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Whole–genome characterization of chemoresistant ovarian cancer

Published on May 1, 2015in Nature43.07
· DOI :10.1038/nature14410
Ann-Marie Patch24
Estimated H-index: 24
(UQ: University of Queensland),
Elizabeth L. Christie7
Estimated H-index: 7
(Peter MacCallum Cancer Centre)
+ 79 AuthorsDavid Bowtell73
Estimated H-index: 73
(Imperial College London)
Cite
Abstract
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
  • References (62)
  • Citations (417)
Cite
References62
Newest
Published on Oct 1, 2014in Genome Research9.94
Bettina Meier11
Estimated H-index: 11
(Dund.: University of Dundee),
Susanna L. Cooke25
Estimated H-index: 25
(Wellcome Trust Sanger Institute)
+ 9 AuthorsMichael R. Stratton135
Estimated H-index: 135
(Wellcome Trust Sanger Institute)
Mutation is associated with developmental and hereditary disorders, aging, and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was approximately one per genome per generation, not ove...
Published on Sep 1, 2014in International Journal of Cancer4.98
Katia Nones29
Estimated H-index: 29
(UQ: University of Queensland),
Nicola Waddell25
Estimated H-index: 25
(UQ: University of Queensland)
+ 35 AuthorsPeter J. Bailey31
Estimated H-index: 31
(UQ: University of Queensland)
The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and ...
Published on Mar 27, 2014in PLOS Genetics5.22
Kalpana Kannan8
Estimated H-index: 8
(BCM: Baylor College of Medicine),
Cristian Coarfa38
Estimated H-index: 38
(BCM: Baylor College of Medicine)
+ 4 AuthorsLaising Yen9
Estimated H-index: 9
(BCM: Baylor College of Medicine)
Ovarian cancer is the fifth leading cause of cancer death in women. Almost 70% of ovarian cancer deaths are due to the high-grade serous subtype, which is typically detected only after it has metastasized. Characterization of high-grade serous cancer is further complicated by the significant heterogeneity and genome instability displayed by this cancer. Other than mutations in TP53, which is common to many cancers, highly recurrent recombinant events specific to this cancer have yet to be identi...
Published on Feb 1, 2014in Nature43.07
Akinyemi I. Ojesina22
Estimated H-index: 22
(Harvard University),
Lee Lichtenstein15
Estimated H-index: 15
(Harvard University)
+ 53 AuthorsBjørn Enge Bertelsen7
Estimated H-index: 7
(University of Bergen)
To provide an overview of the genomic aberrations that contribute to cervical cancer these authors performed whole-exome sequencing and analysis of 115 cervical cancernormal pairs, transcriptome sequences of 79 cervical carcinomas and whole-genomes from 14 cervical cancernormal pairs. Analyses identify MAPK1, HLA-B and ELF3 as novel significantly mutated genes and provide evidence that human papilloma virus integration is a common mechanism for target gene overexpression in cervical cancer. The ...
Published on Jan 10, 2014in Science41.04
Brett E. Johnson8
Estimated H-index: 8
(UCSF: University of California, San Francisco),
Tali Mazor9
Estimated H-index: 9
(UCSF: University of California, San Francisco)
+ 31 AuthorsKenji Tatsuno11
Estimated H-index: 11
(UTokyo: University of Tokyo)
Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP5...
Published on Nov 8, 2013in PLOS ONE2.78
Karin S. Kassahn25
Estimated H-index: 25
(UQ: University of Queensland),
Oliver Holmes12
Estimated H-index: 12
(UQ: University of Queensland)
+ 31 AuthorsMatthew P. Anderson30
Estimated H-index: 30
(UQ: University of Queensland)
Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/) for somatic mutation calling...
Published on Oct 1, 2013in Nature Genetics25.45
Giovanni Ciriello24
Estimated H-index: 24
,
Martin L. Miller21
Estimated H-index: 21
+ 3 AuthorsChristian A. Sander137
Estimated H-index: 137
Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. Here we distilled thousands of genetic and epigenetic features altered in cancers to ~500 selected functional events (SFEs). Using this simplified description, we derived a hierarchic...
Published on Sep 1, 2013in British Journal of Cancer5.42
Charlotte Wilhelm-Benartzi12
Estimated H-index: 12
,
Devin C. Koestler26
Estimated H-index: 26
+ 6 AuthorsRobert H. Brown120
Estimated H-index: 120
The promise of epigenome-wide association studies and cancer-specific somatic DNA methylation changes in improving our understanding of cancer, coupled with the decreasing cost and increasing coverage of DNA methylation microarrays, has brought about a surge in the use of these technologies. Here, we aim to provide both a review of issues encountered in the processing and analysis of array-based DNA methylation data and a summary of the advantages of recent approaches proposed for handling those...
Published on Sep 1, 2013in The Journal of Pathology5.94
Ali Bashashati26
Estimated H-index: 26
,
Gavin Ha35
Estimated H-index: 35
+ 22 AuthorsJanine Senz39
Estimated H-index: 39
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 ...
Published on Aug 1, 2013in Nature43.07
Ludmil B. Alexandrov42
Estimated H-index: 42
(Wellcome Trust Sanger Institute),
Serena Nik-Zainal37
Estimated H-index: 37
(University of Cambridge)
+ 68 AuthorsMichael R. Stratton135
Estimated H-index: 135
(University of Barcelona)
All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, wher...
Cited By417
Newest
Published on Dec 1, 2019in Journal of Ovarian Research2.47
Yan Gao (PKU: Peking University), Yuan Li (PKU: Peking University)+ 4 AuthorsHongyan Guo2
Estimated H-index: 2
(PKU: Peking University)
To compare the chemoresistance and survival in patients with stage IIIC or IV epithelial ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) or primary debulking surgery (PDS). The clinical characteristics of patients who benefited from NACT were further evaluated. We retrospectively analyzed 220 patients who underwent NACT followed by IDS or PDS from January 2002 to December 2016. Differences in clinicopathological features, chemores...
Published on Mar 20, 2019in Nature Communications11.88
Elizabeth L. Christie7
Estimated H-index: 7
(University of Melbourne),
Swetansu Pattnaik1
Estimated H-index: 1
(Garvan Institute of Medical Research)
+ 12 AuthorsGreg Lamb (UofU: University of Utah)
ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple disti...
Published on Mar 29, 2019in Genome Medicine10.89
Matthew W. Fittall4
Estimated H-index: 4
(UCL: University College London),
Peter Van Loo37
Estimated H-index: 37
(Katholieke Universiteit Leuven),
Peter Van Loo3
Estimated H-index: 3
(Katholieke Universiteit Leuven)
Accelerating technological advances have allowed the widespread genomic profiling of tumors. As yet, however, the vast catalogues of mutations that have been identified have made only a modest impact on clinical medicine. Massively parallel sequencing has informed our understanding of the genetic evolution and heterogeneity of cancers, allowing us to place these mutational catalogues into a meaningful context. Here, we review the methods used to measure tumor evolution and heterogeneity, and the...
Published on Mar 5, 2019in Scientific Reports4.01
Paul M. Krzyzanowski11
Estimated H-index: 11
(OICR: Ontario Institute for Cancer Research),
Fabrice Sircoulomb (U of T: University of Toronto)+ 8 AuthorsJohn Douglas Mcpherson29
Estimated H-index: 29
(UC Davis: University of California, Davis)
Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local exp...
Published on Jul 18, 2019in Nature Communications11.88
Felicity Newell13
Estimated H-index: 13
(QIMR: QIMR Berghofer Medical Research Institute),
Yan Kong12
Estimated H-index: 12
(PKU: Peking University)
+ 41 AuthorsTristan Dodds2
Estimated H-index: 2
(USYD: University of Sydney)
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, C...
Published on Dec 1, 2019in BMC Cancer2.93
Weiwei Gong (TUM: Technische Universität München), Yueyang Liu1
Estimated H-index: 1
(TUM: Technische Universität München)
+ 6 AuthorsJulia Dorn14
Estimated H-index: 14
(TUM: Technische Universität München)
Background In ovarian cancer, dysregulation of mRNA expression of several components of the family of the kallikrein-related peptidases (KLKs) is observed. In this study, we have analyzed the KLK5 mRNA expression pattern in tumor tissue of patients suffering from high-grade serous ovarian cancer stage FIGO III/IV. Moreover, we have correlated the KLK5 mRNA levels with clinical outcome.
Published on May 14, 2019in Molecular Cytogenetics1.33
Andréa E. Tijhuis (QMUL: Queen Mary University of London), Sarah C. Johnson1
Estimated H-index: 1
(QMUL: Queen Mary University of London),
Sarah E. McClelland8
Estimated H-index: 8
(QMUL: Queen Mary University of London)
Many cancers possess an incorrect number of chromosomes, a state described as aneuploidy. Aneuploidy is often caused by Chromosomal Instability (CIN), a process of continuous chromosome mis-segregation. CIN is believed to endow tumours with enhanced evolutionary capabilities due to increased intratumour heterogeneity, and facilitating adaptive resistance to therapies. Recently, however, additional consequences and associations with CIN have been revealed, prompting the need to understand this un...
Published on Mar 27, 2019in Scientific Reports4.01
Katharina Bischof4
Estimated H-index: 4
(University of Bergen),
Stian Knappskog26
Estimated H-index: 26
(University of Bergen)
+ 5 AuthorsLine Bjørge25
Estimated H-index: 25
(University of Bergen)
High-grade serous ovarian carcinoma (HGSOC) is characterised by alterations in the p53 pathway. The expression levels of p53 isoforms have been shown to be associated with patient survival in several cancers. This study examined the predictive and prognostic effects of the expression levels of TP53 pre-mRNA splicing isoforms and TP53 mutations in tumour tissues in 40 chemotherapy responders and 29 non-responders with HGSOC. The mRNA expression levels from total p53, and total Δ133p53, p53β, p53γ...
Published on May 15, 2019in BMC Cancer2.93
Arne van Hoeck3
Estimated H-index: 3
,
Niels H. Tjoonk + 1 AuthorsEdwin Cuppen62
Estimated H-index: 62
Background In the past decade, systematic and comprehensive analyses of cancer genomes have identified cancer driver genes and revealed unprecedented insight into the molecular mechanisms underlying the initiation and progression of cancer. These studies illustrate that although every cancer has a unique genetic make-up, there are only a limited number of mechanisms that shape the mutational landscapes of cancer genomes, as reflected by characteristic computationally-derived mutational signature...
Published on Apr 11, 2019in Nature Communications11.88
Ting Yan (Shanxi Medical University), Heyang Cui (Shanxi Medical University)+ 30 AuthorsJiayi Li
Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature...
View next paperRethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer