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ItemGlucagonoma Masquerading as a Mucinous Cancer of the Ovary: Lessons from Cell BiologyHo, GY ; Ananda, S ; Vandenberg, CJ ; McNally, O ; Tie, J ; Gorringe, K ; Bowtell, D ; Pyman, J ; Wakefield, MJ ; Scott, CL ; Ho, GY ; Frentzas, S (IntechOpen, 2020-06-17)High-grade mucinous ovarian cancer (HGMOC) is often a misnomer as the majority of cases are metastatic disease with a gastro-intestinal origin. The standard platinum-based ovarian cancer (OC) chemotherapy regimens are often ineffective, and there are insufficient data to support the use of colorectal cancer (CRC) chemotherapy regimens due to the rarity of HGMOC. We described a cohort of four consecutive suspected HGMOC cases treated at the Royal Women’s Hospital, Melbourne in 2012. Two cases were treated as primary MOC, whereas the other two were considered to be metastatic CRC based on histopathological and clinical evidence. From the RNAseq analysis, we identified two cases of HGMOC whose gene expression profiles were consistent with mucinous epithelial OC, one case that was treated as metastatic CRC with gene expression profile correlated with CRC and one case with neuroendocrine (NET) gene expression features. Interestingly, glucagon was over-expressed in this tumor that was subsequently confirmed by immunohistochemistry. These findings suggest a rare glucagonoma-like NET appendiceal tumor that had metastasized to the surface of ovary and were unresponsive to CRC chemotherapy regimens. In summary, a carefully curated panel of expression markers and selected functional genomics could provide diagnosis and treatment guidance for patients with possible HGMOC.
ItemTherapeutic options for mucinous ovarian carcinomaGorringe, KL ; Cheasley, D ; Wakefield, MJ ; Ryland, GL ; Allan, PE ; Alsop, K ; Amarasinghe, KC ; Ananda, S ; Bowtell, DDL ; Christie, M ; Chiew, Y-E ; Churchman, M ; DeFazio, A ; Fereday, S ; Gilks, CB ; Gourley, C ; Hadley, AM ; Hendley, J ; Hunter, SM ; Kaufmann, SH ; Kennedy, CJ ; Kobel, M ; Le Page, C ; Li, J ; Lupat, R ; McNally, OM ; McAlpine, JN ; Pyman, J ; Rowley, SM ; Salazar, C ; Saunders, H ; Semple, T ; Stephens, AN ; Thio, N ; Torres, MC ; Traficante, N ; Zethoven, M ; Antill, YC ; Campbell, IG ; Scott, CL (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-03-01)OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
ItemMethylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinomaKondrashova, O ; Topp, M ; Nesic, K ; Lieschke, E ; Ho, G-Y ; Harrell, M ; Zapparoli, G ; Hadley, A ; Holian, R ; Boehm, E ; Heong, V ; Sanij, E ; Pearson, RB ; Krais, JJ ; Johnson, N ; McNally, O ; Ananda, S ; Alsop, K ; Hutt, KJ ; Kaufmann, SH ; Lin, KK ; Harding, TC ; Traficante, N ; deFazio, A ; McNeish, LA ; Bowtell, DD ; Swisher, EM ; Dobrovic, A ; Wakefield, MJ ; Scott, CL ; Chenevix-Trench, G ; Green, A ; Webb, P ; Gertig, D ; Fereday, S ; Moore, S ; Hung, J ; Harrap, K ; Sadkowsky, T ; Pandeya, N ; Malt, M ; Mellon, A ; Robertson, R ; Vanden Bergh, T ; Jones, M ; Mackenzie, P ; Maidens, J ; Nattress, K ; Chiew, YE ; Stenlake, A ; Sullivan, H ; Alexander, B ; Ashover, P ; Brown, S ; Corrish, T ; Green, L ; Jackman, L ; Ferguson, K ; Martin, K ; Martyn, A ; Ranieri, B ; White, J ; Jayde, V ; Mamers, P ; Bowes, L ; Galletta, L ; Giles, D ; Hendley, J ; Schmidt, T ; Shirley, H ; Ball, C ; Young, C ; Viduka, S ; Tran, H ; Bilic, S ; Glavinas, L ; Brooks, J ; Stuart-Harris, R ; Kirsten, F ; Rutovitz, J ; Clingan, P ; Glasgow, A ; Proietto, A ; Braye, S ; Otton, G ; Shannon, J ; Bonaventura, T ; Stewart, J ; Begbie, S ; Friedlander, M ; Bell, D ; Baron-Hay, S ; Ferrier, A ; Gard, G ; Nevell, D ; Pavlakis, N ; Valmadre, S ; Young, B ; Camaris, C ; Crouch, R ; Edwards, L ; Hacker, N ; Marsden, D ; Robertson, G ; Beale, P ; Beith, J ; Carter, J ; Dalrymple, C ; Houghton, R ; Russell, P ; Links, M ; Grygiel, J ; Hill, J ; Brand, A ; Byth, K ; Jaworski, R ; Harnett, P ; Sharma, R ; Wain, G ; Ward, B ; Papadimos, D ; Crandon, A ; Cummings, M ; Horwood, K ; Obermair, A ; Perrin, L ; Wyld, D ; Nicklin, J ; Davy, M ; Oehler, MK ; Hall, C ; Dodd, T ; Healy, T ; Pittman, K ; Henderson, D ; Miller, J ; Pierdes, J ; Blomfield, P ; Challis, D ; Mclntosh, R ; Parker, A ; Brown, B ; Rome, R ; Allen, D ; Grant, P ; Hyde, S ; Laurie, R ; Robbie, M ; Healy, D ; Jobling, T ; Manolitsas, T ; McNealage, J ; Rogers, P ; Susil, B ; Sumithran, E ; Simpson, I ; Phillips, K ; Rischin, D ; Fox, S ; Johnson, D ; Lade, S ; Loughrey, M ; O'Callaghan, N ; Murray, W ; Waring, P ; Billson, V ; Pyman, J ; Neesham, D ; Quinn, M ; Underhill, C ; Bell, R ; Ng, LF ; Blum, R ; Ganju, V ; Hammond, I ; Leung, Y ; McCartney, A ; Buck, M ; Haviv, I ; Purdie, D ; Whiteman, D ; Zeps, N (NATURE PUBLISHING GROUP, 2018-09-28)Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.
ItemNo Preview AvailableLRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal DoxorubicinCowin, PA ; George, J ; Fereday, S ; Loehrer, E ; Van Loo, P ; Cullinane, C ; Etemadmoghadam, D ; Ftouni, S ; Galletta, L ; Anglesio, MS ; Hendley, J ; Bowes, L ; Sheppard, KE ; Christie, EL ; Pearson, RB ; Harnett, PR ; Heinzelmann-Schwarz, V ; Friedlander, M ; McNally, O ; Quinn, M ; Campbell, P ; deFazio, A ; Bowtell, DDL (AMER ASSOC CANCER RESEARCH, 2012-08-15)High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients.