Sir Peter MacCallum Department of Oncology - Research Publications

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    Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma
    Stewart, CJR ; Bowtell, DDL ; Doherty, DA ; Leung, YC (WILEY-BLACKWELL, 2017-01-01)
    AIMS: Gynaecological cancer patients with germline mutations appear to have a better prognosis than those with sporadic malignancies. Following the observation of long-term survival in a patient with stage III ovarian clear cell carcinoma (CCC) and possible Lynch syndrome (LS), DNA mismatch repair (MMR) protein immunohistochemistry was performed in a series of high-stage CCC and correlated with patient outcomes. METHODS AND RESULTS: Thirty-two consecutive cases of stage III/IV ovarian CCCs accessioned between 1992 and 2015 were examined. The tumours from two patients (6%), including the index case, showed loss of MSH2/MSH6 expression while MLH1/PMS2 staining was retained. The index patient subsequently developed colonic and rectal carcinomas that were also MSH2/MSH6-deficient, while the second patient had a genetically confirmed germline MSH2 mutation. All other tumours showed retained expression of the four MMR proteins. The two patients with MMR protein-deficient tumours were alive 160 months and 124 months following surgery, whereas the median survival of patients with MMR protein-intact CCCs was 11.8 months (75th and 25th percentiles of 8.1 months and 39.3 months, respectively), with 21 patients deceased due to tumour. CONCLUSIONS: Larger studies are required but high-stage, MMR protein-deficient CCCs may have a relatively favourable prognosis.
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    Going to extremes: determinants of extraordinary response and survival in patients with cancer
    Saner, FAM ; Herschtal, A ; Nelson, BH ; deFazio, A ; Goode, EL ; Ramus, SJ ; Pandey, A ; Beach, JA ; Fereday, S ; Berchuck, A ; Lheureux, S ; Pearce, CL ; Pharoah, PD ; Pike, MC ; Garsed, DW ; Bowtell, DDL (NATURE PUBLISHING GROUP, 2019-06-01)
    Research into factors affecting treatment response or survival in patients with cancer frequently involves cohorts that span the most common range of clinical outcomes, as such patients are most readily available for study. However, attention has turned to highly unusual patients who have exceptionally favourable or atypically poor responses to treatment and/or overall survival, with the expectation that patients at the extremes may provide insights that could ultimately improve the outcome of individuals with more typical disease trajectories. While clinicians can often recount surprising patients whose clinical journey was very unusual, given known clinical characteristics and prognostic indicators, there is a lack of consensus among researchers on how best to define exceptional patients, and little has been proposed for the optimal design of studies to identify factors that dictate unusual outcome. In this Opinion article, we review different approaches to identifying exceptional patients with cancer and possible study designs to investigate extraordinary clinical outcomes. We discuss pitfalls with finding these rare patients, including challenges associated with accrual of patients across different treatment centres and time periods. We describe recent molecular and immunological factors that have been identified as contributing to unusual patient outcome and make recommendations for future studies on these intriguing patients.
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    Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference
    Bast, RC ; Matulonis, UA ; Sood, AK ; Ahmed, AA ; Amobi, AE ; Balkwill, FR ; Wielgos-Bonvallet, M ; Bowtell, DDL ; Brenton, JD ; Brugge, JS ; Coleman, RL ; Draetta, GF ; Doberstein, K ; Drapkin, RI ; Eckert, MA ; Edwards, RP ; Elias, KM ; Ennis, D ; Futreal, A ; Gershenson, DM ; Greenberg, RA ; Huntsman, DG ; Ji, JXY ; Kohn, EC ; Iavarone, C ; Lengyel, ER ; Levine, DA ; Lord, CJ ; Lu, Z ; Mills, GB ; Modugno, F ; Nelson, BH ; Odunsi, K ; Pilsworth, JA ; Rottapel, RK ; Powell, DJ ; Shen, L ; Shih, I-M ; Spriggs, DR ; Walton, J ; Zhang, K ; Zhang, R ; Zou, L (WILEY, 2019-06-15)
    Substantial progress has been made in understanding ovarian cancer at the molecular and cellular level. Significant improvement in 5-year survival has been achieved through cytoreductive surgery, combination platinum-based chemotherapy, and more effective treatment of recurrent cancer, and there are now more than 280,000 ovarian cancer survivors in the United States. Despite these advances, long-term survival in late-stage disease has improved little over the last 4 decades. Poor outcomes relate, in part, to late stage at initial diagnosis, intrinsic drug resistance, and the persistence of dormant drug-resistant cancer cells after primary surgery and chemotherapy. Our ability to accelerate progress in the clinic will depend on the ability to answer several critical questions regarding this disease. To assess current answers, an American Association for Cancer Research Special Conference on "Critical Questions in Ovarian Cancer Research and Treatment" was held in Pittsburgh, Pennsylvania, on October 1-3, 2017. Although clinical, translational, and basic investigators conducted much of the discussion, advocates participated in the meeting, and many presentations were directly relevant to patient care, including treatment with poly adenosine diphosphate ribose polymerase (PARP) inhibitors, attempts to improve immunotherapy by overcoming the immune suppressive effects of the microenvironment, and a better understanding of the heterogeneity of the disease.
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    Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study
    Rambau, PF ; Vierkant, RA ; Intermaggio, MP ; Kelemen, LE ; Goodman, MT ; Herpel, E ; Pharoah, PD ; Kommoss, S ; Jimenez-Linan, M ; Karlan, BY ; Gentry-Maharaj, A ; Menon, U ; Polo, SH ; Candido dos Reis, FJ ; Doherty, JA ; Gayther, SA ; Sharma, R ; Larson, MC ; Harnett, PR ; Hatfield, E ; de Andrade, JM ; Nelson, GS ; Steed, H ; Schildkraut, JM ; Carney, ME ; Hogdall, E ; Whittemore, AS ; Widschwendter, M ; Kennedy, CJ ; Wang, F ; Wang, Q ; Wang, C ; Armasu, SM ; Daley, F ; Coulson, P ; Jones, ME ; Anglesio, MS ; Chow, C ; de Fazio, A ; Garcia-Closas, M ; Brucker, SY ; Cybulski, C ; Harris, HR ; Hartkopf, AD ; Huzarski, T ; Jensen, A ; Lubinski, J ; Oszurek, O ; Benitez, J ; Mina, F ; Staebler, A ; Taran, FA ; Pasternak, J ; Talhouk, A ; Rossing, MA ; Hendley, J ; Edwards, RP ; Fereday, S ; Modugno, F ; Ness, RB ; Sieh, W ; El-Bahrawy, MA ; Winham, SJ ; Lester, J ; Kjaer, SK ; Gronwald, J ; Sinn, P ; Fasching, PA ; Chang-Claude, J ; Moysich, KB ; Bowtell, DD ; Hernandez, BY ; Luk, H ; Behrens, S ; Shah, M ; Jung, A ; Ghatage, P ; Alsop, J ; Alsop, K ; Garcia-Donas, J ; Thompson, PJ ; Swerdlow, AJ ; Karpinskyj, C ; Cazorla-Jimenez, A ; Garcia, MJ ; Deen, S ; Wilkens, LR ; Palacios, J ; Berchuck, A ; Koziak, JM ; Brenton, JD ; Cook, LS ; Goode, EL ; Huntsman, DG ; Ramus, SJ ; Koebel, M (WILEY, 2018-10-01)
    We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
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    Genomic Analysis Using Regularized Regression in High-Grade Serous Ovarian Cancer
    Natanzon, Y ; Earp, M ; Cunningham, JM ; Kalli, KR ; Wang, C ; Armasu, SM ; Larson, MC ; Bowtell, DDL ; Garsed, DW ; Fridley, BL ; Winham, SJ ; Goode, EL (SAGE PUBLICATIONS LTD, 2018-02-01)
    High-grade serous ovarian cancer (HGSOC) is a complex disease in which initiation and progression have been associated with copy number alterations, epigenetic processes, and, to a lesser extent, germline variation. We hypothesized that, when summarized at the gene level, tumor methylation and germline genetic variation, alone or in combination, influence tumor gene expression in HGSOC. We used Elastic Net (ENET) penalized regression method to evaluate these associations and adjust for somatic copy number in 3 independent data sets comprising tumors from more than 470 patients. Penalized regression models of germline variation, with or without methylation, did not reveal a role in HGSOC gene expression. However, we observed significant association between regional methylation and expression of 5 genes (WDPCP, KRT6C, BRCA2, EFCAB13, and ZNF283). CpGs retained in ENET model for BRCA2 and ZNF283 appeared enriched in several regulatory elements, suggesting that regularized regression may provide a novel utility for integrative genomic analysis.
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    Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers
    Stany, MP ; Vathipadiekal, V ; Ozbun, L ; Stone, RL ; Mok, SC ; Xue, H ; Kagami, T ; Wang, Y ; McAlpine, JN ; Bowtell, D ; Gout, PW ; Miller, DM ; Gilks, CB ; Huntsman, DG ; Ellard, SL ; Wang, Y-Z ; Vivas-Mejia, P ; Lopez-Berestein, G ; Sood, AK ; Birrer, MJ ; Creighton, C (PUBLIC LIBRARY SCIENCE, 2011-07-06)
    Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.
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    The ubiquitin ligase Siah2 regulates obesity-induced adipose tissue inflammation
    Kilroy, G ; Carter, LE ; Newman, S ; Burk, DH ; Manuel, J ; Moeller, A ; Bowtell, DD ; Mynatt, RL ; Ghosh, S ; Floyd, ZE (WILEY-BLACKWELL, 2015-11-01)
    OBJECTIVE: Chronic, low-grade adipose tissue inflammation associated with adipocyte hypertrophy is an important link in the relationship between obesity and insulin resistance. Although ubiquitin ligases regulate inflammatory processes, the role of these enzymes in metabolically driven adipose tissue inflammation is relatively unexplored. Herein, the effect of the ubiquitin ligase Siah2 on obesity-related adipose tissue inflammation was examined. METHODS: Wild-type and Siah2KO mice were fed a low- or high-fat diet for 16 weeks. Indirect calorimetry, body composition, and glucose and insulin tolerance were assayed along with glucose and insulin levels. Gene and protein expression, immunohistochemistry, adipocyte size distribution, and lipolysis were also analyzed. RESULTS: Enlarged adipocytes in obese Siah2KO mice were not associated with obesity-induced insulin resistance. Proinflammatory gene expression, stress kinase signaling, fibrosis, and crown-like structures were reduced in the Siah2KO adipose tissue, and Siah2KO adipocytes were more responsive to insulin-dependent inhibition of lipolysis. Loss of Siah2 increased expression of PPARγ target genes involved in lipid metabolism and decreased expression of proinflammatory adipokines regulated by PPARγ. CONCLUSIONS: Siah2 links adipocyte hypertrophy with adipocyte dysfunction and recruitment of proinflammatory immune cells to adipose tissue. Selective regulation of PPARγ activity is a Siah2-mediated mechanism contributing to obesity-induced adipose tissue inflammation.
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    Siah2 regulates tight junction integrity and cell polarity through control of ASPP2 stability
    Kim, H ; Claps, G ; Moeller, A ; Bowtell, D ; Lu, X ; Ronai, ZA (NATURE PUBLISHING GROUP, 2014-04-10)
    Changes in cell adhesion and polarity are closely associated with epithelial cell transformation and metastatic capacity. The tumor suppressor protein ASPP (Apoptosis-Stimulating Proteins of p53) 2 has been implicated in control of cell adhesion and polarity through its effect on the PAR complex. Here we demonstrate that under hypoxic conditions, the ubiquitin ligase Siah (seven in absentia homolog)2 controls ASPP2 availability, with concomitant effect on epithelial cell polarity. LC-MS/MS analysis identified ASPP2 and ASPP1 as Siah2-interacting proteins. Biochemical analysis confirmed this interaction and mapped degron motifs within ASPP2, which are required for Siah2-mediated ubiquitination and proteasomal-dependent degradation. Inhibition of Siah2 expression increases ASPP2 levels and enhances ASPP2-dependent maintenance of tight junction (TJ) integrity, and polarized architecture in three dimensional (3D) organotypic culture. Conversely, increase of Siah2 expression under hypoxia decreases ASPP2 levels and the formation of apical polarity in 3D culture. In all, our studies demonstrate the role of Siah2 in regulation of TJ integrity and cell polarity under hypoxia, through its regulation of ASPP2 stability.
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    The Antioxidant N-Acetylcysteine Prevents HIF-1 Stabilization under Hypoxia In Vitro but Does Not Affect Tumorigenesis in Multiple Breast Cancer Models In Vivo
    Sceneay, J ; Liu, MCP ; Chen, A ; Wong, CSF ; Bowtell, DDL ; Moeller, A ; Lawson, V (PUBLIC LIBRARY SCIENCE, 2013-06-20)
    Intratumoral hypoxia is a poor prognostic factor associated with reduced disease-free survival in many cancer types, including breast cancer. Hypoxia encourages tumor cell proliferation, stimulates angiogenesis and lymphangiogenesis, and promotes epithelial-mesenchymal transition and metastasis. Tumor cells respond to a hypoxic state by stabilizing the Hif-1α subunit of the Hypoxia-Inducible Factor (HIF) transcription factor to promote expression of various tumor- and metastasis-promoting hypoxic response genes. The antioxidant N-acetylcysteine (NAC) was recently shown to prevent Hif-1α stabilization under hypoxia, and has been identified as a potential alternative method to target the hypoxic response in tumors. We utilized three orthotopic syngeneic murine models of breast cancer, the PyMT, EO771 and 4T1.2 models, to investigate the ability of NAC to modulate the hypoxic response in vitro and in vivo. While NAC prevented Hif-1α stabilization under hypoxia in vitro and increased levels of glutathione in the blood of mice in vivo, this did not translate to a difference in tumor growth or the hypoxic state of the tumor compared to untreated control mice. In addition, NAC treatment actually increased metastatic burden in an experimental metastasis model. This work raises questions regarding the validity of NAC as an anti-tumorigenic agent in breast cancer, and highlights the need to further investigate its properties in vivo in different cancer models.
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    Deregulation of MYCN, LIN28B and LET7 in a Molecular Subtype of Aggressive High-Grade Serous Ovarian Cancers
    Helland, A ; Anglesio, MS ; George, J ; Cowin, PA ; Johnstone, CN ; House, CM ; Sheppard, KE ; Etemadmoghadam, D ; Melnyk, N ; Rustgi, AK ; Phillips, WA ; Johnsen, H ; Holm, R ; Kristensen, GB ; Birrer, MJ ; Pearson, RB ; Borresen-Dale, A-L ; Huntsman, DG ; deFazio, A ; Creighton, CJ ; Smyth, GK ; Bowtell, DDL ; Tan, P (PUBLIC LIBRARY SCIENCE, 2011-04-13)
    Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention.