Medical Biology - Research Publications

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Author: Ananda, Sumitra × Author: Bowtell, David × End date: 2020 ×

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    Glucagonoma Masquerading as a Mucinous Cancer of the Ovary: Lessons from Cell Biology
    Ho, 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.
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    Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
    Kondrashova, 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.