Copy number signatures and mutational processes in ovarian carcinoma

Macintyre, Geoff; Goranova, Teodora; Silva, Dilrini De; Ennis, Darren; Piskorz, Anna; Eldridge, Matthew; Sie, Daoud; Lewsley, Liz-Anne; Hanif, Aishah; Wilson, Cheryl A.; Dowson, Suzanne; Glasspool, Rosalind; Lockley, Michelle; Brockbank, Elly; Montes, Ana; Walther, Axel; Sundar, Sudha; Edmondson, Richard J.; Hall, Geoff; Clamp, Andrew R.; Gourley, Charlie; Hall, Marcia; Fotopoulou, Christina; Gabra, Hani; Paul, James; Supernat, Anna; Millan, David; Hoyle, Aoisha; Bryson, Gareth; Nourse, Craig; Mincarelli, Laura; Sánchez, Luis Navarro; Ylstra, Bauke; Jimenez-Liñan, Mercedes; Moore, Luiza; Hofmann, Oliver; Markowetz, Florian; McNeish, Iain A.; Brenton, James D.

doi:10.1038/s41588-018-0179-8

Cited by 341 publications

(442 citation statements)

References 60 publications

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“…All patients enrolled in cohort B died for relapsed resistant disease . Results were then compared in silico with published genomic data to find out whether the identified recurrent genomic alterations were hallmark of the HGS‐EOC subtype. Demographics and clinical features of patients in cohort A are detailed in Supporting Information Results Section 1, while for cohort B they were similar to prior reports …”

Section: Resultssupporting

confidence: 78%

“…No data were available for region γ. As TCGA only includes ovary biopsies taken at the time of diagnosis, we used another independent data set including both spatial and temporal biopsies to confirm our results. Analysis of recurrent alterations on this dataset with GISTIC (Supporting Information Methods, Section 5) confirmed that regions α and β show gain respectively in almost 74 and 85% of the samples (Supporting Information Results Section 6, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…From the 591 samples of serous ovarian cancer in the repository, were selected samples from patients with HGS‐EOC stage III and IV tumors and with copy number alteration data available (Supporting Information Methods, Section 5). The second cohort was a selection of 91 temporal and spatial biopsies with high data quality from a previously published data set where segmented copy number data were available (see Supporting Information Methods, Section 5).…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies with small cohorts of patients have tried to answer these questions by analyzing matched synchronous and, whenever possible, metachronous lesions. The few concordant data so far suggest that: ( i ) the branching pattern of HGS‐EOC evolution sustains the marked genomic heterogeneity of single nucleotide variants (SNVs) among synchronous lesions . Most of these genomic abnormalities arise in a random fashion and are lesion‐specific; ( ii ) relapsed‐molecular features are largely derived from selective pressure of already distinct genetic events present in the primary tumor rather than acquired de novo .…”

Section: Introductionmentioning

confidence: 99%

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Multisite analysis of high‐grade serous epithelial ovarian cancers identifies genomic regions of focal and recurrent copy number alteration in 3q26.2 and 8q24.3

Ballabio

Craparotta

Paracchini

et al. 2019

Intl Journal of Cancer

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High‐grade serous epithelial ovarian cancer (HGS‐EOC) is a systemic disease, with marked intra and interpatient tumor heterogeneity. The issue of spatial and temporal heterogeneity has long been overlooked, hampering the possibility to identify those genomic alterations that persist, before and after therapy, in the genome of all tumor cells across the different anatomical districts. This knowledge is the first step to clarify those molecular determinants that characterize the tumor biology of HGS‐EOC and their route toward malignancy. In our study, ‐omics data were generated from 79 snap frozen matched tumor biopsies, withdrawn before and after chemotherapy from 24 HGS‐EOC patients, gathered together from independent cohorts. The landscape of somatic copy number alterations depicts a more homogenous and stable genomic portrait than the single nucleotide variant profile. Genomic identification of significant targets in cancer analysis identified two focal and minimal common regions (FMCRs) of amplification in the cytoband 3q26.2 (region α, 193 kb long) and 8q24.3 (region β, 495 kb long). Analysis in two external databases confirmed regions α and β are features of HGS‐EOC. The MECOM gene is located in region α, and 15 genes are in region β. No functional data are yet available for the genes in the β region. In conclusion, we have identified for the first time two FMCRs of amplification in HGS‐EOC, opening up a potential biological role in its etiopathogenesis.

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Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multisite analysis of high‐grade serous epithelial ovarian cancers identifies genomic regions of focal and recurrent copy number alteration in 3q26.2 and 8q24.3

Ballabio

Craparotta

Paracchini

et al. 2019

Intl Journal of Cancer

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“…Recently, we have used low‐cost shallow WGS (sWGS) to identify CN signatures in the genomes of HGSC . We used biopsy samples from the BriTROC‐1 study (the first study of the UK Translational Research in Ovarian Cancer Consortium – detailed in ) of relapsed HGSC, and combined relative CN data from sWGS (mean ×0.1) and TP53 mutant allele frequency from deep tagged‐amplicon sequencing to generate absolute CN profiles.…”

Section: Genome‐wide Biomarkers Of Hrdmentioning

confidence: 99%

Targeting DNA repair: the genome as a potential biomarker

Nesic

Wakefield

Kondrashova

et al. 2018

The Journal of Pathology

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Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used as both prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next-generation sequencing and improved bioinformatic analyses are revealing mutational signatures, i.e. broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalized treatment decisions. In this review, we use ovarian high-grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but that lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome-wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma

et al. 2023

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ImportancePatients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity.ObjectiveTo evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC.Design, Setting, and ParticipantsThis phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022.InterventionsPatients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo.Main Outcomes and MeasuresThe primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life.ResultsA total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (weekly paclitaxel plus vistusertib) vs 36.7% (weekly paclitaxel plus placebo), and there was no difference in quality of life.Conclusions and RelevanceIn this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel.Trial Registrationisrctn.org Identifier: ISRCTN16426935

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Copy number signatures and mutational processes in ovarian carcinoma

Cited by 341 publications

References 60 publications

Multisite analysis of high‐grade serous epithelial ovarian cancers identifies genomic regions of focal and recurrent copy number alteration in 3q26.2 and 8q24.3

Multisite analysis of high‐grade serous epithelial ovarian cancers identifies genomic regions of focal and recurrent copy number alteration in 3q26.2 and 8q24.3

Targeting DNA repair: the genome as a potential biomarker

Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma

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