Distinct evolutionary trajectories of primary high‐grade serous ovarian cancers revealed through spatial mutational profiling

Abstract

High‐grade serous ovarian cancer ( HGSC ) is characterized by poor outcome, often attributed to the emergence of treatment‐resistant subclones. We sought to measure the degree of genomic diversity within primary, untreated HGSCs to examine the natural state of tumour evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on 31 spatially and temporally separated HGSC tumour specimens (six patients), including ovarian masses, distant metastases and fallopian tube lesions. We found widespread intratumoural variation in mutation, copy number and gene expression profiles, with key driver alterations in genes present in only a subset of samples (eg PIK3CA , CTNNB1 , NF1 ). On average, only 51.5% of mutations were present in every sample of a given case (range 10.2–91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole‐genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology, with common aetiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating that diversity arises at early stages of tumourigenesis. Our results revealed that HGSCs exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug‐resistance mechanisms. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Cited by papers we hold 23

• Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor · 2022
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• High-grade serous tubo-ovarian cancer refined with single-cell RNA sequencing: specific cell subtypes influence survival and determine molecular subtype classification · 2021
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• Distinct transcriptional programs stratify ovarian cancer cell lines into the five major histological subtypes · 2021
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• Drug resistance and combating drug resistance in cancer · 2019
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• Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma · 2019
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• Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy · 2019
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• The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy · 2018
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• Ovarian Cancers: Genetic Abnormalities, Tumor Heterogeneity and Progression, Clonal Evolution and Cancer Stem Cells · 2018
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• Tumor evolution and chemoresistance in ovarian cancer · 2018
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• Reconstructing metastatic seeding patterns of human cancers · 2017
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• Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations · 2017
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• Heterogeneous Tumor-Immune Microenvironments among Differentially Growing Metastases in an Ovarian Cancer Patient · 2017
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• High grade serous ovarian carcinomas originate in the fallopian tube · 2017
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• The NF1 somatic mutational landscape in sporadic human cancers · 2017
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• Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment · 2016
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• Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis · 2015
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• Harnessing Pandemonium: The clinical implications of tumour heterogeneity in ovarian cancer · 2015
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• Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer · 2015
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• Fast and scalable inference of multi-sample cancer lineages · 2015
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• Single-cell mRNA sequencing identifies subclonal heterogeneity in anti-cancer drug responses of lung adenocarcinoma cells · 2015
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and 3 more

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