المؤلفون: Smith, Philip, Bradley, Thomas, Gavarró, Lena Morrill, Goranova, Teodora, Ennis, Darren P., Mirza, Hasan B., De Silva, Dilrini, Piskorz, Anna M., Sauer, Carolyn, Al-Khalidi, Sarwah, Funingana, Ionat-Gabriel, Reinius, Marika A. V., Giannone, Gaia, Lewsley, Liz-Anne, Stobo, Jamie, Mcqueen, John, Bryson, Gareth, Eldridge, Matthew, Macintyre, Geoff, Markowetz, Florian, Brenton, James D., McNeish, Iain A.

الوصف: 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 samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification 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.

وصف الملف: text

العلاقة: https://eprints.gla.ac.uk/304594/2/304594.pdfTest; Smith, P. et al. (2023) The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma. Nature Communications , 14(1), 4387. (doi:10.1038/s41467-023-39867-7 ) (PMID:37474499) (PMCID:PMC10359414)

الإتاحة: https://doi.org/10.1038/s41467-023-39867-7Test
https://eprints.gla.ac.uk/304594Test/
https://eprints.gla.ac.uk/304594/2/304594.pdfTest

المؤلفون: Smith, Philip, Bradley, Thomas, Gavarró, Lena Morrill, Goranova, Teodora, Ennis, Darren P., Mirza, Hasan B., De Silva, Dilrini, Piskorz, Anna M., Sauer, Carolin M., Al-Khalidi, Sarwah, Funingana, Ionut-Gabriel, Reinius, Marika A. V., Giannone, Gaia, Lewsley, Liz-Anne, Stobo, Jamie, McQueen, John, Bryson, Gareth, Eldridge, Matthew, Glasspool, R. M., Gourley, C., Kennedy, R., Hall, G., Edmondson, R., Clamp, A., Sundar, S., Walter, A., Hall, M., Gabra, H., Fotopoulou, C., Brockbank, E., Montes, A., Lockley, M., Macintyre, Geoff, Markowetz, Florian, Brenton, James D., McNeish, Iain A.

المصدر: Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الإتاحة: https://doi.org/10.1038/s41467-023-41611-0Test
https://www.nature.com/articles/s41467-023-41611-0.pdfTest
https://www.nature.com/articles/s41467-023-41611-0Test

المؤلفون: Ergasti, Raffaella, Russo, Giorgia, Lim, Mi Qi, Giannone, Gaia, Ennis, Darren P, Dye, Isabel Ca, Mirza, Hasan B, Marchetti, Claudia, Fagotti, Anna, Scambia, Giovanni, Mcneish, Iain

المصدر: Poster and E-Posters

الإتاحة: https://doi.org/10.1136/ijgc-2024-esgo.987Test

المؤلفون: Cheng, Zhao, Ennis, Darren P, Lu, Bingxin, Mirza, Hasan B, Sokota, Chishimba, Kaur, Baljeet, Singh, Naveena, Le Saux, Olivia, Russo, Giorgia, Giannone, Gaia, Tookman, Laura A, Krell, Jonathan, Barnes, Chris, McDermott, Jackie, McNeish, Iain A

مصطلحات موضوعية: high‐grade serous carcinoma, whole‐genome duplication, evolution, STIC

الوصف: Publication status: Published ; Funder: La Ligue contre le Cancer ; Funder: La Fondation Nuovo‐Soldati ; Funder: Canceropole Lyon Auvergne Rhone‐Alpes ; AbstractOvarian high‐grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early‐ and late‐stage HGSC and found higher ploidy in late‐stage (median 3.1) than early‐stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole‐genome duplication (WGD) observed in late‐stage disease were determined early in the evolution of HGSC, we analysed archival formalin‐fixed paraffin‐embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser‐capture microdissected and sequenced using shallow whole‐genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next‐generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises ...

وصف الملف: application/pdf; text/xml

العلاقة: https://www.repository.cam.ac.uk/handle/1810/370474Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/370474Test

المؤلفون: Ergasti, Raffaella, Lim, Mi Qi, Giannone, Gaia, Ennis, Darren P, Dye, Isabel CA, Mirza, Hasan B, Russo, Giorgia, Fagotti, Anna, Scambia, Giovanni, Mcneish, Iain

المصدر: Poster/ePoster Sessions

الإتاحة: https://doi.org/10.1136/ijgc-2023-esgo.782Test

المؤلفون: Banerjee, Susana, Giannone, Gaia, Clamp, Andrew R., Ennis, Darren P., Glasspool, Rosalind M., Herbertson, Rebecca, Krell, Jonathan, Riisnaes, Ruth, Mirza, Hasan B., Cheng, Zhao, McDermott, Jacqueline, Green, Clare, Kristeleit, Rebecca S., George, Angela, Gourley, Charlie, Lewsley, Liz-Anne, Rai, Debbie, Banerji, Udai, Hinsley, Samantha, Mcneish, Iain A.

الوصف: Importance: Patients 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. Objective: To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC. Design, Setting, and Participants: This 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. Interventions Patients 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 Measures: The 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. Results: A 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 ...

العلاقة: Banerjee, S. et al. (2023) Efficacy and safety of weekly paclitaxel plus vistusertib vs paclitaxel alone in patients with platinum-resistant ovarian high-grade serous carcinoma: the OCTOPUS multicenter, phase 2, randomized clinical trial. JAMA Oncology , 9(5), pp. 675-682. (doi:10.1001/jamaoncol.2022.7966 ) (PMID:36928279) (PMCID:PMC10020933)

الإتاحة: https://doi.org/10.1001/jamaoncol.2022.7966Test
https://eprints.gla.ac.uk/295098Test/

المؤلفون: Ergasti, Raffaella, Lim, Mi Qi, Giannone, Gaia, Ennis, Darren P, Dye, Isabel CA, Mirza, Hasan B, Fagotti, Anna, Scambia, Giovanni, McNeish, Iain

المصدر: Translational research/biomarkers

الإتاحة: https://doi.org/10.1136/ijgc-2022-esgo.888Test