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Genomic characterization of metastatic breast cancers

Author

Listed:
  • François Bertucci

    (CRCM, Predictive Oncology team, Inserm, Aix-Marseille Univ, CNRS, Institut Paoli-Calmettes)

  • Charlotte K. Y. Ng

    (University Hospital Basel
    University of Basel
    University of Bern)

  • Anne Patsouris

    (Inserm
    Institut de Cancérologie de l’Ouest - René Gauducheau)

  • Nathalie Droin

    (Genomic Core Facility UMS AMMICA Gustave Roussy Cancer Campus
    INSERM
    CNRS)

  • Salvatore Piscuoglio

    (University Hospital Basel
    University of Basel)

  • Nadine Carbuccia

    (CRCM, Predictive Oncology team, Inserm, Aix-Marseille Univ, CNRS, Institut Paoli-Calmettes)

  • Jean Charles Soria

    (Université Paris Sud
    Gustave Roussy Cancer Campus)

  • Alicia Tran Dien

    (Gustave Roussy Cancer Campus)

  • Yahia Adnani

    (Gustave Roussy Cancer Campus)

  • Maud Kamal

    (Institut Curie)

  • Séverine Garnier

    (CRCM, Predictive Oncology team, Inserm, Aix-Marseille Univ, CNRS, Institut Paoli-Calmettes)

  • Guillaume Meurice

    (Gustave Roussy Cancer Campus)

  • Marta Jimenez

    (Unicancer)

  • Semih Dogan

    (Inserm, Gustave Roussy Cancer Campus)

  • Benjamin Verret

    (Inserm, Gustave Roussy Cancer Campus)

  • Max Chaffanet

    (CRCM, Predictive Oncology team, Inserm, Aix-Marseille Univ, CNRS, Institut Paoli-Calmettes)

  • Thomas Bachelot

    (Centre Léon Bérard)

  • Mario Campone

    (Inserm
    Institut de Cancérologie de l’Ouest - René Gauducheau)

  • Claudia Lefeuvre

    (Centre Eugène Marquis)

  • Herve Bonnefoi

    (Institut Bergonié)

  • Florence Dalenc

    (Institut Claudius-Regaud, IUCT-oncopôle)

  • Alexandra Jacquet

    (Unicancer)

  • Maria R. Filippo

    (University Hospital Basel)

  • Naveen Babbar

    (Novartis Pharmaceuticals Corporation)

  • Daniel Birnbaum

    (CRCM, Predictive Oncology team, Inserm, Aix-Marseille Univ, CNRS, Institut Paoli-Calmettes)

  • Thomas Filleron

    (Institut Claudius-Regaud, IUCT-oncopôle)

  • Christophe Tourneau

    (Institut Curie
    INSERM U900
    Versailles Saint Quentin en Yvelines University)

  • Fabrice André

    (Université Paris Sud
    Inserm, Gustave Roussy Cancer Campus
    Gustave Roussy)

Abstract

Metastasis is the main cause of death for patients with breast cancer. Many studies have characterized the genomic landscape of breast cancer during its early stages. However, there is evidence that genomic alterations are acquired during the evolution of cancers from their early to late stages, and that the genomic landscape of early cancers is not representative of that of lethal cancers1–7. Here we investigated the landscape of somatic alterations in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A and RB1) were more frequently mutated in metastatic breast cancers that expressed hormone receptors (oestrogen and/or progesterone receptors; HR+) but did not have high levels of HER2 (HER2−; n = 381), when compared to early breast cancers from The Cancer Genome Atlas. In addition, 18 amplicons were more frequently observed in HR+/HER2− metastatic breast cancers. These cancers showed an increase in mutational signatures S2, S3, S10, S13 and S17. Among the gene alterations that were enriched in HR+/HER2− metastatic breast cancers, mutations in TP53, RB1 and NF1, together with S10, S13 and S17, were associated with poor outcome. Metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair, compared to early triple-negative breast cancers (7% versus 2%). Finally, metastatic breast cancers showed an increase in mutational burden and clonal diversity compared to early breast cancers. Thus, the genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer. The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials. The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course.

Suggested Citation

  • François Bertucci & Charlotte K. Y. Ng & Anne Patsouris & Nathalie Droin & Salvatore Piscuoglio & Nadine Carbuccia & Jean Charles Soria & Alicia Tran Dien & Yahia Adnani & Maud Kamal & Séverine Garnie, 2019. "Genomic characterization of metastatic breast cancers," Nature, Nature, vol. 569(7757), pages 560-564, May.
  • Handle: RePEc:nat:nature:v:569:y:2019:i:7757:d:10.1038_s41586-019-1056-z
    DOI: 10.1038/s41586-019-1056-z
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    Cited by:

    1. Jorge Gómez Tejeda Zañudo & Romualdo Barroso-Sousa & Esha Jain & Qingchun Jin & Tianyu Li & Jorge E. Buendia-Buendia & Alyssa Pereslete & Daniel L. Abravanel & Arlindo R. Ferreira & Eileen Wrabel & Ka, 2024. "Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Yael Aylon & Noa Furth & Giuseppe Mallel & Gilgi Friedlander & Nishanth Belugali Nataraj & Meng Dong & Ori Hassin & Rawan Zoabi & Benjamin Cohen & Vanessa Drendel & Tomer Meir Salame & Saptaparna Mukh, 2022. "Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Jian Ma & Lei Li & Bohan Ma & Tianjie Liu & Zixi Wang & Qi Ye & Yunhua Peng & Bin Wang & Yule Chen & Shan Xu & Ke Wang & Fabin Dang & Xinyang Wang & Zixuan Zeng & Yanlin Jian & Zhihua Ren & Yizeng Fan, 2024. "MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Jianjie Li & Xiaodong Shu & Jun Xu & Sek Man Su & Un In Chan & Lihua Mo & Jianlin Liu & Xin Zhang & Ragini Adhav & Qiang Chen & Yuqing Wang & Tingting An & Xu Zhang & Xueying Lyu & Xiaoling Li & Josh , 2022. "S100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Aditya Bardia & Sarat Chandarlapaty & Hannah M. Linden & Gary A. Ulaner & Alice Gosselin & Sylvaine Cartot-Cotton & Patrick Cohen & Séverine Doroumian & Gautier Paux & Marina Celanovic & Vasiliki Pele, 2022. "AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. S. Mouron & M. J. Bueno & A. Lluch & L. Manso & I. Calvo & J. Cortes & J. A. Garcia-Saenz & M. Gil-Gil & N. Martinez-Janez & J. V. Apala & E. Caleiras & Pilar Ximénez-Embún & J. Muñoz & L. Gonzalez-Co, 2022. "Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. 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.
    8. Poon, Charlotte & Haderi, Artes & Roediger, Alexander & Yuan, Megan, 2022. "Should we screen for lung cancer? A 10-country analysis identifying key decision-making factors," Health Policy, Elsevier, vol. 126(9), pages 879-888.

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