Evolutionary states and trajectories characterized by distinct pathways stratify patients with ovarian high grade serous carcinoma
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cancer Cell |
| Vol/bind | 41 |
| Udgave nummer | 6 |
| Sider (fra-til) | 1103-1117.e12 |
| ISSN | 1535-6108 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This project received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 965193 (DECIDER), 667403 (HERCULES), and 845045 (RESIST3D); the Academy of Finland (projects 325956 and 322927 ); the Sigrid Jusélius Foundation ; Cancer Foundation Finland ; and the Danish National Research Foundation ( DNRF125 ). We are grateful to Dr. Ann-Christin Ostwaldt for proofreading the manuscript, Dr. Anna Vähärautio for critical comments on the manuscript, and Prof. Krister Wennerberg for helping with the organoid experiments. The authors wish to acknowledge the CSC-IT Center for Science (Finland) for computational resources.
Funding Information:
This project received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreements 965193 (DECIDER), 667403 (HERCULES), and 845045 (RESIST3D); the Academy of Finland (projects 325956 and 322927); the Sigrid Jusélius Foundation; Cancer Foundation Finland; and the Danish National Research Foundation (DNRF125). We are grateful to Dr. Ann-Christin Ostwaldt for proofreading the manuscript, Dr. Anna Vähärautio for critical comments on the manuscript, and Prof. Krister Wennerberg for helping with the organoid experiments. The authors wish to acknowledge the CSC-IT Center for Science (Finland) for computational resources. Conceptualization, A.L. K.L. A.V. T.K. A.H. J.O. and S. Hautaniemi; Methodology and Software, K.L. Y.L. S.J. W.S. and A.H.; Formal Analysis, A.L. K.L. A.V. Y.L. A.S. A.R.L. V.A. O.L. K.Z. S.J. A.H. and J.O.; Investigation, A.L. K.L. A.V. Y.L. A.S. A.R.L. K.H. A.H. J.O. and S. Hautaniemi; Resources, K.L. A.V. Y.L. G.M. S.J. K.Z. V.-M.I. K.H. O.C. S. Hietanen, W.S. T.K. A.H. J.H. and S. Hautaniemi; Data Curation, Y.L. A.V. J.H. T.A.M. J.O. and S. Hautaniemi; Visualization, K.L. A.L. A.V. A.S. A.R.L. A.H. and J.O.; Supervision, T.K. A.H. J.O. and S. Hautaniemi; Project Administration, J.O. and S. Hautaniemi; Funding Acquisition, A.V. O.C. W.S. T.K. A.H. J.H. and S. Hautaniemi; Writing – Original Draft, A.L. J.O. and S. Hautaniemi; Writing – Review & Editing, all authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
© 2023 The Author(s)
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