Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer

Burdett, Nikki; Willis, Madelynne O.; Alsop, Kathryn; Hunt, Allison L.; Pandey, Ahwan; Hamilton, Phineas T.; Abulez, Tamara; Li, Xuan; Hoang, Therese; Craig, Stuart; Fereday, Sián; Hendley, Joy; Garsed, Dale W.; Milne, Katy; Kalaria, Shreena; Marshall, Ashley; Hood, Brian L.; Wilson, Kerry; Conrads, Kelly A.; Pishas, Kathleen I.; Ananda, Sumitra; Scott, Clare L.; Antill, Yoland; McNally, Orla; Mileshkin, Linda; Hamilton, Anne; Au-Yeung, George; Devereux, Lisa; Thorne, Heather; Bild, Andrea H; Bateman, Nicholas W.; Maxwell, G. Larry; Chang, Jeffrey T.; Conrads, Thomas P.; Nelson, Brad H.; Bowtell, David D.L.; Christie, Elizabeth L.

doi:10.1038/s41588-023-01320-2

Cited by 30 publications

(30 citation statements)

References 84 publications

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“…This has already enabled high‐impact research, as highlighted in Figure 4B and Table 2 with examples from the 14 programmes. Genomics, particularly sequencing multiple metastases per patient, has revealed insights into metastatic seeding, driver events, treatment resistance, and disease phylogenetics [15,44–66]. Additionally, it has allowed the exploration of the use of liquid biopsies to profile the different metastases [67].…”

Section: Resultsmentioning

confidence: 99%

“…Methylation of assessed promotor regions was more similar [68] Limited heterogeneity in driver events, copy number profile, cell cycle activity, and androgen receptor activity between metastases within one patient with prostate cancer [44] Important heterogeneity in subclonal structure between primary and metastatic disease in breast cancer. Treatment drives genomic subclonal heterogeneity [15] Analysis of multiple metastases per patient allowed the evaluation of intra-patient heterogeneity in the presence of specific gene fusion events in breast cancer [45] Multiple subclones with a variety of mechanisms of therapeutic resistance can co-exist in one patient with ovarian cancer [46] Intra-patient inter-metastasis heterogeneity of HER2-low status complicates its assessment on one biopsy in metastatic breast cancer [69] Characterisation and evaluation of distribution of polypoid giant cancer cells in metastatic castration-resistant prostate cancer [72] Intra-patient inter-lesion heterogeneity in phenotype was observed in metastatic prostate cancer, including differences in androgen receptor expression and PSA expression [70] DNA methylation changes are very similar between metastases within patients with prostate cancer. Regions with consistent methylation show enrichment for cancer-related genes [47] Metastatic lesions within patients and between patients with urothelial carcinoma shared actionable mutations [48] Many of the genetic changes conferring treatment resistance were shared between metastases in the same patient with melanoma [49] No correlation between ERG and expression of PSA or androgen receptor in individual metastases in prostate cancer [71] Prognostic and predictive biomarker expression differs between primary breast cancer and matched metastases and might depend on the organ of metastasis.…”

Section: Intra-patient Inter-lesion Heterogeneity In Genomic and Phen...mentioning

confidence: 99%

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Research autopsy programmes in oncology: shared experience from 14 centres across the world

Geukens,

Maetens,

Hooper

et al. 2024

The Journal of Pathology

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While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high‐volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non‐tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro‐environment, and tumour representation in liquid biopsies. Tumour patient‐derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 99%

Section: Intra-patient Inter-lesion Heterogeneity In Genomic and Phen...mentioning

confidence: 99%

Research autopsy programmes in oncology: shared experience from 14 centres across the world

Geukens,

Maetens,

Hooper

et al. 2024

The Journal of Pathology

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“…Interestingly, homozygous Brca1 D11/D11 mice are embryonic lethal, and derived cells are PARPi sensitive (24)(25)(26). Therefore, it is likely that additional rewiring events accompany SSMs, such as reduced expression of end resection inhibitory proteins, which work in conjunction with the BRCA1 D11 or D11q protein to promote robust HR and PARPi resistance (47,48). Alternatively, in the setting of cancer, BRCA1 D11 or D11q expression and the residual HR it provides is sufficient to induce PARPi resistance in tumors.…”

Section: Discussionmentioning

confidence: 99%

BRCA1secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance

Nesic

Krais

Vandenberg

et al. 2023

Preprint

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BRCA1 splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out mutation-containing exons, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of BRCA1 exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for splice isoform expression and therapy response. This included a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi regimen. BRCA1 exon 11-deficient isoform expression was generally elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs), predicted in silico to drive exon skipping. Predictions were confirmed using qRT-PCR, RNA sequencing, western blots and BRCA1 minigene modelling. SSMs were also enriched in post-PARPi OC patient cohorts from the ARIEL2 and ARIEL4 clinical trials. We demonstrate that SSMs drive BRCA1 exon 11 skipping and PARPi resistance, and should be clinically monitored, along with frame-restoring secondary mutations.

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“…Additionally, ascites occurs in most cases of relapse, where further surgery is rarely performed 3 . Relapsed ovarian cancer is often molecularly distinct from its predecessor 24, 25 . Thereby cfDNA in ascites may provide earlier access to an uncompromised tumour sample, as well as unique access to evolved disease.…”

Section: Introductionmentioning

confidence: 99%

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer

Werner,

Powell,

Duggan

et al. 2024

Preprint

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Background The emergence of targeted therapies and predictive biomarkers is transforming the ovarian cancer treatment paradigm. However, the demand for high quality, tumour-enriched samples for biomarker profiling can be limited by access to adequate tissue samples. The use of cell-free DNA (cfDNA) in ascites presents a potential solution to this clinical challenge. Methods A unique set of sequential ascites-derived cfDNA samples (26 samples from 15 human participants) were collected from people with ovarian cancer (age range 36-82 years). cfDNA was sequenced using targeted next-generation sequencing, along with matched DNA from ascites-derived tumour cells (n=5) and archived FFPE-tissue from surgery (n=5). Results Similar tumour purity, variant detection and reference alignment were achieved with cfDNA when compared to FFPE and ascites derived tumour cell DNA, as well as improved coverage. No artefactual single-base mutation signatures were identified in cfDNA. Combined analysis of large-scale genomic alterations, loss of heterozygosity and tumour mutation burden identified 6 cases of high genomic instability (including 4 with pathogenic variants in BRCA1 and BRCA2). Copy number profiles and subclone prevalence changed between sequential ascites samples, particularly in a case study where deletions and chromothripsis in Chr17p13.1 and Chr8q resulted in changes in clinically relevant TP53 and MYC variants over time. Conclusions Ascites cfDNA successfully identified clinically actionable information, concordant to tissue biopsies, enabling opportunistic molecular profiling. These findings advocate for analysis of ascites cfDNA in lieu of accessing tumour tissue via biopsy.

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Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer

Cited by 30 publications

References 84 publications

Research autopsy programmes in oncology: shared experience from 14 centres across the world

Research autopsy programmes in oncology: shared experience from 14 centres across the world

BRCA1secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer

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