Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Alsop, Kathryn × Author: Au-Yeung, George × Author: Bowtell, David × Start date: 2020 × Type: Journal Article ×

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    Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer
    Burdett, NL ; Willis, MO ; Pandey, A ; Fereday, S ; DeFazio, A ; Bowtell, DDL ; Christie, EL (NATURE PORTFOLIO, 2023-12-10)
    While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.
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    Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer
    Burdett, NL ; Willis, MO ; Alsop, K ; Hunt, AL ; Pandey, A ; Hamilton, PT ; Abulez, T ; Liu, X ; Hoang, T ; Craig, S ; Fereday, S ; Hendley, J ; Garsed, DW ; Milne, K ; Kalaria, S ; Marshall, A ; Hood, BL ; Wilson, KN ; Conrads, KA ; Pishas, K ; Ananda, S ; Scott, CL ; Antill, Y ; McNally, O ; Mileshkin, L ; Hamilton, A ; Au-Yeung, G ; Devereux, L ; Thorne, H ; Bild, A ; Bateman, NW ; Maxwell, GL ; Chang, JT ; Conrads, TPP ; Nelson, BH ; Bowtell, DDL ; Christie, ELL (NATURE PORTFOLIO, 2023-03)
    High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.
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    The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer
    Garsed, DW ; Pandey, A ; Fereday, S ; Kennedy, CJ ; Takahashi, K ; Alsop, K ; Hamilton, PT ; Hendley, J ; Chiew, Y-E ; Traficante, N ; Provan, P ; Ariyaratne, D ; Au-Yeung, G ; Bateman, NW ; Bowes, L ; Brand, A ; Christie, EL ; Cunningham, JM ; Friedlander, M ; Grout, B ; Harnett, P ; Hung, J ; McCauley, B ; McNally, O ; Piskorz, AM ; Saner, FAM ; Vierkant, RA ; Wang, C ; Winham, SJ ; Pharoah, PDP ; Brenton, JD ; Conrads, TP ; Maxwell, GL ; Ramus, SJ ; Pearce, CL ; Pike, MC ; Nelson, BH ; Goode, EL ; DeFazio, A ; Bowtell, DDL (NATURE PORTFOLIO, 2022-12)
    Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.