Sir Peter MacCallum Department of Oncology - Research Publications

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    The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas
    Heinze, K ; Cairns, ES ; Thornton, S ; Harris, B ; Milne, K ; Grube, M ; Meyer, C ; Karnezis, AN ; Fereday, S ; Garsed, DW ; Leung, SCY ; Chiu, DS ; Moubarak, M ; Harter, P ; Heitz, F ; McAlpine, JN ; DeFazio, A ; Bowtell, DDL ; Goode, EL ; Pike, M ; Ramus, SJ ; Pearce, CL ; Staebler, A ; Kobel, M ; Kommoss, S ; Talhouk, A ; Nelson, BH ; Anglesio, MS (AMER ASSOC CANCER RESEARCH, 2023-09-01)
    PURPOSE: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%-20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. EXPERIMENTAL DESIGN: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. RESULTS: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P > 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0; 95% confidence interval, 1.1-14.7; P < 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. CONCLUSIONS: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.
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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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    Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma
    Wang, C ; Block, MS ; Cunningham, JM ; Sherman, ME ; McCauley, BM ; Armasu, SM ; Vierkant, RA ; Traficante, N ; Talhouk, A ; Doherty, JA ; Pejovic, N ; Kobel, M ; Jorgensen, BD ; Garsed, DW ; Fereday, S ; Ramus, SJ ; Ariyaratne, D ; Anglesio, MS ; Widschwendter, M ; Pejovic, T ; Bosquet, JG ; Bowtell, DD ; Winham, SJ ; Goode, EL (AMER ASSOC CANCER RESEARCH, 2023-04)
    BACKGROUND: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. METHODS: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. RESULTS: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10-2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17-3.81; P = 2.2 × 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66-2.95; P = 4.1 × 10-8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10-7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10-4) in covariate-adjusted analysis. CONCLUSIONS: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. IMPACT: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.
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    A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary
    Posner, A ; Prall, OW ; Sivakumaran, T ; Etemadamoghadam, D ; Thio, N ; Pattison, A ; Balachander, S ; Fisher, K ; Webb, S ; Wood, C ; DeFazio, A ; Wilcken, N ; Gao, B ; Karapetis, CS ; Singh, M ; Collins, IM ; Richardson, G ; Steer, C ; Warren, M ; Karanth, N ; Wright, G ; Williams, S ; George, J ; Hicks, RJ ; Boussioutas, A ; Gill, AJ ; Solomon, BJ ; Xu, H ; Fellowes, A ; Fox, SB ; Schofield, P ; Bowtell, D ; Mileshkin, L ; Tothill, RW (WILEY, 2023-01)
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    Beating the odds: molecular characteristics of long-term survivors of ovarian cancer
    Garsed, DW ; Bowtell, DDL (Nature Research, 2022-12-01)
    High-grade serous ovarian cancer, the most common form of the disease, is often fatal. This study investigated the genomic and immune characteristics of tumors from women who survived more than 10 years after their initial diagnosis, and compared them with short-term and moderate-term survivors.
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    CCNE1 Amplification as a Therapeutic Target
    Au-Yeung, G ; Mileshkin, L ; Bowtell, DDL (LIPPINCOTT WILLIAMS & WILKINS, 2023-03-20)
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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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    Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2
    O'Mahony, DG ; Ramus, SJ ; Southey, MC ; Meagher, NS ; Hadjisavvas, A ; John, EM ; Hamann, U ; Imyanitov, EN ; Andrulis, IL ; Sharma, P ; Daly, MB ; Hake, CR ; Weitzel, JN ; Jakubowska, A ; Godwin, AK ; Arason, A ; Bane, A ; Simard, J ; Soucy, P ; Caligo, MA ; Mai, PL ; Claes, KBM ; Teixeira, MR ; Chung, WK ; Lazaro, C ; Hulick, PJ ; Toland, AE ; Pedersen, IS ; Neuhausen, SL ; Vega, A ; de la Hoya, M ; Nevanlinna, H ; Dhawan, M ; Zampiga, V ; Danesi, R ; Varesco, L ; Gismondi, V ; Vellone, VG ; James, PA ; Janavicius, R ; Nikitina-Zake, L ; Nielsen, FC ; van Overeem Hansen, T ; Pejovic, T ; Borg, A ; Rantala, J ; Offit, K ; Montagna, M ; Nathanson, KL ; Domchek, SM ; Osorio, A ; Garcia, MJ ; Karlan, BY ; De Fazio, A ; Bowtell, D ; McGuffog, L ; Leslie, G ; Parsons, MT ; Doerk, T ; Speith, L-M ; dos Santos, ES ; da Costa, AABA ; Radice, P ; Peterlongo, P ; Papi, L ; Engel, C ; Hahnen, E ; Schmutzler, RK ; Wappenschmidt, B ; Easton, DF ; Tischkowitz, M ; Singer, CF ; Tan, YY ; Whittemore, AS ; Sieh, W ; Brenton, JD ; Yannoukakos, D ; Fostira, F ; Konstantopoulou, I ; Soukupova, J ; Vocka, M ; Chenevix-Trench, G ; Pharoah, PDP ; Antoniou, AC ; Goldgar, DE ; Spurdle, AB ; Michailidou, K ; Mourits, MJE ; Lesueur, F (SPRINGERNATURE, 2023-06-29)
    BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.
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    Profiling the immune landscape in mucinous ovarian carcinoma
    Meagher, NS ; Hamilton, P ; Milne, K ; Thornton, S ; Harris, B ; Weir, A ; Alsop, J ; Bisinoto, C ; Brenton, JD ; Brooks-Wilsoni, A ; Chiu, DS ; Cushing-Haugen, KL ; Fereday, S ; Garsed, DW ; Gayther, SA ; Gentry-Maharaj, A ; Gilks, B ; Jimenez-Linan, M ; Kennedy, CJ ; Le, ND ; Piskorz, AM ; Riggan, MJ ; Shah, M ; Singh, N ; Talhoukj, A ; Widschwendter, M ; Bowtell, DDL ; dos Reis, FJC ; Cook, LS ; Fortner, RT ; Garcia, MJ ; Harris, HR ; Huntsman, DG ; Karnezis, AN ; Kobel, M ; Menon, U ; Pharoah, PDP ; Doherty, JA ; Anglesioj, MS ; Pike, MC ; Pearce, CL ; Friedlander, ML ; DeFazio, A ; Nelson, BH ; Ramus, SJ (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-01)
    OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.
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    Lifestyle and personal factors associated with having macroscopic residual disease after ovarian cancer primary cytoreductive surgery
    Phung, MT ; Webb, PM ; DeFazio, A ; Fereday, S ; Lee, AW ; Bowtell, DDL ; Fasching, PA ; Goode, EL ; Goodman, MT ; Karlan, BY ; Lester, J ; Matsuo, K ; Modugno, F ; Brenton, JD ; Van Gorp, T ; Pharoah, PDP ; Schildkraut, JM ; McLean, K ; Meza, R ; Mukherjee, B ; Richardson, J ; Grout, B ; Chase, A ; Deurloo, CM ; Terry, KL ; Hanley, GE ; Pike, MC ; Berchuck, A ; Ramus, SJ ; Pearce, CL (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-01)
    OBJECTIVE: The presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery. METHODS: This analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS. RESULTS: Menopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53). CONCLUSIONS: The association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy.