IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29920-2.html
   My bibliography  Save this article

Mutational landscape of normal epithelial cells in Lynch Syndrome patients

Author

Listed:
  • Bernard C. H. Lee

    (The University of Hong Kong, Queen Mary Hospital)

  • Philip S. Robinson

    (Wellcome Sanger Institute
    University of Cambridge)

  • Tim H. H. Coorens

    (Wellcome Sanger Institute)

  • Helen H. N. Yan

    (The University of Hong Kong, Queen Mary Hospital)

  • Sigurgeir Olafsson

    (Wellcome Sanger Institute)

  • Henry Lee-Six

    (Wellcome Sanger Institute)

  • Mathijs A. Sanders

    (Wellcome Sanger Institute)

  • Hoi Cheong Siu

    (The University of Hong Kong, Queen Mary Hospital)

  • James Hewinson

    (Wellcome Sanger Institute)

  • Sarah S. K. Yue

    (The University of Hong Kong, Queen Mary Hospital)

  • Wai Yin Tsui

    (The University of Hong Kong, Queen Mary Hospital)

  • Annie S. Y. Chan

    (The University of Hong Kong, Queen Mary Hospital)

  • Anthony K. W. Chan

    (The University of Hong Kong, Queen Mary Hospital)

  • Siu Lun Ho

    (The University of Hong Kong, Queen Mary Hospital)

  • Peter J. Campbell

    (Wellcome Sanger Institute)

  • Inigo Martincorena

    (Wellcome Sanger Institute)

  • Simon J. A. Buczacki

    (University of Oxford, Headington)

  • Siu Tsan Yuen

    (The University of Hong Kong, Queen Mary Hospital)

  • Suet Yi Leung

    (The University of Hong Kong, Queen Mary Hospital
    The University of Hong Kong)

  • Michael R. Stratton

    (Wellcome Sanger Institute)

Abstract

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.

Suggested Citation

  • Bernard C. H. Lee & Philip S. Robinson & Tim H. H. Coorens & Helen H. N. Yan & Sigurgeir Olafsson & Henry Lee-Six & Mathijs A. Sanders & Hoi Cheong Siu & James Hewinson & Sarah S. K. Yue & Wai Yin Tsu, 2022. "Mutational landscape of normal epithelial cells in Lynch Syndrome patients," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29920-2
    DOI: 10.1038/s41467-022-29920-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29920-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-29920-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Sharon Christensen & Bastiaan Roest & Nicolle Besselink & Roel Janssen & Sander Boymans & John W. M. Martens & Marie-Laure Yaspo & Peter Priestley & Ewart Kuijk & Edwin Cuppen & Arne Van Hoeck, 2019. "5-Fluorouracil treatment induces characteristic T>G mutations in human cancer," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    2. Francis Blokzijl & Joep de Ligt & Myrthe Jager & Valentina Sasselli & Sophie Roerink & Nobuo Sasaki & Meritxell Huch & Sander Boymans & Ewart Kuijk & Pjotr Prins & Isaac J. Nijman & Inigo Martincorena, 2016. "Tissue-specific mutation accumulation in human adult stem cells during life," Nature, Nature, vol. 538(7624), pages 260-264, October.
    3. Teh, Yee Whye & Jordan, Michael I. & Beal, Matthew J. & Blei, David M., 2006. "Hierarchical Dirichlet Processes," Journal of the American Statistical Association, American Statistical Association, vol. 101, pages 1566-1581, December.
    4. Ludmil B. Alexandrov & Serena Nik-Zainal & David C. Wedge & Samuel A. J. R. Aparicio & Sam Behjati & Andrew V. Biankin & Graham R. Bignell & Niccolò Bolli & Ake Borg & Anne-Lise Børresen-Dale & Sandri, 2013. "Correction: Corrigendum: Signatures of mutational processes in human cancer," Nature, Nature, vol. 502(7470), pages 258-258, October.
    5. Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2020. "The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 578(7793), pages 94-101, February.
    6. Henry Lee-Six & Sigurgeir Olafsson & Peter Ellis & Robert J. Osborne & Mathijs A. Sanders & Luiza Moore & Nikitas Georgakopoulos & Franco Torrente & Ayesha Noorani & Martin Goddard & Philip Robinson &, 2019. "The landscape of somatic mutation in normal colorectal epithelial cells," Nature, Nature, vol. 574(7779), pages 532-537, October.
    7. Luiza Moore & Daniel Leongamornlert & Tim H. H. Coorens & Mathijs A. Sanders & Peter Ellis & Stefan C. Dentro & Kevin J. Dawson & Tim Butler & Raheleh Rahbari & Thomas J. Mitchell & Francesco Maura & , 2020. "The mutational landscape of normal human endometrial epithelium," Nature, Nature, vol. 580(7805), pages 640-646, April.
    8. Ludmil B. Alexandrov & Serena Nik-Zainal & David C. Wedge & Samuel A. J. R. Aparicio & Sam Behjati & Andrew V. Biankin & Graham R. Bignell & Niccolò Bolli & Ake Borg & Anne-Lise Børresen-Dale & Sandri, 2013. "Signatures of mutational processes in human cancer," Nature, Nature, vol. 500(7463), pages 415-421, August.
    9. Cayetano Pleguezuelos-Manzano & Jens Puschhof & Axel Rosendahl Huber & Arne van Hoeck & Henry M. Wood & Jason Nomburg & Carino Gurjao & Freek Manders & Guillaume Dalmasso & Paul B. Stege & Fernanda L., 2020. "Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli," Nature, Nature, vol. 580(7802), pages 269-273, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Philip S. Robinson & Laura E. Thomas & Federico Abascal & Hyunchul Jung & Luke M. R. Harvey & Hannah D. West & Sigurgeir Olafsson & Bernard C. H. Lee & Tim H. H. Coorens & Henry Lee-Six & Laura Butlin, 2022. "Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Ewart Kuijk & Onno Kranenburg & Edwin Cuppen & Arne Van Hoeck, 2022. "Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Sujath Abbas & Oriol Pich & Ginny Devonshire & Shahriar A. Zamani & Annalise Katz-Summercorn & Sarah Killcoyne & Calvin Cheah & Barbara Nutzinger & Nicola Grehan & Nuria Lopez-Bigas & Rebecca C. Fitzg, 2023. "Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Thomas G. Paulson & Patricia C. Galipeau & Kenji M. Oman & Carissa A. Sanchez & Mary K. Kuhner & Lucian P. Smith & Kevin Hadi & Minita Shah & Kanika Arora & Jennifer Shelton & Molly Johnson & Andre Co, 2022. "Somatic whole genome dynamics of precancer in Barrett’s esophagus reveals features associated with disease progression," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Heather E. Machado & Nina F. Øbro & Nicholas Williams & Shengjiang Tan & Ahmed Z. Boukerrou & Megan Davies & Miriam Belmonte & Emily Mitchell & E. Joanna Baxter & Nicole Mende & Anna Clay & Philip Anc, 2023. "Convergent somatic evolution commences in utero in a germline ribosomopathy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Michelle Dietzen & Haoran Zhai & Olivia Lucas & Oriol Pich & Christopher Barrington & Wei-Ting Lu & Sophia Ward & Yanping Guo & Robert E. Hynds & Simone Zaccaria & Charles Swanton & Nicholas McGranaha, 2024. "Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    7. Teresa Maria Rosaria Noviello & Anna Maria Giacomo & Francesca Pia Caruso & Alessia Covre & Roberta Mortarini & Giovanni Scala & Maria Claudia Costa & Sandra Coral & Wolf H. Fridman & Catherine Sautès, 2023. "Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Eline J. M. Bertrums & Jurrian K. Kanter & Lucca L. M. Derks & Mark Verheul & Laurianne Trabut & Markus J. Roosmalen & Henrik Hasle & Evangelia Antoniou & Dirk Reinhardt & Michael N. Dworzak & Nora Mü, 2024. "Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Luan Nguyen & Arne Hoeck & Edwin Cuppen, 2022. "Machine learning-based tissue of origin classification for cancer of unknown primary diagnostics using genome-wide mutation features," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. Caralyn Reisle & Laura M. Williamson & Erin Pleasance & Anna Davies & Brayden Pellegrini & Dustin W. Bleile & Karen L. Mungall & Eric Chuah & Martin R. Jones & Yussanne Ma & Eleanor Lewis & Isaac Beck, 2022. "A platform for oncogenomic reporting and interpretation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    11. Antonio Rodriguez-Calero & John Gallon & Dilara Akhoundova & Sina Maletti & Alison Ferguson & Joanna Cyrta & Ursula Amstutz & Andrea Garofoli & Viola Paradiso & Scott A. Tomlins & Ekkehard Hewer & Ver, 2022. "Alterations in homologous recombination repair genes in prostate cancer brain metastases," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    12. Mei Lin & Xiao-Long Zhang & Rui You & You-Ping Liu & Hong-Min Cai & Li-Zhi Liu & Xue-Fei Liu & Xiong Zou & Yu-Long Xie & Ru-Hai Zou & Yi-Nuan Zhang & Rui Sun & Wei-Yi Feng & Hai-Yan Wang & Gui-Hua Tao, 2023. "Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    13. Maarten H. Geurts & Shashank Gandhi & Matteo G. Boretto & Ninouk Akkerman & Lucca L. M. Derks & Gijs Son & Martina Celotti & Sarina Harshuk-Shabso & Flavia Peci & Harry Begthel & Delilah Hendriks & Pa, 2023. "One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Mischan Vali-Pour & Solip Park & Jose Espinosa-Carrasco & Daniel Ortiz-Martínez & Ben Lehner & Fran Supek, 2022. "The impact of rare germline variants on human somatic mutation processes," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    15. Ambrocio Sanchez & Pedro Ortega & Ramin Sakhtemani & Lavanya Manjunath & Sunwoo Oh & Elodie Bournique & Alexandrea Becker & Kyumin Kim & Cameron Durfee & Nuri Alpay Temiz & Xiaojiang S. Chen & Reuben , 2024. "Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    16. Thomas R. W. Oliver & Lia Chappell & Rashesh Sanghvi & Lauren Deighton & Naser Ansari-Pour & Stefan C. Dentro & Matthew D. Young & Tim H. H. Coorens & Hyunchul Jung & Tim Butler & Matthew D. C. Nevill, 2022. "Clonal diversification and histogenesis of malignant germ cell tumours," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    17. Francesca Menghi & Edison T. Liu, 2022. "Functional genomics of complex cancer genomes," Nature Communications, Nature, vol. 13(1), pages 1-4, December.
    18. Josefine Radke & Naveed Ishaque & Randi Koll & Zuguang Gu & Elisa Schumann & Lina Sieverling & Sebastian Uhrig & Daniel Hübschmann & Umut H. Toprak & Cristina López & Xavier Pastor Hostench & Simone B, 2022. "The genomic and transcriptional landscape of primary central nervous system lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    19. Yasha Butt & Ramin Sakhtemani & Rukshana Mohamad-Ramshan & Michael S. Lawrence & Ashok S. Bhagwat, 2024. "Distinguishing preferences of human APOBEC3A and APOBEC3B for cytosines in hairpin loops, and reflection of these preferences in APOBEC-signature cancer genome mutations," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    20. Peter Georgeson & Tabitha A. Harrison & Bernard J. Pope & Syed H. Zaidi & Conghui Qu & Robert S. Steinfelder & Yi Lin & Jihoon E. Joo & Khalid Mahmood & Mark Clendenning & Romy Walker & Efrat L. Amita, 2022. "Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29920-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.