IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30753-2.html
   My bibliography  Save this article

Estimating tumor mutational burden from RNA-sequencing without a matched-normal sample

Author

Listed:
  • Rotem Katzir

    (University of Maryland
    Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology)

  • Noam Rudberg

    (Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology)

  • Keren Yizhak

    (Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology)

Abstract

Detection of somatic mutations using patients sequencing data has many clinical applications, including the identification of cancer driver genes, detection of mutational signatures, and estimation of tumor mutational burden (TMB). We have previously developed a tool for detection of somatic mutations using tumor RNA and a matched-normal DNA. Here, we further extend it to detect somatic mutations from RNA sequencing data without a matched-normal sample. This is accomplished via a machine-learning approach that classifies mutations as either somatic or germline based on various features. When applied to RNA-sequencing of >450 melanoma samples high precision and recall are achieved, and both mutational signatures and driver genes are correctly identified. Finally, we show that RNA-based TMB is significantly associated with patient survival, showing similar or higher significance level as compared to DNA-based TMB. Our pipeline can be utilized in many future applications, analyzing novel and existing datasets where only RNA is available.

Suggested Citation

  • Rotem Katzir & Noam Rudberg & Keren Yizhak, 2022. "Estimating tumor mutational burden from RNA-sequencing without a matched-normal sample," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30753-2
    DOI: 10.1038/s41467-022-30753-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30753-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-30753-2?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. Monkol Lek & Konrad J. Karczewski & Eric V. Minikel & Kaitlin E. Samocha & Eric Banks & Timothy Fennell & Anne H. O’Donnell-Luria & James S. Ware & Andrew J. Hill & Beryl B. Cummings & Taru Tukiainen , 2016. "Analysis of protein-coding genetic variation in 60,706 humans," Nature, Nature, vol. 536(7616), pages 285-291, August.
    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. Michael S. Lawrence & Petar Stojanov & Paz Polak & Gregory V. Kryukov & Kristian Cibulskis & Andrey Sivachenko & Scott L. Carter & Chip Stewart & Craig H. Mermel & Steven A. Roberts & Adam Kiezun & Pe, 2013. "Mutational heterogeneity in cancer and the search for new cancer-associated genes," Nature, Nature, vol. 499(7457), pages 214-218, July.
    4. Jennifer Ma & Jeremy Setton & Nancy Y. Lee & Nadeem Riaz & Simon N. Powell, 2018. "The therapeutic significance of mutational signatures from DNA repair deficiency in cancer," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    5. Michael S. Lawrence & Petar Stojanov & Craig H. Mermel & James T. Robinson & Levi A. Garraway & Todd R. Golub & Matthew Meyerson & Stacey B. Gabriel & Eric S. Lander & Gad Getz, 2014. "Discovery and saturation analysis of cancer genes across 21 tumour types," Nature, Nature, vol. 505(7484), pages 495-501, January.
    6. 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.
    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. Naser Ansari-Pour & Yonglan Zheng & Toshio F. Yoshimatsu & Ayodele Sanni & Mustapha Ajani & Jean-Baptiste Reynier & Avraam Tapinos & Jason J. Pitt & Stefan Dentro & Anna Woodard & Padma Sheila Rajagop, 2021. "Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. 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.
    3. Eun Seop Seo & Ji Won Lee & Jinyeong Lim & Sunghwan Shin & Hee Won Cho & Hee Young Ju & Keon Hee Yoo & Ki Woong Sung & Woong-Yang Park, 2024. "Germline functional variants contribute to somatic mutation and outcomes in neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. 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.
    6. Farshad Farshidfar & Kahn Rhrissorrakrai & Chaya Levovitz & Cong Peng & James Knight & Antonella Bacchiocchi & Juan Su & Mingzhu Yin & Mario Sznol & Stephan Ariyan & James Clune & Kelly Olino & Laxmi , 2022. "Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Martin Boström & Erik Larsson, 2022. "Somatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer," Nature Communications, Nature, vol. 13(1), pages 1-9, 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. Sumana Srivatsa & Hesam Montazeri & Gaia Bianco & Mairene Coto-Llerena & Mattia Marinucci & Charlotte K. Y. Ng & Salvatore Piscuoglio & Niko Beerenwinkel, 2022. "Discovery of synthetic lethal interactions from large-scale pan-cancer perturbation screens," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. 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.
    11. Benjamin A. Nacev & Francisco Sanchez-Vega & Shaleigh A. Smith & Cristina R. Antonescu & Evan Rosenbaum & Hongyu Shi & Cerise Tang & Nicholas D. Socci & Satshil Rana & Rodrigo Gularte-Mérida & Ahmet Z, 2022. "Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    12. Josh N. Vo & Yi-Mi Wu & Jeanmarie Mishler & Sarah Hall & Rahul Mannan & Lisha Wang & Yu Ning & Jin Zhou & Alexander C. Hopkins & James C. Estill & Wallace K. B. Chan & Jennifer Yesil & Xuhong Cao & Ar, 2022. "The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    13. Ryan N. Ptashkin & Mark D. Ewalt & Gowtham Jayakumaran & Iwona Kiecka & Anita S. Bowman & JinJuan Yao & Jacklyn Casanova & Yun-Te David Lin & Kseniya Petrova-Drus & Abhinita S. Mohanty & Ruben Bacares, 2023. "Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    14. Erik Elias & Arman Ardalan & Markus Lindberg & Susanne E. Reinsbach & Andreas Muth & Ola Nilsson & Yvonne Arvidsson & Erik Larsson, 2021. "Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    15. Minghao Li & Zicheng Zhang & Qianrong Wang & Yan Yi & Baosheng Li, 2022. "Integrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    16. Qingli Guo & Eszter Lakatos & Ibrahim Al Bakir & Kit Curtius & Trevor A. Graham & Ville Mustonen, 2022. "The mutational signatures of formalin fixation on the human genome," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Sebastian Carrasco Pro & Heather Hook & David Bray & Daniel Berenzy & Devlin Moyer & Meimei Yin & Adam Thomas Labadorf & Ryan Tewhey & Trevor Siggers & Juan Ignacio Fuxman Bass, 2023. "Widespread perturbation of ETS factor binding sites in cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. John K. L. Wong & Christian Aichmüller & Markus Schulze & Mario Hlevnjak & Shaymaa Elgaafary & Peter Lichter & Marc Zapatka, 2022. "Association of mutation signature effectuating processes with mutation hotspots in driver genes and non-coding regions," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    19. Mark Bustoros & Shankara Anand & Romanos Sklavenitis-Pistofidis & Robert Redd & Eileen M. Boyle & Benny Zhitomirsky & Andrew J. Dunford & Yu-Tzu Tai & Selina J. Chavda & Cody Boehner & Carl Jannes Neu, 2022. "Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    20. N. Shukla & M. F. Levine & G. Gundem & D. Domenico & B. Spitzer & N. Bouvier & J. E. Arango-Ossa & D. Glodzik & J. S. Medina-Martínez & U. Bhanot & J. Gutiérrez-Abril & Y. Zhou & E. Fiala & E. Stockfi, 2022. "Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers," Nature Communications, Nature, vol. 13(1), pages 1-15, 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_s41467-022-30753-2. 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.