Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Au-Yeung, George × Author: McNally, Orla × Start date: 2020 × Type: Journal Article ×

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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.
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    Endometriosis and menopausal hormone therapy impact the hysterectomy-ovarian cancer association.
    Khoja, L ; Weber, RP ; Australian Ovarian Cancer Study Group, ; Webb, PM ; Jordan, SJ ; Muthukumar, A ; Chang-Claude, J ; Fortner, RT ; Jensen, A ; Kjaer, SK ; Risch, H ; Doherty, JA ; Harris, HR ; Goodman, MT ; Modugno, F ; Moysich, K ; Berchuck, A ; Schildkraut, JM ; Cramer, D ; Terry, KL ; Anton-Culver, H ; Ziogas, A ; Phung, MT ; Hanley, GE ; Wu, AH ; Mukherjee, B ; McLean, K ; Cho, K ; Pike, MC ; Pearce, CL ; Lee, AW (Elsevier BV, 2022-01)
    OBJECTIVE: To evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association. METHODS: We conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Overall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99). CONCLUSIONS: The hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.