25 results on '"Laura Galletta"'
Search Results
2. Supplementary Highlighted Methods from Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver
- Author
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Anna deFazio, David D.L. Bowtell, Paul R. Harnett, Christine L. Clarke, Hongdo Do, Stephen Q. Wong, Alexander Dobrovic, Ian Campbell, Sally M. Hunter, Emanuele Palescandolo, Laura MacConaill, Rosemary Balleine, Alison Brand, Gerard V. Wain, Russell Hogg, Laura Galletta, Jillian Hung, Sian Fereday, Catherine Kennedy, Peter Russell, Raghwa Sharma, Michael S. Anglesio, Dariush Etemadmoghadam, Joshy George, Yoke-Eng Chiew, and Catherine Emmanuel
- Abstract
Supplementary Highlighted Methods. This document contains the revised supplementary methods and results with changes highlighted
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- 2023
3. Supplementary Tables 1-7 from Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver
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Anna deFazio, David D.L. Bowtell, Paul R. Harnett, Christine L. Clarke, Hongdo Do, Stephen Q. Wong, Alexander Dobrovic, Ian Campbell, Sally M. Hunter, Emanuele Palescandolo, Laura MacConaill, Rosemary Balleine, Alison Brand, Gerard V. Wain, Russell Hogg, Laura Galletta, Jillian Hung, Sian Fereday, Catherine Kennedy, Peter Russell, Raghwa Sharma, Michael S. Anglesio, Dariush Etemadmoghadam, Joshy George, Yoke-Eng Chiew, and Catherine Emmanuel
- Abstract
Supplementary Tables 1-7. Supplementary Table 1. SBT-EOC cases used for molecular analyses Supplementary Table 2. Mutations Screened on the Sequenom/OncoMap3 Platform Supplementary Table 3. Primer sequences for the indicated exons of TP53, ERBB2 and NRAS Supplementary Table 4. Clinico-pathologic characteristics of the subset of SBT-EOC used for molecular analysis compared to the entire SBT-EOC cohort Supplementary Table 5A. Somatic mutations found in borderline and invasive ovarian tumors Supplementary Table 5B. Genes in which somatic mutations were found according to grade and co-existing serous borderline regions Supplementary Table 6. Genes differentially expressed between paired borderline and invasive regions of SBTEOC (p
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- 2023
4. Data from Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver
- Author
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Anna deFazio, David D.L. Bowtell, Paul R. Harnett, Christine L. Clarke, Hongdo Do, Stephen Q. Wong, Alexander Dobrovic, Ian Campbell, Sally M. Hunter, Emanuele Palescandolo, Laura MacConaill, Rosemary Balleine, Alison Brand, Gerard V. Wain, Russell Hogg, Laura Galletta, Jillian Hung, Sian Fereday, Catherine Kennedy, Peter Russell, Raghwa Sharma, Michael S. Anglesio, Dariush Etemadmoghadam, Joshy George, Yoke-Eng Chiew, and Catherine Emmanuel
- Abstract
Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies.Experimental Design: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling.Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC.Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. Clin Cancer Res; 20(24); 6618–30. ©2014 AACR.
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- 2023
5. Supplementary Methods from LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin
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David D.L. Bowtell, Anna deFazio, Peter Campbell, Michael Quinn, Orla McNally, Michael Friedlander, Viola Heinzelmann-Schwarz, Paul R. Harnett, Richard B. Pearson, Elizabeth L. Christie, Karen E. Sheppard, Leanne Bowes, Joy Hendley, Michael S. Anglesio, Laura Galletta, Sarah Ftouni, Dariush Etemadmoghadam, Carleen Cullinane, Peter Van Loo, Elizabeth Loehrer, Sian Fereday, Joshy George, and Prue A. Cowin
- Abstract
PDF file - 150K
- Published
- 2023
6. Supplementary Figure 3 from A Dynamic Inflammatory Cytokine Network in the Human Ovarian Cancer Microenvironment
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Frances R. Balkwill, David D. Bowtell, Donal J. Brennan, Thorsten Hagemann, John F. Smyth, Michael A. Salako, Laura Galletta, William M. Gallagher, Stephen C. Robinson, Tiziana Schioppa, Jermaine I. Coward, Richard G. Thompson, Joseph Kwong, Kellie A. Charles, D. Andrew Leinster, Probir Chakravarty, and Hagen Kulbe
- Abstract
PDF file - 1MB
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- 2023
7. Supplementary Table 2 from A Dynamic Inflammatory Cytokine Network in the Human Ovarian Cancer Microenvironment
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Frances R. Balkwill, David D. Bowtell, Donal J. Brennan, Thorsten Hagemann, John F. Smyth, Michael A. Salako, Laura Galletta, William M. Gallagher, Stephen C. Robinson, Tiziana Schioppa, Jermaine I. Coward, Richard G. Thompson, Joseph Kwong, Kellie A. Charles, D. Andrew Leinster, Probir Chakravarty, and Hagen Kulbe
- Abstract
PDF file - 5.1MB
- Published
- 2023
8. Supplementary Tables 1-6 from LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin
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David D.L. Bowtell, Anna deFazio, Peter Campbell, Michael Quinn, Orla McNally, Michael Friedlander, Viola Heinzelmann-Schwarz, Paul R. Harnett, Richard B. Pearson, Elizabeth L. Christie, Karen E. Sheppard, Leanne Bowes, Joy Hendley, Michael S. Anglesio, Laura Galletta, Sarah Ftouni, Dariush Etemadmoghadam, Carleen Cullinane, Peter Van Loo, Elizabeth Loehrer, Sian Fereday, Joshy George, and Prue A. Cowin
- Abstract
PDF file - 119K, Supp Table S1. Regions of differential copy number change between primary tumor samples and most distant abdominal deposit Supp Table S2. Top 50 pathways altered between primary tumors and abdominal deposits Supp Table S3. Individual patient chemotherapy regimens for paired primary and relapse ovarian tumors Supp Table S4. BRCA mutation details for mutation positive cases Supp Table S5. Regions of discrete copy number amplification Supp Table S6. Regions of discrete copy number deletion
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- 2023
9. Supplementary Figure 4 from A Dynamic Inflammatory Cytokine Network in the Human Ovarian Cancer Microenvironment
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Frances R. Balkwill, David D. Bowtell, Donal J. Brennan, Thorsten Hagemann, John F. Smyth, Michael A. Salako, Laura Galletta, William M. Gallagher, Stephen C. Robinson, Tiziana Schioppa, Jermaine I. Coward, Richard G. Thompson, Joseph Kwong, Kellie A. Charles, D. Andrew Leinster, Probir Chakravarty, and Hagen Kulbe
- Abstract
PDF file - 4.3MB
- Published
- 2023
10. Supplementary Figure 1 from A Dynamic Inflammatory Cytokine Network in the Human Ovarian Cancer Microenvironment
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Frances R. Balkwill, David D. Bowtell, Donal J. Brennan, Thorsten Hagemann, John F. Smyth, Michael A. Salako, Laura Galletta, William M. Gallagher, Stephen C. Robinson, Tiziana Schioppa, Jermaine I. Coward, Richard G. Thompson, Joseph Kwong, Kellie A. Charles, D. Andrew Leinster, Probir Chakravarty, and Hagen Kulbe
- Abstract
PDF file - 577K
- Published
- 2023
11. Supplementary Figure Legends 1-4 from A Dynamic Inflammatory Cytokine Network in the Human Ovarian Cancer Microenvironment
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Frances R. Balkwill, David D. Bowtell, Donal J. Brennan, Thorsten Hagemann, John F. Smyth, Michael A. Salako, Laura Galletta, William M. Gallagher, Stephen C. Robinson, Tiziana Schioppa, Jermaine I. Coward, Richard G. Thompson, Joseph Kwong, Kellie A. Charles, D. Andrew Leinster, Probir Chakravarty, and Hagen Kulbe
- Abstract
PDF file - 83K
- Published
- 2023
12. Supplementary Figure 2 from A Dynamic Inflammatory Cytokine Network in the Human Ovarian Cancer Microenvironment
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Frances R. Balkwill, David D. Bowtell, Donal J. Brennan, Thorsten Hagemann, John F. Smyth, Michael A. Salako, Laura Galletta, William M. Gallagher, Stephen C. Robinson, Tiziana Schioppa, Jermaine I. Coward, Richard G. Thompson, Joseph Kwong, Kellie A. Charles, D. Andrew Leinster, Probir Chakravarty, and Hagen Kulbe
- Abstract
PDF file - 279K
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- 2023
13. Supplementary Table 1 from A Dynamic Inflammatory Cytokine Network in the Human Ovarian Cancer Microenvironment
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Frances R. Balkwill, David D. Bowtell, Donal J. Brennan, Thorsten Hagemann, John F. Smyth, Michael A. Salako, Laura Galletta, William M. Gallagher, Stephen C. Robinson, Tiziana Schioppa, Jermaine I. Coward, Richard G. Thompson, Joseph Kwong, Kellie A. Charles, D. Andrew Leinster, Probir Chakravarty, and Hagen Kulbe
- Abstract
PDF file - 58K
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- 2023
14. Efficient molecular subtype classification of high-grade serous ovarian cancer
- Author
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Laura Galletta, Dariush Etemadmoghadam, Martin Köbel, Huei San Leong, Joshy George, David D.L. Bowtell, and Susan J. Ramus
- Subjects
Gene expression profiling ,Serous fluid ,Microarray ,Sequence analysis ,Microarray analysis techniques ,Gene expression ,TaqMan ,Cancer research ,Biology ,Molecular biology ,Gene ,Pathology and Forensic Medicine - Abstract
High-grade serous carcinomas (HGSCs) account for approximately 70% of all epithelial ovarian cancers diagnosed. Using microarray gene expression profiling, we previously identified four molecular subtypes of HGSC: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative), which correlate with patient survival and have distinct biological features. Here, we describe molecular classification of HGSC based on a limited number of genes to allow cost-effective and high-throughput subtype analysis. We determined a minimal signature for accurate classification, including 39 differentially expressed and nine control genes from microarray experiments. Taqman-based (low-density arrays and Fluidigm), fluorescent oligonucleotides (Nanostring), and targeted RNA sequencing (Illumina) assays were then compared for their ability to correctly classify fresh and formalin-fixed, paraffin-embedded samples. All platforms achieved > 90% classification accuracy with RNA from fresh frozen samples. The Illumina and Nanostring assays were superior with fixed material. We found that the C1, C2, and C4 molecular subtypes were largely consistent across multiple surgical deposits from individual chemo-naive patients. In contrast, we observed substantial subtype heterogeneity in patients whose primary ovarian sample was classified as C5. The development of an efficient molecular classifier of HGSC should enable further biological characterization of molecular subtypes and the development of targeted clinical trials.
- Published
- 2015
15. Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver
- Author
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Christine L. Clarke, Sally M Hunter, Michael S. Anglesio, Emanuele Palescandolo, Alexander Dobrovic, Russell Hogg, Catherine Kennedy, Raghwa Sharma, Gerard Wain, Hongdo Do, David D.L. Bowtell, Anna deFazio, Ian G. Campbell, Sian Fereday, Laura Galletta, Stephen Q. Wong, Rosemary L. Balleine, Joshy George, Paul R. Harnett, Peter Russell, Yoke-Eng Chiew, Laura E. MacConaill, Alison Brand, Jillian Hung, Dariush Etemadmoghadam, and Catherine Emmanuel
- Subjects
Adult ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,Pathology ,medicine.medical_specialty ,DNA Copy Number Variations ,endocrine system diseases ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Cohort Studies ,Young Adult ,medicine ,Carcinoma ,Cluster Analysis ,Humans ,Neoplasm Invasiveness ,Cystadenocarcinoma ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Ovarian Neoplasms ,Oncogene ,Melanoma ,Middle Aged ,medicine.disease ,Cystadenocarcinoma, Serous ,Gene expression profiling ,Serous fluid ,Cell Transformation, Neoplastic ,Oncology ,Mutation ,ras Proteins ,Cancer research ,Female ,KRAS ,Neoplasm Grading ,Tumor Suppressor Protein p53 ,Receptors, Progesterone ,Signal Transduction - Abstract
Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. Experimental Design: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. Clin Cancer Res; 20(24); 6618–30. ©2014 AACR.
- Published
- 2014
16. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study
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Kirsten B. Moysich, Michael E. Carney, Aleksandra Gentry-Maharaj, Susan J. Ramus, Georgia Chenevix-Trench, Carl Morrison, Julie M. Cunningham, Andre E. Kim, Anna V. Tinker, Shashikant Lele, Jennifer Alsop, Allan Jensen, Weiva Sieh, Teri A. Longacre, C. Blake Gilks, Susanne K. Kjaer, Joshy George, Usha Menon, Suha Deen, Michael S. Anglesio, Paul D.P. Pharoah, Rayna K. Matsuno, Estrid Høgdall, Montserrat Garcia-Closas, Leah M Prentice, Marie Mack, Martin Köbel, Jolanta Lissowska, Brooke L. Fridley, Lynne R. Wilkens, Lara Sucheston, Galina Lurie, Kristy Driver, Valerie McGuire, Pamela J. Thompson, Barry P. Rosen, Marcus Q. Bernardini, Christine Chow, Simon A. Gayther, Wiam Bshara, Anna deFazio, Eva Wozniak, Ellen L. Goode, Gary L. Keeney, David D.L. Bowtell, James D. Brenton, Robert A. Vierkant, Louise A. Brinton, Blaise Clarke, Kimberly R. Kalli, Marc T. Goodman, Nicolas Wentzensen, Sian Fereday, Joseph H. Rothstein, Elizabeth Benjamin, Sharon E. Johnatty, Amit M. Oza, Hannah P. Yang, Alice S. Whittemore, Kunle Odunsi, Claus Høgdall, Laura Galletta, David G. Huntsman, Mark E. Sherman, Helen Mackay, Jason Madore, and Mercedes Jimenez-Linan
- Subjects
Oncology ,medicine.medical_specialty ,endocrine system diseases ,Serous carcinoma ,Immunoenzyme Techniques ,03 medical and health sciences ,Ovarian tumor ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Mucinous carcinoma ,Neoplasm Invasiveness ,Neoplasm Staging ,030304 developmental biology ,Ovarian Neoplasms ,0303 health sciences ,Tissue microarray ,business.industry ,Ovary ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Adenocarcinoma, Mucinous ,female genital diseases and pregnancy complications ,Cystadenocarcinoma, Serous ,3. Good health ,Survival Rate ,Serous fluid ,Receptors, Estrogen ,Tissue Array Analysis ,Case-Control Studies ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Female ,Neoplasm Grading ,Receptors, Progesterone ,business ,Ovarian cancer ,Carcinoma, Endometrioid ,Adenocarcinoma, Clear Cell ,Follow-Up Studies - Abstract
Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (1% tumour cell nuclei), weak (1 to50%), or strong (≥50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.
- Published
- 2013
17. Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas
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Sarah E. Ferguson, Joaquin J. Garcia, Ghassan Allo, Sambasivarao Damaraju, David G. Huntsman, Blaise A. Clarke, C. Blake Gilks, Helen Steed, Jessica N. McAlpine, Jamie N. Bakkum-Gamez, Steve E. Kalloger, Laura Galletta, David D.L. Bowtell, Patricia Shaw, Anna V. Tinker, Mary Catherine Tolcher, Michael S. Anglesio, Janine Senz, John K. Schoolmeester, Sian Fereday, Attila Teoman, Boris Winterhoff, Henry Porter, Winnie Yang, and Stefan Kommoss
- Subjects
Sanger sequencing ,Oncology ,medicine.medical_specialty ,Concordance ,Disease ,Biology ,medicine.disease ,medicine.disease_cause ,Pathology and Forensic Medicine ,symbols.namesake ,Internal medicine ,medicine ,symbols ,Immunohistochemistry ,KRAS ,skin and connective tissue diseases ,CISH ,Ovarian cancer ,neoplasms ,Progressive disease - Abstract
Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.
- Published
- 2012
18. ARID1AMutations in Endometriosis-Associated Ovarian Carcinomas
- Author
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Marco A. Marra, Gulisa Turashvili, Michael S. Anglesio, Steve E. Kalloger, Niki Boyd, Andrew McPherson, Sian Fereday, Diane Provencher, Ryan Giuliany, Patricia N. Tonin, Jason Madore, Blake Gilks, Angela Tam, Osama M. Al-Agha, Nataliya Melnyk, David D.L. Bowtell, Stephen Yip, Gavin Ha, Christine Chow, Kane Tse, Samuel Aparicio, Allen Delaney, Lynda Bell, Anne Marie Mes-Masson, Alireza Heravi-Moussavi, Thomas Zeng, Laura Galletta, Yongjun Zhao, Janine Senz, Steven J.M. Jones, Sohrab P. Shah, Martin Hirst, Gregg B. Morin, Ie Ming Shih, Winnie Yang, Leah M Prentice, David G. Huntsman, Dianne Miller, Kimberly C. Wiegand, Melissa K. McConechy, Abdalnasser Zayed, John Fee, Arusha Oloumi, and Richard A. Moore
- Subjects
endocrine system ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,ARID1A ,Endometriosis ,Gene Expression ,Biology ,Ovarian Clear Cell Adenocarcinoma ,Cell Line, Tumor ,medicine ,Carcinoma ,Humans ,Genes, Tumor Suppressor ,Clear-cell ovarian carcinoma ,Ovarian Neoplasms ,Sequence Analysis, RNA ,Gene Expression Profiling ,Nuclear Proteins ,General Medicine ,medicine.disease ,female genital diseases and pregnancy complications ,DNA-Binding Proteins ,Serous fluid ,Mutation ,Adenocarcinoma ,Female ,Atypical Endometriosis ,Carcinoma, Endometrioid ,Adenocarcinoma, Clear Cell ,Transcription Factors - Abstract
Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described.We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas.ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions.These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.).
- Published
- 2010
19. Pembrolizumab and chemoradiotherapy for muscle invasive bladder cancer: The ANZUP 1502 PCR-MIB trial
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Siobhan Ng, Andrew Weickhardt, Colin Chen, Nitya Patanjali, Alan Herschtal, Shomik Sengupta, Tom Jarvis, Robert Goodwin, Ian D. Davis, Farshad Foroudi, Laura Galletta, Shahneen Sandhu, Nathan Lawrentschuk, Elizabeth Hovey, Colin Tang, Keen Hun Tai, and Peter Grimison
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Bladder cancer ,business.industry ,Muscle invasive ,Cancer ,Pembrolizumab ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Clinical research ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Urologic disease ,030212 general & internal medicine ,business ,Chemoradiotherapy - Abstract
TPS531 Background: Pembrolizumab leads to responses in ~20% of metastatic bladder cancer patients. Irradiation of bladder cancer cells in-vitro and in-vivo leads to upregulation of PD-L1, and in immunocompetent mouse models blockade of PD-L1 leads to delayed tumour growth following irradiation. Randomised data from PACIFIC trial in NSCLC shows the addition of PD-L1 inhibition to chemoradiation significantly prolongs PFS. A trial of chemoradiotherapy with pembrolizumab will assess safety and synergy of the combination in localised bladder cancer. Methods: This pilot study enrols patients with maximally resected non-metastatic muscle invasive bladder cancer, who either wish for bladder preservation or are ineligible for cystectomy. This study will assess the safety and feasibility of combining pembrolizumab with chemoradiotherapy in ECOG 0-1 patients without contraindications to pembrolizumab. The study has enrolled 4 of a planned 30 patients. All patients treated with 64Gy of radiation therapy in 32 fractions over 6 weeks, 2 days. Cisplatin 35mg/m2 IV concurrently weekly for 6 doses with radiation. Pembrolizumab commences concurrently with radiation and is given 200mg IV q21 days for 7 doses. Surveillance cystoscopy is performed 12 & 24 weeks after the commencement of chemoradiotherapy to assess response to therapy. Patients will enter follow up with clinical assessment, cystoscopy and CT staging performed at intervals until close of study. The primary endpoint assessed will be safety, as defined by a satisfactorily low rate of unacceptable toxicity (G3-4 adverse events or failure of completion of planned chemotherapy and radiotherapy according to defined parameters). The secondary endpoint will be efficacy, as assessed by the proportion of patients achieving a best response of complete response based on the first two 12 and 24 week post chemoradiotherapy cystoscopic assessments. Exploratory analysis will include assessment of tumour histopathological, molecular, genetic and immunological parameters. It is expected that it will take two years to accrue the 30 patients across 5 Australian centres. NCT02662062. Clinical trial information: NCT02662062.
- Published
- 2018
20. Efficient molecular subtype classification of high-grade serous ovarian cancer
- Author
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Huei San, Leong, Laura, Galletta, Dariush, Etemadmoghadam, Joshy, George, Martin, Köbel, Susan J, Ramus, and David, Bowtell
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Ovarian Neoplasms ,Paraffin Embedding ,Sequence Analysis, RNA ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,Carcinoma, Ovarian Epithelial ,Cystadenocarcinoma, Serous ,Gene Expression Regulation, Neoplastic ,Frozen Sections ,Humans ,Female ,Neoplasms, Glandular and Epithelial ,Oligonucleotide Array Sequence Analysis - Abstract
High-grade serous carcinomas (HGSCs) account for approximately 70% of all epithelial ovarian cancers diagnosed. Using microarray gene expression profiling, we previously identified four molecular subtypes of HGSC: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative), which correlate with patient survival and have distinct biological features. Here, we describe molecular classification of HGSC based on a limited number of genes to allow cost-effective and high-throughput subtype analysis. We determined a minimal signature for accurate classification, including 39 differentially expressed and nine control genes from microarray experiments. Taqman-based (low-density arrays and Fluidigm), fluorescent oligonucleotides (Nanostring), and targeted RNA sequencing (Illumina) assays were then compared for their ability to correctly classify fresh and formalin-fixed, paraffin-embedded samples. All platforms achieved90% classification accuracy with RNA from fresh frozen samples. The Illumina and Nanostring assays were superior with fixed material. We found that the C1, C2, and C4 molecular subtypes were largely consistent across multiple surgical deposits from individual chemo-naive patients. In contrast, we observed substantial subtype heterogeneity in patients whose primary ovarian sample was classified as C5. The development of an efficient molecular classifier of HGSC should enable further biological characterization of molecular subtypes and the development of targeted clinical trials.
- Published
- 2015
21. Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts
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David D.L. Bowtell, Lauren McShane, Stephen B. Fox, Karla J. Hutt, Valerie Heong, Sumitra Ananda, Scott H. Kaufmann, Matthew Wakefield, Jan Pyman, Michele Cook, Orla McNally, Emma Boehm, Dariush Etemadmoghadam, Gillian Mitchell, Marisol Harrell, Kathryn Alsop, Jeffrey B. Kerr, Elizabeth M. Swisher, Lynne Hartley, Laura Galletta, Clare L. Scott, and Monique Topp
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Cancer Research ,endocrine system ,endocrine system diseases ,medicine.medical_treatment ,Transplantation, Heterologous ,Ovary ,Antineoplastic Agents ,Mice, SCID ,Biology ,digestive system ,Mice ,Genetics ,medicine ,Carcinoma ,Animals ,Humans ,Research Articles ,Cisplatin ,BRCA2 Protein ,Ovarian Neoplasms ,Chemotherapy ,BRCA1 Protein ,Cancer ,General Medicine ,DNA Methylation ,medicine.disease ,female genital diseases and pregnancy complications ,Transplantation ,medicine.anatomical_structure ,Oncology ,Mutation ,Cancer research ,Molecular Medicine ,Female ,Ovarian cancer ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses.We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγ(null) recipient mice, completed molecular annotation and assessed platinum sensitivity.The success rate of xenografting was 83%. Of ten HG-SOC PDXs, all contained mutations in TP53, two were mutated for BRCA1, three for BRCA2, and in two, BRCA1 was methylated. In vivo cisplatin response, determined as platinum sensitive (progression-free interval ≥ 100 d, n = 4), resistant (progression-free interval100 d, n = 3) or refractory (n = 3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDXs contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDXs overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2).Because PDX platinum response reflected clinical outcome, these annotated PDXs will provide a unique model system for preclinical testing of novel therapies for HG-SOC.
- Published
- 2013
22. Pembrolizumab with ChemoRadiotherapy for Muscle Invasive Bladder Cancer: the ANZUP PCR-MIB trial
- Author
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Robert Goodwin, S. Leslie, Shahneen Sandhu, C. Chen, Elizabeth Hovey, Farshad Foroudi, Andrew Weickhardt, Siobhan Ng, Nathan Lawrentschuk, Laura Galletta, Shomik Sengupta, T. Jarvis, K.H. Tai, Colin Tang, Alan Herschtal, Nitya Patanjali, Peter Grimison, and Ian D. Davis
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Oncology ,medicine.medical_specialty ,Bladder cancer ,business.industry ,Muscle invasive ,Urology ,Hematology ,Pembrolizumab ,medicine.disease ,Internal medicine ,medicine ,business ,Chemoradiotherapy - Published
- 2016
23. Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas
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Michael S, Anglesio, Stefan, Kommoss, Mary C, Tolcher, Blaise, Clarke, Laura, Galletta, Henry, Porter, Sambasivarao, Damaraju, Sian, Fereday, Boris J, Winterhoff, Steve E, Kalloger, Janine, Senz, Winnie, Yang, Helen, Steed, Ghassan, Allo, Sarah, Ferguson, Patricia, Shaw, Attila, Teoman, Joaquin J, Garcia, John K, Schoolmeester, Jamie, Bakkum-Gamez, Anna V, Tinker, David D, Bowtell, David G, Huntsman, C Blake, Gilks, and Jessica N, McAlpine
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Adult ,Canada ,Time Factors ,Adolescent ,Receptor, ErbB-2 ,DNA Mutational Analysis ,Kaplan-Meier Estimate ,Risk Assessment ,Disease-Free Survival ,Proto-Oncogene Proteins p21(ras) ,Young Adult ,Risk Factors ,Proto-Oncogene Proteins ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Molecular Targeted Therapy ,In Situ Hybridization, Fluorescence ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,Aged, 80 and over ,Ovarian Neoplasms ,Australia ,Gene Amplification ,Middle Aged ,Prognosis ,Adenocarcinoma, Mucinous ,Immunohistochemistry ,United States ,Phenotype ,Multivariate Analysis ,Mutation ,Disease Progression ,ras Proteins ,Female ,Neoplasm Grading ,Neoplasm Recurrence, Local - Abstract
Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.
- Published
- 2012
24. Abstract 38: Using molecularly characterized patient-derived models to delineate underlying drivers and vulnerabilities of epithelial ovarian cancer
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Laura Galletta, Jan Pyman, Scott H. Kaufmann, Sumi Ananda, Dariush Etemadmoghadam, Emma Boehm, Clare L. Scott, Matthew M. Wakefield, Kathryn Alsop, David D.L. Bowtell, Lynne Hartley, Maria I. Harell, Gillian Mitchell, Karla J. Hutt, Valerie Heong, Michele Cook, Stephen B. Fox, Lauren McShane, Orla McNally, Monique D. Topp, Jeff B. Kerr, and Elizabeth M. Swisher
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Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,Pathology ,business.industry ,DNA repair ,Cancer ,Drug resistance ,medicine.disease ,Somatic evolution in cancer ,Clinical trial ,In vivo ,Internal medicine ,medicine ,business ,Ovarian cancer ,medicine.drug - Abstract
Background: Treatment options for women with ovarian cancer remain very limited and acquired resistance to current therapies is very common. Altered DNA repair capability in epithelial ovarian cancer (EOC) may underlie response to both standard therapy and novel treatments, such as PARP inhibitors. Molecular sub-classification of high-grade serous ovarian cancer (HG-SOC) may uncover potential drug targets and possible mechanisms of drug resistance. Understanding the contribution of DNA repair and other driver mutations to drug response and resistance requires the development of molecularly annotated preclinical models reflective of the clinic. Methods: A patient derived xenograft (PDX) cohort has been generated from consecutive, chemotherapy-naïve human HG-SOC and stratified according to in vivo response to standard chemotherapy, DNA repair capability and molecular characteristics, including next generation sequencing by Foundation Medicine. Resistance to therapy is driven by re-treating relapsed PDX in vivo providing invaluable “paired samples” (pre and post drug treatment), which are difficult to obtain from patients, to allow clonal evolution analysis of mechanisms of drug response and resistance. Results: The xenograft success rate was 83%. Of ten HG-SOC PDX, all exhibited mutations in TP53, five in BRCA1/2 (two of which were germline) and two were methylated for BRCA1. In vivo cisplatin response, determined as platinum sensitive (progression-free interval (PFI) ≥100 d, n=4), platinum resistant (PFI Conclusion: PDX with histologic, molecular and therapeutic annotation, as well as clinical outcome data allow interrogation of molecular aberrations and drug resistance in vivo. This will inform targeting of novel therapies and the design of clinical trials for women. Citation Format: Monique D. Topp, Lynne Hartley, Michele Cook, Valerie Heong, Emma Boehm, Lauren McShane, Jan Pyman, Orla McNally, Sumi Ananda, Maria I. Harell, Dariush Etemadmoghadam, Laura Galletta, Kathryn Alsop, Gillian Mitchell, Stephen B. Fox, Jeff B. Kerr, Karla J. Hutt, Scott H. Kaufmann, Australian Ovarian Cancer Study (AOCS), Elizabeth M. Swisher, David D. Bowtell, Matthew M. Wakefield, Clare L. Scott. Using molecularly characterized patient-derived models to delineate underlying drivers and vulnerabilities of epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 38. doi:10.1158/1538-7445.CANSUSC14-38
- Published
- 2014
25. The Australian Ovarian Cancer Study
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Jillian Hung, A Iuga, Georgia Chenevix-Trench, Joy Hendley, Anna deFazio, David D.L. Bowtell, Nadia Traficante, David H. Giles, Kathryn Alsop, Laura Galletta, Sian Fereday, Adèle C. Green, and Penelope M. Webb
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medicine.medical_specialty ,lcsh:QH426-470 ,business.industry ,General surgery ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Patient recruitment ,Tumour tissue ,lcsh:Genetics ,Oncology ,Cancer centre ,Meeting Abstract ,Medicine ,Primary treatment ,business ,Ovarian cancer ,Genetics (clinical) - Abstract
Background AOCS commenced in 2000 as a collaborative study between researchers at the Peter MacCallum Cancer Centre (PMCC), Queensland Institute for Medical Research (QIMR), Westmead Institute for Cancer Research (WICR) and University of Melbourne. Patient recruitment ceased on June 30, 2006. AOCS recruited a total of 1834 women with invasive or borderline ovarian cancer, far exceeding the initial target. We have received a total of 1815 completed questionnaires and have collected 1080 fresh tumour tissue samples and 1582 blood samples. Control recruitment is also complete and a total of 1066 control women that did not have ovarian cancer were recruited. Clinical details have been recorded for all AOCS patients, with clinical follow-up done at 6-monthly intervals: we have primary treatment data, including surgery and chemotherapy details on 99% of cases; and 89% of eligible cases have follow-up to five years post-diagnosis.. Thus far only 123 patients (6.5%) have been lost to follow-up, despite that fact that 30-40% of our patients return to regional areas for ongoing treatment.
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