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

Martins, Filipe Correia; Couturier, Dominique-Laurent; De Santiago, Ines; Sauer, Carolin Margarethe; Vias, Maria; Angelova, Mihaela; Sanders, Deborah; ... Brenton, James D; + view all (2022) Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer. Nature Communications , 13 (1) , Article 6360. 10.1038/s41467-022-33870-0. Green open access

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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.

Type: Article
Title: Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-022-33870-0
Publisher version: https://doi.org/10.1038/s41467-022-33870-0
Language: English
Additional information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Cancer, Cancer genomics, Cancer models, Ovarian cancer, Targeted therapies
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10158422
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