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Modeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers

Author

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  • Alexander Martinez-Fundichely

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Austin Dixon

    (Weill Cornell Medicine
    Children’s National Hospital)

  • Ekta Khurana

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

Structural variations (SVs) in cancer cells often impact large genomic regions with functional consequences. However, identification of SVs under positive selection is a challenging task because little is known about the genomic features related to the background breakpoint distribution in different cancers. We report a method that uses a generalized additive model to investigate the breakpoint proximity curves from 2,382 whole-genomes of 32 cancer types. We find that a multivariate model, which includes linear and nonlinear partial contributions of various tissue-specific features and their interaction terms, can explain up to 57% of the observed deviance of breakpoint proximity. In particular, three-dimensional genomic features such as topologically associating domains (TADs), TAD-boundaries and their interaction with other features show significant contributions. The model is validated by identification of known cancer genes and revealed putative drivers in cancers different than those with previous evidence of positive selection.

Suggested Citation

  • Alexander Martinez-Fundichely & Austin Dixon & Ekta Khurana, 2022. "Modeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32945-2
    DOI: 10.1038/s41467-022-32945-2
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    1. Paz Polak & Rosa Karlić & Amnon Koren & Robert Thurman & Richard Sandstrom & Michael S. Lawrence & Alex Reynolds & Eric Rynes & Kristian Vlahoviček & John A. Stamatoyannopoulos & Shamil R. Sunyaev, 2015. "Cell-of-origin chromatin organization shapes the mutational landscape of cancer," Nature, Nature, vol. 518(7539), pages 360-364, February.
    2. Esther Rheinbay & Prasanna Parasuraman & Jonna Grimsby & Grace Tiao & Jesse M. Engreitz & Jaegil Kim & Michael S. Lawrence & Amaro Taylor-Weiner & Sergio Rodriguez-Cuevas & Mara Rosenberg & Julian Hes, 2017. "Recurrent and functional regulatory mutations in breast cancer," Nature, Nature, vol. 547(7661), pages 55-60, July.
    3. Simon N. Wood, 2011. "Fast stable restricted maximum likelihood and marginal likelihood estimation of semiparametric generalized linear models," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 73(1), pages 3-36, January.
    4. Kseniia Cheloshkina & Maria Poptsova, 2021. "Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements," PLOS Computational Biology, Public Library of Science, vol. 17(3), pages 1-23, March.
    5. Moritz Gerstung & Clemency Jolly & Ignaty Leshchiner & Stefan C. Dentro & Santiago Gonzalez & Daniel Rosebrock & Thomas J. Mitchell & Yulia Rubanova & Pavana Anur & Kaixian Yu & Maxime Tarabichi & Ami, 2020. "The evolutionary history of 2,658 cancers," Nature, Nature, vol. 578(7793), pages 122-128, February.
    6. Esther Rheinbay & Morten Muhlig Nielsen & Federico Abascal & Jeremiah A. Wala & Ofer Shapira & Grace Tiao & Henrik Hornshøj & Julian M. Hess & Randi Istrup Juul & Ziao Lin & Lars Feuerbach & Radhakris, 2020. "Analyses of non-coding somatic drivers in 2,658 cancer whole genomes," Nature, Nature, vol. 578(7793), pages 102-111, February.
    7. Jesse R. Dixon & Siddarth Selvaraj & Feng Yue & Audrey Kim & Yan Li & Yin Shen & Ming Hu & Jun S. Liu & Bing Ren, 2012. "Topological domains in mammalian genomes identified by analysis of chromatin interactions," Nature, Nature, vol. 485(7398), pages 376-380, May.
    8. 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.
    9. Scott A. Tomlins & Bharathi Laxman & Saravana M. Dhanasekaran & Beth E. Helgeson & Xuhong Cao & David S. Morris & Anjana Menon & Xiaojun Jing & Qi Cao & Bo Han & Jindan Yu & Lei Wang & James E. Montie, 2007. "Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer," Nature, Nature, vol. 448(7153), pages 595-599, August.
    10. Michael Fraser & Veronica Y. Sabelnykova & Takafumi N. Yamaguchi & Lawrence E. Heisler & Julie Livingstone & Vincent Huang & Yu-Jia Shiah & Fouad Yousif & Xihui Lin & Andre P. Masella & Natalie S. Fox, 2017. "Genomic hallmarks of localized, non-indolent prostate cancer," Nature, Nature, vol. 541(7637), pages 359-364, January.
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