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The impact of rare germline variants on human somatic mutation processes

Author

Listed:
  • Mischan Vali-Pour

    (The Barcelona Institute of Science and Technology (BIST)
    Universitat Pompeu Fabra (UPF))

  • Solip Park

    (Centro Nacional de Investigaciones Oncológicas (CNIO))

  • Jose Espinosa-Carrasco

    (The Barcelona Institute of Science and Technology (BIST))

  • Daniel Ortiz-Martínez

    (The Barcelona Institute of Science and Technology (BIST))

  • Ben Lehner

    (The Barcelona Institute of Science and Technology (BIST)
    Universitat Pompeu Fabra (UPF)
    Catalan Institution for Research and Advanced Studies (ICREA))

  • Fran Supek

    (The Barcelona Institute of Science and Technology (BIST)
    Catalan Institution for Research and Advanced Studies (ICREA))

Abstract

Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31483-1
    DOI: 10.1038/s41467-022-31483-1
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    as
    1. Gabriele A. Fontana & Daniel Hess & Julia K. Reinert & Stefano Mattarocci & Benoît Falquet & Dominique Klein & David Shore & Nicolas H. Thomä & Ulrich Rass, 2019. "Rif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Philip Jonsson & Chaitanya Bandlamudi & Michael L. Cheng & Preethi Srinivasan & Shweta S. Chavan & Noah D. Friedman & Ezra Y. Rosen & Allison L. Richards & Nancy Bouvier & S. Duygu Selcuklu & Craig M., 2019. "Tumour lineage shapes BRCA-mediated phenotypes," Nature, Nature, vol. 571(7766), pages 576-579, July.
    3. Yilong Li & Nicola D. Roberts & Jeremiah A. Wala & Ofer Shapira & Steven E. Schumacher & Kiran Kumar & Ekta Khurana & Sebastian Waszak & Jan O. Korbel & James E. Haber & Marcin Imielinski & Joachim We, 2020. "Patterns of somatic structural variation in human cancer genomes," Nature, Nature, vol. 578(7793), pages 112-121, February.
    4. Maria Escala-Garcia & Jean Abraham & Irene L. Andrulis & Hoda Anton-Culver & Volker Arndt & Alan Ashworth & Paul L. Auer & Päivi Auvinen & Matthias W. Beckmann & Jonathan Beesley & Sabine Behrens & Ja, 2020. "A network analysis to identify mediators of germline-driven differences in breast cancer prognosis," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    5. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    6. Jonathan Frazer & Pascal Notin & Mafalda Dias & Aidan Gomez & Joseph K. Min & Kelly Brock & Yarin Gal & Debora S. Marks, 2021. "Disease variant prediction with deep generative models of evolutionary data," Nature, Nature, vol. 599(7883), pages 91-95, November.
    7. Fran Supek & Ben Lehner, 2015. "Differential DNA mismatch repair underlies mutation rate variation across the human genome," Nature, Nature, vol. 521(7550), pages 81-84, May.
    8. Peter Priestley & Jonathan Baber & Martijn P. Lolkema & Neeltje Steeghs & Ewart Bruijn & Charles Shale & Korneel Duyvesteyn & Susan Haidari & Arne Hoeck & Wendy Onstenk & Paul Roepman & Mircea Voda & , 2019. "Pan-cancer whole-genome analyses of metastatic solid tumours," Nature, Nature, vol. 575(7781), pages 210-216, November.
    9. Jurica Levatić & Marina Salvadores & Francisco Fuster-Tormo & Fran Supek, 2022. "Mutational signatures are markers of drug sensitivity of cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    10. Benjamin M Neale & Manuel A Rivas & Benjamin F Voight & David Altshuler & Bernie Devlin & Marju Orho-Melander & Sekar Kathiresan & Shaun M Purcell & Kathryn Roeder & Mark J Daly, 2011. "Testing for an Unusual Distribution of Rare Variants," PLOS Genetics, Public Library of Science, vol. 7(3), pages 1-8, March.
    11. Nazneen Rahman, 2014. "Realizing the promise of cancer predisposition genes," Nature, Nature, vol. 505(7483), pages 302-308, January.
    12. Quanli Wang & Ryan S. Dhindsa & Keren Carss & Andrew R. Harper & Abhishek Nag & Ioanna Tachmazidou & Dimitrios Vitsios & Sri V. V. Deevi & Alex Mackay & Daniel Muthas & Michael Hühn & Susan Monkley & , 2021. "Rare variant contribution to human disease in 281,104 UK Biobank exomes," Nature, Nature, vol. 597(7877), pages 527-532, September.
    13. Edmond M. Chan & Tsukasa Shibue & James M. McFarland & Benjamin Gaeta & Mahmoud Ghandi & Nancy Dumont & Alfredo Gonzalez & Justine S. McPartlan & Tianxia Li & Yanxi Zhang & Jie Liu & Jean-Bernard Laza, 2019. "WRN helicase is a synthetic lethal target in microsatellite unstable cancers," Nature, Nature, vol. 568(7753), pages 551-556, April.
    14. 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.
    15. Benjamin Schuster-Böckler & Ben Lehner, 2012. "Chromatin organization is a major influence on regional mutation rates in human cancer cells," Nature, Nature, vol. 488(7412), pages 504-507, August.
    16. 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.
    17. Nazneen Rahman, 2014. "Correction: Corrigendum: Realizing the promise of cancer predisposition genes," Nature, Nature, vol. 510(7503), pages 176-176, June.
    18. Beryl B. Cummings & Konrad J. Karczewski & Jack A. Kosmicki & Eleanor G. Seaby & Nicholas A. Watts & Moriel Singer-Berk & Jonathan M. Mudge & Juha Karjalainen & F. Kyle Satterstrom & Anne H. O’Donnell, 2020. "Transcript expression-aware annotation improves rare variant interpretation," Nature, Nature, vol. 581(7809), pages 452-458, May.
    19. Sandro Morganella & Ludmil B. Alexandrov & Dominik Glodzik & Xueqing Zou & Helen Davies & Johan Staaf & Anieta M. Sieuwerts & Arie B. Brinkman & Sancha Martin & Manasa Ramakrishna & Adam Butler & Hyun, 2016. "The topography of mutational processes in breast cancer genomes," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    20. Manuel Rodrigues & Lenha Mobuchon & Alexandre Houy & Alice Fiévet & Sophie Gardrat & Raymond L. Barnhill & Tatiana Popova & Vincent Servois & Aurore Rampanou & Aurore Mouton & Stéphane Dayot & Virgini, 2018. "Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors," Nature Communications, Nature, vol. 9(1), pages 1-6, December.
    21. Solip Park & Fran Supek & Ben Lehner, 2018. "Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    22. Miguel C. Coelho & Ricardo M. Pinto & Andrew W. Murray, 2019. "Heterozygous mutations cause genetic instability in a yeast model of cancer evolution," Nature, Nature, vol. 566(7743), pages 275-278, February.
    23. 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.
    24. Xueqing Zou & Michel Owusu & Rebecca Harris & Stephen P. Jackson & Joanna I. Loizou & Serena Nik-Zainal, 2018. "Validating the concept of mutational signatures with isogenic cell models," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
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