yoshida K Tobacco smoking and somatic mutations in human bronchial epithelium Nature 2020 578 266 272 31996850 PMC7021511
  15. [23]Martincorena I Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin Science 2015 348 880 886 25999502 PMC4471149
  16. [25]Martincorena I Campbell PJ Somatic mutation in cancer and normal cells Science 2015 349 1483 1489 26404825
  17. [26]Colom B Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium Nat. Genet 2020 52 604 614 32424351 PMC7116672
  18. [27]Emera D Romero R Wagner G The evolution of menstruation: a new model for genetic assimilation: explaining molecular origins of maternal responses to fetal invasiveness Bioessays 2012 34 26 35 22057551 PMC3528014
  19. [28]Gray CA Developmental biology of uterine glands Biol. Reprod. 2001 65 1311 1323 11673245
  20. [29]Tanaka M Evidence of the monoclonal composition of human endometrial epithelial glands and mosaic pattern of clonal distribution in luminal epithelium Am. J. Pathol. 2003 163 295 301 12819034 PMC1868187
  21. [30]Tempest N Histological 3D reconstruction and in vivo lineage tracing of the human endometrium J. Pathol. 2020 251 440 451 32476144
  22. [31]Yamaguchi M Three-dimensional understanding of the morphological complexity of the human uterine endometrium iScience 2021 24 102258 33796844 PMC7995615
  23. [32]Arora R Insights from imaging the implanting embryo and the uterine environment in three dimensions Development 2016 143 4749 4754 27836961 PMC5201036
  24. [33]Vue Z Gonzalez G Stewart CA Mehra S Behringer RR Volumetric imaging of the developing prepubertal mouse uterine epithelium using light sheet microscopy Mol. Reprod. Dev. 2018 85 397 405 29543367 PMC6644676
  25. [34]Alexandrov LB The repertoire of mutational signatures in human cancer Nature 2020 578 94 101 32025018 PMC7054213
  26. [35]Waters TR Swann PF Thymine-DNA glycosylase and G to A transition mutations at CpG sites Mutat. Res 2000 462 137 147 10767625
  27. [36]Alexandrov LB Clock-like mutational processes in human somatic cells Nat. Genet 2015 47 1402 1407 26551669 PMC4783858
  28. [37]Roberts SA Gordenin DA Hypermutation in human cancer genomes: footprints and mechanisms Nat. Rev. Cancer 2014 14 786 800 25568919 PMC4280484
  29. [38]Tate JG COSMIC: the catalogue of somatic mutations in cancer Nucleic Acids Res. 2019 47 D941 d947 30371878 PMC6323903
  30. [39]Martincorena I Universal patterns of selection in cancer and somatic tissues Cell 2017 171 1029 1041.e21 29056346 PMC5720395
  31. [41]Berger AC A comprehensive pan-cancer molecular study of gynecologic and breast cancers Cancer Cell 2018 33 690 705.e9 29622464 PMC5959730
  32. [42]Tashiro H Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies Cancer Res. 1997 57 3935 3940 9307275
  33. [43]Mitchell TJ Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal Cell 2018 173 611 623.e17 29656891 PMC5927631
  34. [45]Tainaka K Chemical landscape for tissue clearing based on hydrophilic reagents Cell Rep. 2018 24 2196 2210.e9 30134179
  35. [46]Roth A PyClone: statistical inference of clonal population structure in cancer Nat. Methods 2014 11 396 398 24633410 PMC4864026
  36. [47]Dang HX ClonEvol: clonal ordering and visualization in cancer sequencing Ann. Oncol. 2017 28 3076 3082 28950321 PMC5834020
  37. [49]Nik-Zainal S Hall BA Cellular survival over genomic perfection Science 2019 366 802 803 31727818 PMC6872451
  38. [50]Zhu M Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease Cell 2019 177 608 621.e12 30955891 PMC6519461
  39. [51]Kakiuchi, N. & Ogawa, S. Clonal expansion in non-cancer tissues. Nat. Rev. Cancer21, 239–256 (2021). 33627798
  40. [52]Greaves LC Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission Proc. Natl Acad. Sci. USA 2006 103 714 719 16407113 PMC1325106
  41. [53]Sangiorgi E Capecchi MR Bmi1 is expressed in vivo in intestinal stem cells Nat. Genet 2008 40 915 920 18536716 PMC2906135
  42. [55]Garry R Hart R Karthigasu KA Burke C Structural changes in endometrial basal glands during menstruation BJOG 2010 117 1175 1185 20560946
  43. [56]Ferenczy A Studies on the cytodynamics of human endometrial regeneration. I. Scanning electron microscopy Am. J. Obstet. Gynecol. 1976 124 64 74 1244749
  44. [57]Salamonsen LA Tissue injury and repair in the female human reproductive tract Reproduction 2003 125 301 311 12611594
  45. [58]Inoue S Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations Nat. Commun. 2019 10 5785 31857578 PMC6923389
  46. [59]Suda K Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis Cancer Sci. 2020 111 3000 3009 32473611 PMC7419022
  47. [60]Michels KA Pfeiffer RM Brinton LA Trabert B Modification of the associations between duration of oral contraceptive use and ovarian, endometrial, breast, and colorectal cancers JAMA Oncol. 2018 4 516 521 29346467 PMC5885214
  48. [61]Vercellini P Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis Hum. Reprod. Update 2011 17 159 170 20833638
  49. [62]Ahmadloo S Rapid and cost-effective high-throughput sequencing for identification of germline mutations of BRCA1 and BRCA2 J. Hum. Genet 2017 62 561 567 28179634
  50. [63]Suda, K. et al. Different mutation profiles between epithelium and stroma in endometriosis and normal endometrium. Hum. Reprod.34, 1899–1905 (2019). 31621846
  51. [64]Jones S Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma Science 2010 330 228 231 20826764 PMC3076894
  52. [65]Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma Nature 2011 474 609 615 21720365 PMC3163504
  53. [66]Norquist BM Inherited mutations in women with ovarian carcinoma JAMA Oncol. 2016 2 482 490 26720728 PMC4845939
  54. [67]Bolger AM Lohse M Usadel B Trimmomatic: a flexible trimmer for Illumina sequence data Bioinformatics 2014 30 2114 2120 24695404 PMC4103590
  55. [68]Li H Durbin R Fast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics 2009 25 1754 1760 19451168 PMC2705234
  56. [69]Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv 1303.3997v2. Preprint at https://arxiv.org/abs/1303.3997 (2013). · arXiv
  57. [70]Li H The sequence alignment/map format and SAMtools Bioinformatics 2009 25 2078 2079 19505943 PMC2723002
  58. [71]McKenna A The genome analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data Genome Res 2010 20 1297 1303 20644199 PMC2928508
  59. [72]DePristo MA A framework for variation discovery and genotyping using next-generation DNA sequencing data Nat. Genet 2011 43 491 498 21478889 PMC3083463
  60. [73]Neph S BEDOPS: high-performance genomic feature operations Bioinformatics 2012 28 1919 1920 22576172 PMC3389768
  61. [74]Quinlan AR Hall IM BEDTools: a flexible suite of utilities for comparing genomic features Bioinformatics 2010 26 841 842 20110278 PMC2832824
  62. [75]Kim S Strelka2: fast and accurate calling of germline and somatic variants Nat. Methods 2018 15 591 594 30013048
  63. [76]Chen X Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications Bioinformatics 2016 32 1220 1222 26647377
  64. [77]Auton A A global reference for human genetic variation Nature 2015 526 68 74 26432245 PMC4750478
  65. [79]Karczewski KJ The mutational constraint spectrum quantified from variation in 141,456 humans Nature 2020 581 434 443 32461654 PMC7334197
  66. [80]McLaren W The ensembl variant effect predictor Genome Biol. 2016 17 122 27268795 PMC4893825
  67. [81]Baez-Ortega A Gori K Computational approaches for discovery of mutational signatures in cancer Brief. Bioinform. 2019 20 77 88 28968631 PMC6357558
  68. [82]Maura F A practical guide for mutational signature analysis in hematological malignancies Nat. Commun. 2019 10 2969 31278357 PMC6611883
  69. [83]Gori, K. & Baez-Ortega, A. sigfit: flexible Bayesian inference of mutational signatures. bioRxiv, 372896. Preprint at 10.1101/372896 (2020). · DOI
  70. [84]Greenman C Wooster R Futreal PA Stratton MR Easton DF Statistical analysis of pathogenicity of somatic mutations in cancer Genetics 2006 173 2187 2198 16783027 PMC1569711
  71. [86]Barter RL Yu B Superheat: an R package for creating beautiful and extendable heatmaps for visualizing complex data J. Comput Graph Stat. 2018 27 910 922 30911216 PMC6430237
  72. [87]Li H Toward better understanding of artifacts in variant calling from high-coverage samples Bioinformatics 2014 30 2843 2851 24974202 PMC4271055
  73. [89]Imielinski M Guo G Meyerson M Insertions and deletions target lineage-defining genes in human cancers Cell 2017 168 460 472.e14 28089356 PMC5564321
  74. [90]Shen R Seshan VE FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing Nucleic Acids Res. 2016 44 e131 27270079 PMC5027494
  75. [91]Saitou N Nei M The neighbor-joining method: a new method for reconstructing phylogenetic trees Mol. Biol. Evol. 1987 4 406 425 3447015
  76. [92]Paradis E Claude J Strimmer K APE: analyses of phylogenetics and evolution in R language Bioinformatics 2004 20 289 290 14734327
  77. [93]Schliep KP phangorn: phylogenetic analysis in R Bioinformatics 2011 27 592 593 21169378 PMC3035803
  78. [94]Schindelin J Fiji: an open-source platform for biological-image analysis Nat. Methods 2012 9 676 682 22743772 PMC3855844

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Authors
Yamaguchi, M., Nakaoka, H., Suda, K., Yoshihara, K., Ishiguro, T., Yachida, N., Saito, K., Ueda, H., Sugino, K., Mori, Y., Yamawaki, K., Tamura, R., Revathidevi, S., Motoyama, T., Tainaka, K., Verhaak, R. G. W., Inoue, I., & Enomoto, T.
Affiliations
  • Niigata University (JP)
  • National Institute of Genetics (JP)
  • RIKEN Center for Biosystems Dynamics Research (JP)
  • Amsterdam University Medical Centers (NL)
Corresponding author
  • Nakaoka, Hirofumi
  • Yoshihara, Kosuke
  • Inoue, Ituro
  • Enomoto, Takayuki
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-02-17
Volume
13
Issue
1
Pages
943-943
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-28568-2
PMC
PMC8854701
OpenAlex
W4213022417
Cited by
54
References
14
Citations by year
2026: 11 · 2025: 11 · 2024: 10 · 2023: 13 · 2022: 9
FWCI
4.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • MEXT | Japan Society for the Promotion of Science (81-25-227-2320, 20K07318, 19K0982, 17H04336)
  • Research Organization of Information and Systems
  • Uehara Memorial Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
endometrium, clonal expansion, somatic mutations, cancer genes, clonal diversification, copy-neutral loss of heterozygosity, endometrial regeneration, endometrial glands, endometrial cancer prevention
MeSH terms
Adult, DNA Mutational Analysis, Endometrium, Epithelium, Female, Humans, Menstrual Cycle, Middle Aged, Mutation, Ovarian Neoplasms, Biomarkers, Tumor, Endometrial Neoplasms, Polymorphism, Single Nucleotide, Young Adult, Mutation Rate, Clonal Evolution, Spatio-Temporal Analysis, Carcinogenesis

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