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Cancer Cell. 2020 Feb 10;37(2):226-242.e7. doi: 10.1016/j.ccell.2020.01.003.

The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells.

Author information

1
Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
2
Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Gene Regulatory Networks in Development and Disease Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
3
Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK.
4
Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK.
5
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
6
Department of Histopathology, Oxford University Hospitals, Oxford OX3 9DU, UK.
7
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
8
Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK.
9
Department of Gynaecology, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK.
10
Oxford Radcliffe Biobank, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK; NIHR Oxford Biomedical Research Centre, Second Floor, Unipart House Business Centre, Oxford OX4 2PG, UK.
11
Oxford Radcliffe Biobank, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK.
12
Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
13
Gene Regulatory Networks in Development and Disease Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
14
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Centre for Computational Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK; Division of Informatics, Imaging and Data Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9PT, UK; Alan Turing Institute, London NW1 2DB, UK. Electronic address: christopher.yau@manchester.ac.uk.
15
Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK. Electronic address: ahmed.ahmed@wrh.ox.ac.uk.

Abstract

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.

KEYWORDS:

fallopian tube; non-genetic heterogeneity; ovarian cancer; single-cell RNA sequencing

Conflict of interest statement

Declaration of Interests A.A.A., C.Y., and Z.H. filed a patent application for the use of the 52-gene panel for predicting the prognosis in ovarian cancer.

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