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  3. Evolutionary states and trajectories characterized by distinct pathways stratify patients with ovarian high grade serous carcinoma

Evolutionary states and trajectories characterized by distinct pathways stratify patients with ovarian high grade serous carcinoma

  • Cancer Cell. 2023 May 11;S1535-6108(23)00143-5. doi: 10.1016/j.ccell.2023.04.017.
Alexandra Lahtinen 1,  Kari Lavikka 1,  Anni Virtanen 2,  Yilin Li 1,  Sanaz Jamalzadeh 1,  Aikaterini Skorda 3,  Anna Røssberg Lauridsen 3,  Kaiyang Zhang 1,  Giovanni Marchi 1,  Veli-Matti Isoviita 1,  Valeria Ariotta 1,  Oskari Lehtonen 1,  Taru A Muranen 1,  Kaisa Huhtinen 4,  Olli Carpén 5,  Sakari Hietanen 6,  Wojciech Senkowski 7,  Tuula Kallunki 8,  Antti Häkkinen 1,  Johanna Hynninen 6,  Jaana Oikkonen 9,  Sampsa Hautaniemi 10
Affiliations

Affiliations

  • 1 Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
  • 2 Department of Pathology, University of Helsinki and HUS Diagnostic Center, Helsinki University Hospital, 00029 Helsinki, Finland.
  • 3 Cancer Invasion and Resistance Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark.
  • 4 Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; Cancer Research Unit, Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, 20014 Turku, Finland.
  • 5 Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; Department of Pathology, University of Helsinki and HUS Diagnostic Center, Helsinki University Hospital, 00029 Helsinki, Finland.
  • 6 Department of Obstetrics and Gynaecology, University of Turku and Turku University Hospital, 200521 Turku, Finland.
  • 7 Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 8 Cancer Invasion and Resistance Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 9 Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland. Electronic address: [email protected].
  • 10 Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland. Electronic address: [email protected].
PMID: 37207655 DOI: 10.1016/j.ccell.2023.04.017
Abstract

Ovarian high-grade serous carcinoma (HGSC) is typically diagnosed at an advanced stage, with multiple genetically heterogeneous clones existing in the tumors long before therapeutic intervention. Herein we integrate clonal composition and topology using whole-genome sequencing data from 510 samples of 148 patients with HGSC in the prospective, longitudinal, multiregion DECIDER study. Our results reveal three evolutionary states, which have distinct features in genomics, pathways, and morphological phenotypes, and significant association with treatment response. Nested pathway analysis suggests two evolutionary trajectories between the states. Experiments with five tumor organoids and three PI3K inhibitors support targeting tumors with enriched PI3K/Akt pathway with alpelisib. Heterogeneity analysis of samples from multiple anatomical sites shows that site-of-origin samples have 70% more unique clones than metastatic tumors or ascites. In conclusion, these analysis and visualization methods enable integrative tumor evolution analysis to identify patient subtypes using data from longitudinal, multiregion cohorts.

Keywords

Cancer; Evolutionary trajectories; Integrative analysis; Multiregion sampling; Organoid experiments; Ovarian cancer; PI3K/AKT; Prospective cohort; Tumor evolution; Tumor heterogeneity.

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