Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Bowtell, David × Author: Campbell, Ian × Author: Fereday, Julie × Author: Ramus, Susan × End date: 2019 × Start date: 2010 × Type: Journal Article ×

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    MyD88 and TLR4 Expression in Epithelial Ovarian Cancer
    Block, MS ; Vierkant, RA ; Rambau, PF ; Winham, SJ ; Wagner, P ; Traficante, N ; Toloczko, A ; Tiezzi, DG ; Taran, FA ; Sinn, P ; Sieh, W ; Sharma, R ; Rothstein, JH ; Ramon y Cajal, T ; Paz-Ares, L ; Oszurek, O ; Orsulic, S ; Ness, RB ; Nelson, G ; Modugno, F ; Menkiszak, J ; McGuire, V ; McCauley, BM ; Mack, M ; Lubinski, J ; Longacre, TA ; Li, Z ; Lester, J ; Kennedy, CJ ; Kalli, KR ; Jung, AY ; Johnatty, SE ; Jimenez-Linan, M ; Jensen, A ; Intermaggio, MP ; Hung, J ; Herpel, E ; Hernandez, BY ; Hartkopf, AD ; Harnett, PR ; Ghatage, P ; Garcia-Bueno, JM ; Gao, B ; Fereday, S ; Eilber, U ; Edwards, RP ; de Sousa, CB ; de Andrade, JM ; Chudecka-Glaz, A ; Chenevix-Trench, G ; Cazorla, A ; Brucker, SY ; Alsop, J ; Whittemore, AS ; Steed, H ; Staebler, A ; Moysich, KB ; Menon, U ; Koziak, JM ; Kommoss, S ; Kjaer, SK ; Kelemen, LE ; Karlan, BY ; Huntsman, DG ; Hogdall, E ; Gronwald, J ; Goodman, MT ; Gilks, B ; Jose Garcia, M ; Fasching, PA ; de Fazio, A ; Deen, S ; Chang-Claude, J ; dos Reis, FJC ; Campbell, IG ; Brenton, JD ; Bowtell, DD ; Benitez, J ; Pharoah, PDP ; Kobel, M ; Ramus, SJ ; Goode, EL (ELSEVIER SCIENCE INC, 2018-03)
    OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
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    Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
    Davis, SJ ; Sheppard, KE ; Anglesio, MS ; George, J ; Traficante, N ; Fereday, S ; Intermaggio, MP ; Menon, U ; Gentry-Maharaj, A ; Lubinski, J ; Gronwald, J ; Pearce, CL ; Pike, MC ; Wu, A ; Kommoss, S ; Pfisterer, J ; du Bois, A ; Hilpert, F ; Ramus, SJ ; Bowtell, DDL ; Huntsman, DG ; Pearson, RB ; Simpson, KJ ; Campbell, IG ; Gorringe, KL (AMER ASSOC CANCER RESEARCH, 2015-06)
    Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling.