ORCID Profile
0000-0002-9387-7586
Current Organisations
Imperial College
,
Imperial College London
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Publisher: American Association for Cancer Research (AACR)
Date: 13-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 13-09-2023
Publisher: Massachusetts Medical Society
Date: 29-12-2011
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419653
Abstract: Association results after the adjustment for nearby GWAS index SNPs for genes with predicted gene expression levels associated with ovarian cancer risk at P 2.21E-6.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2023
DOI: 10.1038/S41467-023-39867-7
Abstract: The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis s les from patients with primary platinum resistance have increased rates of CCNE1 and KRAS lification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.
Publisher: EMBO
Date: 09-03-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419659
Abstract: Known common variants identified from genome-wide assocation studies and their bioinformatically predicted target genes.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482375.V1
Abstract: Supplementary Data from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 15-06-2015
DOI: 10.1038/NG.3336
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482366.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419659.V1
Abstract: Known common variants identified from genome-wide assocation studies and their bioinformatically predicted target genes.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419644
Abstract: Association results between associated genes with P P 2.21E-6 and risk of different histotypes of epithelial ovarian cancer.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.YGYNO.2019.04.679
Abstract: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. We established an international collaboration to conduct a systematic review and meta-analysis, pooling in idual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66 P < 0·001) and 0·65 (95% CI 0·50-0·85, P = 0·002) respectively no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0% OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027). CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419647
Abstract: Genes coregulated in predicted expression at 2q31.1, 9p22.3, 17q21.31 and 17q21.32.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2017
DOI: 10.1158/1055-9965.EPI-16-0631
Abstract: Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive rotumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify in idual SNPs that were significantly associated with survival after correction for multiple testing (P & 3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 in idual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, in idual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev 26(3) 420–4. ©2016 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482378
Abstract: Supplementary Data from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6510431
Abstract: Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue s les from 68 in iduals and 6,124 cross-tissue s les from 369 in iduals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their i cis /i -predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of i P /i 2.2 × 10 sup −6 /sup , we identified 35 genes, including i FZD4 /i at 11q14.2 (Z = 5.08, i P /i = 3.83 × 10 sup −7 /sup , the cross-tissue model 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained ( i P /i 1.47 × 10 sup −3 /sup ). These data identify one novel locus i (FZD4 /i ) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. b Significance: /b Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. i Cancer Res 78(18) 5419–30. ©2018 AACR /i . /
Publisher: American Association for Cancer Research (AACR)
Date: 02-2019
DOI: 10.1158/2159-8290.CD-18-0715
Abstract: BRCA reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple BRCA reversion mutations, highlighting the ability to capture multiclonal heterogeneity. This article is highlighted in the In This Issue feature, p. 151
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482378.V1
Abstract: Supplementary Data from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
DOI: 10.1038/NCOMMS14206
Abstract: The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2017
DOI: 10.1158/2159-8290.CD-17-0419
Abstract: High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy s les collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations. Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov 7(9) 984–98. ©2017 AACR. See related commentary by Domchek, p. 937. See related article by Quigley et al., p. 999. See related article by Goodall et al., p. 1006. This article is highlighted in the In This Issue feature, p. 920
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482384
Abstract: Supplementary Data from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432970
Abstract: Supplementary tables
Publisher: American Association for Cancer Research (AACR)
Date: 30-11-2015
DOI: 10.1158/1078-0432.CCR-15-0632
Abstract: Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res 21(23) 5264–76. ©2015 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482363.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Elsevier BV
Date: 05-2016
Publisher: Elsevier BV
Date: 11-2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482384.V1
Abstract: Supplementary Data from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419662.V1
Abstract: Chromosomal regions with predicted gene expression levels associated with epithelial ovarian cancer risk at P 2.21E-6 with either ovarian or cross-tissue model.
Publisher: American Association for Cancer Research (AACR)
Date: 07-10-2022
DOI: 10.1158/0008-5472.CAN-21-4012
Abstract: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482354.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
DOI: 10.1038/NG.3826
Publisher: Springer Science and Business Media LLC
Date: 30-03-2017
DOI: 10.1038/BJC.2017.86
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419635
Abstract: Association results between minor alleles of 467 variants incorportated in cross tissue gene expression prediction model for the gene of CRHR1.
Publisher: Springer Science and Business Media LLC
Date: 26-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432967
Abstract: Supplementary methods and figures
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419638
Abstract: Variants with P 5E-8 either in BCAC or OCAC between 42,836,399 and 44,910,520 on the chromosome 17.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482339.V1
Abstract: Supplementary Table from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482345.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Elsevier BV
Date: 09-2020
Publisher: American Association for Cancer Research (AACR)
Date: 02-2019
DOI: 10.1158/0008-5472.CAN-17-3864
Abstract: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439
Publisher: Elsevier BV
Date: 08-2015
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6510431.V1
Abstract: Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue s les from 68 in iduals and 6,124 cross-tissue s les from 369 in iduals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their i cis /i -predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of i P /i 2.2 × 10 sup −6 /sup , we identified 35 genes, including i FZD4 /i at 11q14.2 (Z = 5.08, i P /i = 3.83 × 10 sup −7 /sup , the cross-tissue model 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained ( i P /i 1.47 × 10 sup −3 /sup ). These data identify one novel locus i (FZD4 /i ) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. b Significance: /b Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. i Cancer Res 78(18) 5419–30. ©2018 AACR /i . /
Publisher: BMJ
Date: 10-2010
Publisher: Public Library of Science (PLoS)
Date: 19-06-2015
Publisher: Springer Science and Business Media LLC
Date: 19-01-2017
DOI: 10.1038/BJC.2016.426
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482360.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Oxford University Press (OUP)
Date: 25-11-2017
DOI: 10.1093/IJE/DYX236
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419665.V1
Abstract: Internal performance of ovarian and cross-tissue gene expression prediction models built using GTEx data.
Publisher: Elsevier BV
Date: 05-2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530898.V1
Abstract: AbstractPurpose: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. Experimental Design: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment s les from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment s les from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). i TP53 /i mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including i BRCA1 /i and i BRCA2 /i . We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) s les. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Conclusions: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-0336" target="_blank" See related commentary by Yang et al., p. 2730 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 14-09-2018
DOI: 10.1158/0008-5472.CAN-18-0951
Abstract: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue s les from 68 in iduals and 6,124 cross-tissue s les from 369 in iduals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P & 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P & 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res 78(18) 5419–30. ©2018 AACR.
Publisher: Cold Spring Harbor Laboratory
Date: 05-12-2018
DOI: 10.1101/487926
Abstract: Chromosomal aberration and DNA copy number change are robust hallmarks of cancer. Imaging of spots generated using fluorescence in situ hybridisation (FISH) of locus specific probes is routinely used to detect copy number changes in tumour nuclei. However, it often does not perform well on solid tumour tissue sections, where partially represented or overlapping nuclei are common. To overcome these challenges, we have developed a computational approach called FrenchFISH, which comprises a nuclear volume correction method coupled with two types of Poisson models: either a Poisson model for improved manual spot counting without the need for control probes or a homogenous Poisson Point Process model for automated spot counting. We benchmarked the performance of FrenchFISH against previous approaches in a controlled simulation scenario and exemplify its use in 12 ovarian cancer FFPE-tissue sections, for which we assess copy number alterations in three loci (c-Myc, hTERC and SE7). We show that FrenchFISH outperforms standard spot counting approaches and that the automated spot counting is significantly faster than manual without loss of performance. FrenchFISH is a general approach that can be used to enhance clinical diagnosis on sections of any tissue.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482351.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 13-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432967.V1
Abstract: Supplementary methods and figures
Publisher: American Association for Cancer Research (AACR)
Date: 13-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432970.V1
Abstract: Supplementary tables
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482348.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: Springer Science and Business Media LLC
Date: 13-08-2018
Publisher: Springer Science and Business Media LLC
Date: 14-01-2022
DOI: 10.1038/S41431-021-00987-7
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to in idual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries 7,669 women of East Asian ancestries 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419671.V1
Abstract: Online Supplementary Documents
Publisher: Springer Science and Business Media LLC
Date: 10-08-2023
DOI: 10.1038/S41467-023-40315-9
Abstract: Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify erse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an in idual and, in some patients, the co-existence of AR -neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in in idual patients, clusters of metastases occupied by dominant clones with erged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance ( p -values 3.07 × 10 −8 and 6.4 × 10 −4 ). Integration with anatomical sites suggests patterns of spread and points of genomic ergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482333.V1
Abstract: Supplementary Table from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 03-01-2017
Publisher: Elsevier BV
Date: 2016
Publisher: American Association for Cancer Research (AACR)
Date: 13-09-2023
Publisher: Springer Science and Business Media LLC
Date: 23-10-2015
DOI: 10.1038/NRC4019
Abstract: High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482348
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Impact Journals, LLC
Date: 12-07-2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482345
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 02-2019
DOI: 10.1158/0008-5472.CAN-18-2726
Abstract: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482351
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482354
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Wiley
Date: 10-02-2018
DOI: 10.1002/PATH.5025
Abstract: 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 ex les 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 ex le 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.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2019
DOI: 10.1038/S41416-019-0433-6
Abstract: This article was originally published under a CC BY NC SA License, but has now been made available under a CC BY 4.0 License.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530898
Abstract: AbstractPurpose: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. Experimental Design: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment s les from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment s les from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). i TP53 /i mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including i BRCA1 /i and i BRCA2 /i . We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) s les. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Conclusions: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-0336" target="_blank" See related commentary by Yang et al., p. 2730 /a /i /
Publisher: Cold Spring Harbor Laboratory
Date: 05-05-2021
DOI: 10.1101/2021.05.05.440631
Abstract: High grade serous carcinoma (HGSC) is the commonest type of ovarian cancer. Nearly all HGSC cases are diagnosed at late stage and it is not clear whether early stage HGSC has unique characteristics compared to late stage tumours. We analysed s les from 45 patients with FIGO stage I - IIA HGSC - 40 from the pathology archives of three large UK cancer centres and 5 from the BriTROC-1 study. We performed shallow whole genome sequencing (sWGS) and targeted next generation sequencing to investigate somatic mutations and copy number alterations. We compared results to 51 stage IIIC/IV HGSC patients from the BriTROC-1 study. There was no difference in median age between the early stage (median 61.3 years, range 40-84) and late stage (median 62.3 years, range 34-76) patients at diagnosis. TP53 mutations were near-universal (92% early stage, 100% late stage s les) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2 , or focal copy number alterations between early- and late-stage cohorts. There were also no unique lifications or deletions in either cohort. However, median ploidy was greater in late stage (median 3.1) than early stage (median 2.0) s les. In addition, there were higher numbers of breakpoints per 10MB and per chromosome arm and higher absolute copy number in late stage than early stage cohorts early stage s les had longer segment length. Overall copy number signature exposures were significantly different between early and late stage s les with greater signature 3 exposure in early stage and greater signature 4 in late stage. Both simplex plot and unsupervised hierarchical clustering suggested that a subset of late stage s les retain early stage appearances with high signature 3 and co-clustering with the early stage s les These data suggest that there are no unique mutations or focal copy number alterations in early stage HGSC. However, whole genome duplication is significantly more common in late-stage disease, suggesting evolution during disease progression. However, a subset of late stage HGSC retains early-stage features, which are associated with improved overall survival.
Publisher: MDPI AG
Date: 30-05-2022
Abstract: Several non-genetic factors have been associated with ovarian cancer incidence or mortality. To evaluate the strength and validity of the evidence we conducted an umbrella review of the literature that included systematic reviews/meta-analyses that evaluated the link between non-genetic risk factors and ovarian cancer incidence and mortality. We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews and performed a manual screening of references. Evidence was graded into strong, highly suggestive, suggestive or weak based on statistical significance of the random effects summary estimate and the largest study in a meta-analysis, the number of cases, between-study heterogeneity, 95% prediction intervals, small study effects, and presence of excess significance bias. We identified 212 meta-analyses, investigating 55 non-genetic risk factors for ovarian cancer. Risk factors were grouped in eight broad categories: anthropometric indices, dietary intake, physical activity, pre-existing medical conditions, past drug history, biochemical markers, past gynaecological history and smoking. Of the 174 meta-analyses of cohort studies assessing 44 factors, six associations were graded with strong evidence. Greater height (RR per 10 cm 1.16, 95% confidence interval (CI) 1.11–1.20), body mass index (BMI) (RR ≥ 30 kg/m2 versus normal 1.27, 95% CI 1.17–1.38) and three exposures of varying preparations and usage related to hormone replacement therapy (HRT) use increased the risk of developing ovarian cancer. Use of oral contraceptive pill reduced the risk (RR 0.74, 95% CI 0.69–0.80). Refining the significance of genuine risk factors for the development of ovarian cancer may potentially increase awareness in women at risk, aid prevention and early detection.
Publisher: Elsevier BV
Date: 03-2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419638.V1
Abstract: Variants with P 5E-8 either in BCAC or OCAC between 42,836,399 and 44,910,520 on the chromosome 17.
Publisher: Elsevier BV
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 16-08-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482339
Abstract: Supplementary Table from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482336.V1
Abstract: Supplementary Table from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482333
Abstract: Supplementary Table from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482336
Abstract: Supplementary Table from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 22-03-2022
Publisher: American Association for Cancer Research (AACR)
Date: 2021
DOI: 10.1158/1055-9965.EPI-20-0739
Abstract: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni & 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P & 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger s le sets are required to confirm our findings.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482342.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Oxford University Press (OUP)
Date: 24-03-2015
DOI: 10.1093/HMG/DDV101
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482342
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Cold Spring Harbor Laboratory
Date: 29-11-2022
DOI: 10.1101/2022.11.29.518198
Abstract: Dysregulation of the PI3K/AKT pathway is a common occurrence in ovarian carcinomas. Loss of the tumour suppressor PTEN in high-grade serous ovarian carcinoma (HGSOC) is associated with a patient subgroup with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We utilise long-term time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency does not affect proliferation but rather induces PI(3,4,5)P 3 -rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor β1-integrin (ITGB1) as key ARF6 interactors regulating the PTEN loss-associated invasion phenotype. ARF6 functions to promote invasion by controlling the recycling of internalised, active β1-integrin complexes to maintain invasive activity into the ECM. The expression of the ARF6-centred complex in HGSOC patients is inversely associated with outcome, allowing identification of patient groups with improved versus poor outcome. ARF6 may represent a new therapeutic vulnerability in PTEN - depleted HGSOC tumours.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419635.V1
Abstract: Association results between minor alleles of 467 variants incorportated in cross tissue gene expression prediction model for the gene of CRHR1.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419671
Abstract: Online Supplementary Documents
Publisher: Elsevier BV
Date: 10-2017
Publisher: American Association for Cancer Research (AACR)
Date: 13-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6514283.V1
Abstract: Abstract Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8 sup + /sup T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. Significance: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419647.V1
Abstract: Genes coregulated in predicted expression at 2q31.1, 9p22.3, 17q21.31 and 17q21.32.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482366
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 23-09-2011
DOI: 10.1038/NRC3144
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482369
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Elsevier BV
Date: 04-2017
Abstract: This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482375
Abstract: Supplementary Data from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482372
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: EMBO
Date: 14-08-2023
Abstract: Dysregulation of the PI3K/AKT pathway is a common occurrence in high‐grade serous ovarian carcinoma (HGSOC), with the loss of the tumour suppressor PTEN in HGSOC being associated with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We here utilise time‐lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency induces PI(3,4,5)P 3 ‐rich and ‐dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability of HGSOC cells upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase‐activating protein (GAP) AGAP1 and the ECM receptor β1‐integrin (ITGB1) as key ARF6 interactors in HGSOC regulating PTEN loss‐associated invasion. ARF6 functions to promote invasion by controlling the recycling of internalised, active β1‐integrin to maintain invasive activity into the ECM. The expression of the CYTH2‐ARF6‐AGAP1 complex in HGSOC patients is inversely associated with outcome, allowing the identification of patient groups with improved versus poor outcome. ARF6 may represent a therapeutic vulnerability in PTEN‐depleted HGSOC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419653.V1
Abstract: Association results after the adjustment for nearby GWAS index SNPs for genes with predicted gene expression levels associated with ovarian cancer risk at P 2.21E-6.
Publisher: Public Library of Science (PLoS)
Date: 06-07-2018
Publisher: Springer Science and Business Media LLC
Date: 28-09-2018
DOI: 10.1038/S41467-018-05564-Z
Abstract: Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2 -mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1 -methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1- methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 15-10-2020
DOI: 10.1158/1078-0432.CCR-20-0103
Abstract: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of in idual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with & % accuracy that was maintained in all analytic and biological validations. We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419662
Abstract: Chromosomal regions with predicted gene expression levels associated with epithelial ovarian cancer risk at P 2.21E-6 with either ovarian or cross-tissue model.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2202
DOI: 10.1158/0008-5472.22419665
Abstract: Internal performance of ovarian and cross-tissue gene expression prediction models built using GTEx data.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22419644.V1
Abstract: Association results between associated genes with P P 2.21E-6 and risk of different histotypes of epithelial ovarian cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 10-04-2022
DOI: 10.1158/1078-0432.CCR-21-1643
Abstract: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment s les from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment s les from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) s les. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482372.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482363
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 12-01-2015
DOI: 10.1038/NG.3185
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482360
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 03-05-2021
DOI: 10.1038/S41467-021-22582-6
Abstract: ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 s les, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1 / BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22482369.V1
Abstract: Supplementary Figure from The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Iain McNeish.