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Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer

Author

Listed:
  • Filipe Correia Martins

    (University of Cambridge
    University of Cambridge
    University of Cambridge
    The Francis Crick Institute)

  • Dominique-Laurent Couturier

    (University of Cambridge
    University of Cambridge)

  • Ines Santiago

    (University of Cambridge)

  • Carolin Margarethe Sauer

    (University of Cambridge)

  • Maria Vias

    (University of Cambridge)

  • Mihaela Angelova

    (The Francis Crick Institute)

  • Deborah Sanders

    (University of Cambridge)

  • Anna Piskorz

    (University of Cambridge)

  • James Hall

    (University of Cambridge)

  • Karen Hosking

    (Cambridge University Hospitals)

  • Anumithra Amirthanayagam

    (Cambridge University Hospitals)

  • Sabina Cosulich

    (Astrazeneca)

  • Larissa Carnevalli

    (Astrazeneca)

  • Barry Davies

    (Astrazeneca)

  • Thomas B. K. Watkins

    (The Francis Crick Institute)

  • Ionut G. Funingana

    (University of Cambridge
    University of Cambridge)

  • Helen Bolton

    (Cambridge University Hospitals)

  • Krishnayan Haldar

    (Cambridge University Hospitals)

  • John Latimer

    (Cambridge University Hospitals)

  • Peter Baldwin

    (Cambridge University Hospitals)

  • Robin Crawford

    (Cambridge University Hospitals)

  • Matthew Eldridge

    (University of Cambridge)

  • Bristi Basu

    (Cambridge University Hospitals
    University of Cambridge)

  • Mercedes Jimenez-Linan

    (Cambridge University Hospitals)

  • Andrew W. Mcpherson

    (Memorial Sloan Kettering Cancer Centre)

  • Nicholas McGranahan

    (University College London Cancer Institute)

  • Kevin Litchfield

    (The Francis Crick Institute)

  • Sohrab P. Shah

    (Memorial Sloan Kettering Cancer Centre)

  • Iain McNeish

    (Imperial College of London)

  • Carlos Caldas

    (University of Cambridge
    University of Cambridge)

  • Gerard Evan

    (University of Cambridge)

  • Charles Swanton

    (The Francis Crick Institute
    University College London Cancer Institute)

  • James D. Brenton

    (University of Cambridge
    University of Cambridge)

Abstract

Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.

Suggested Citation

  • Filipe Correia Martins & Dominique-Laurent Couturier & Ines Santiago & Carolin Margarethe Sauer & Maria Vias & Mihaela Angelova & Deborah Sanders & Anna Piskorz & James Hall & Karen Hosking & Anumithr, 2022. "Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33870-0
    DOI: 10.1038/s41467-022-33870-0
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    References listed on IDEAS

    as
    1. Ankit Shukla & Thu H. M. Nguyen & Sarat B. Moka & Jonathan J. Ellis & John P. Grady & Harald Oey & Alexandre S. Cristino & Kum Kum Khanna & Dirk P. Kroese & Lutz Krause & Eloise Dray & J. Lynn Fink & , 2020. "Chromosome arm aneuploidies shape tumour evolution and drug response," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Arkajyoti Bhattacharya & Rico D. Bense & Carlos G. Urzúa-Traslaviña & Elisabeth G. E. Vries & Marcel A. T. M. Vugt & Rudolf S. N. Fehrmann, 2020. "Transcriptional effects of copy number alterations in a large set of human cancers," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. Ann-Marie Patch & Elizabeth L. Christie & Dariush Etemadmoghadam & Dale W. Garsed & Joshy George & Sian Fereday & Katia Nones & Prue Cowin & Kathryn Alsop & Peter J. Bailey & Karin S. Kassahn & Felici, 2015. "Whole–genome characterization of chemoresistant ovarian cancer," Nature, Nature, vol. 521(7553), pages 489-494, May.
    4. Louisa Nelson & Anthony Tighe & Anya Golder & Samantha Littler & Bjorn Bakker & Daniela Moralli & Syed Murtuza Baker & Ian J. Donaldson & Diana C. J. Spierings & René Wardenaar & Bethanie Neale & Geor, 2020. "A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
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    Cited by:

    1. Hongyu Shi & Marc J. Williams & Gryte Satas & Adam C. Weiner & Andrew McPherson & Sohrab P. Shah, 2024. "Allele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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