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1. Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Author

Talhouk A, George J, Wang C, Budden T, Tan TZ, Chiu DS, Kommoss S, Leong HS, Chen S, Intermaggio MP, Gilks B, Nazeran TM, Volchek M, Elatre W, Bentley RC, Senz J, Lum A, Chow V, Sudderuddin H, Mackenzie R, Leong SCY, Liu G, Johnson D, Chen B, Group A, Alsop J, Banerjee SN, Behrens S, Bodelon C, Brand AH, Brinton L, Carney ME, Chiew YE, Cushing-Haugen KL, Cybulski C, Ennis D, Fereday S, Fortner RT, García-Donas J, Gentry-Maharaj A, Glasspool R, Goranova T, Greene CS, Haluska P, Harris HR, Hendley J, Hernandez BY, Herpel E, Jimenez-Linan M, Karpinskyj C, Kaufmann SH, Keeney GL, Kennedy CJ, Köbel M, Koziak JM, Larson MC, Lester J, Lewsley LA, Lissowska J, Lubiński J, Luk H, Macintyre G, Mahner S, McNeish IA, Menkiszak J, Nevins N, Osorio A, Oszurek O, Palacios J, Hinsley S, Pearce CL, Pike MC, Piskorz AM, Ray-Coquard I, Rhenius V, Rodriguez-Antona C, Sharma R, Sherman ME, De Silva D, Singh N, Sinn P, Slamon D, Song H, Steed H, Stronach EA, Thompson PJ, Tołoczko A, Trabert B, Traficante N, Tseng CC, Widschwendter M, Wilkens LR, Winham SJ, Winterhoff B, Beeghly-Fadiel A, Benitez J, Berchuck A, Brenton JD, Brown R, Chang-Claude J, Chenevix-Trench G, deFazio A, Fasching PA, García MJ, Gayther SA, Goodman MT, Gronwald J, Henderson MJ, Karlan BY, Kelemen LE, Menon U, Orsulic S, Pharoah PDP, Wentzensen N, Wu AH, Schildkraut JM, Rossing MA, Konecny GE, Huntsman DG, Huang RY, Goode EL, Ramus SJ, Doherty JA, Bowtell DD, and Anglesio MS

Subjects
Aged, Algorithms, Cystadenoma, Serous classification, Cystadenoma, Serous pathology, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Lymphocytes, Tumor-Infiltrating pathology, Middle Aged, Neoplasm Grading, Neoplasm, Residual classification, Neoplasm, Residual genetics, Neoplasm, Residual pathology, Ovarian Neoplasms classification, Ovarian Neoplasms pathology, Cystadenoma, Serous genetics, Neoplasm Proteins genetics, Ovarian Neoplasms genetics, Transcriptome genetics
Abstract

Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features., Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting., Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations., Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271 ., (©2020 American Association for Cancer Research.)

Published
2020
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2. Prognostic gene expression signature for high-grade serous ovarian cancer.

Author

Millstein J, Budden T, Goode EL, Anglesio MS, Talhouk A, Intermaggio MP, Leong HS, Chen S, Elatre W, Gilks B, Nazeran T, Volchek M, Bentley RC, Wang C, Chiu DS, Kommoss S, Leung SCY, Senz J, Lum A, Chow V, Sudderuddin H, Mackenzie R, George J, Fereday S, Hendley J, Traficante N, Steed H, Koziak JM, Köbel M, McNeish IA, Goranova T, Ennis D, Macintyre G, Silva De Silva D, Ramón Y Cajal T, García-Donas J, Hernando Polo S, Rodriguez GC, Cushing-Haugen KL, Harris HR, Greene CS, Zelaya RA, Behrens S, Fortner RT, Sinn P, Herpel E, Lester J, Lubiński J, Oszurek O, Tołoczko A, Cybulski C, Menkiszak J, Pearce CL, Pike MC, Tseng C, Alsop J, Rhenius V, Song H, Jimenez-Linan M, Piskorz AM, Gentry-Maharaj A, Karpinskyj C, Widschwendter M, Singh N, Kennedy CJ, Sharma R, Harnett PR, Gao B, Johnatty SE, Sayer R, Boros J, Winham SJ, Keeney GL, Kaufmann SH, Larson MC, Luk H, Hernandez BY, Thompson PJ, Wilkens LR, Carney ME, Trabert B, Lissowska J, Brinton L, Sherman ME, Bodelon C, Hinsley S, Lewsley LA, Glasspool R, Banerjee SN, Stronach EA, Haluska P, Ray-Coquard I, Mahner S, Winterhoff B, Slamon D, Levine DA, Kelemen LE, Benitez J, Chang-Claude J, Gronwald J, Wu AH, Menon U, Goodman MT, Schildkraut JM, Wentzensen N, Brown R, Berchuck A, Chenevix-Trench G, deFazio A, Gayther SA, García MJ, Henderson MJ, Rossing MA, Beeghly-Fadiel A, Fasching PA, Orsulic S, Karlan BY, Konecny GE, Huntsman DG, Bowtell DD, Brenton JD, Doherty JA, Pharoah PDP, and Ramus SJ

Subjects
Female, Humans, Prognosis, Proportional Hazards Models, Survival Analysis, Transcriptome, Cystadenocarcinoma, Serous genetics, Ovarian Neoplasms genetics
Abstract

Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC., Patients and Methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies., Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years., Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches., Competing Interests: Disclosure BYK served on Invitae Corporation's Advisory Board from 2017 to 2018. IAM has acted on the Advisory Boards for AstraZeneca, Clovis Oncology, Tesaro, Carrick Therapeutics and Takeda. His institution receives funding from AstraZeneca. RG is on the Advisory Boards for AstraZeneca, Tesaro, Clovis and Immunogen and does consultancy work for SOTIO. She has received support to attend conferences from AstraZeneca, Roche and Tesaro. Her institution has received research funding from Boehringer Ingelheim and Lilly/Ignyta and she is the national co-ordinating investigator for the UK for trials sponsored by AstraZeneca and Tesaro and site principal investigator for trials sponsored by AstraZeneca, Tesaro, Immunogen, Pfizer, Lilly and Clovis. PAF has received grants from Novartis, BioNtech and Cepheid as well as personal fees from Novartis, Roche, Pfizer, Celgene, Daiichi-Sankyo, TEVA, Astra Zeneca, Merck Sharp & Dohme, Myelo Therapeutics, MacroGenics, Eisai and Puma during the conduct of the study. JDB has acted on Advisory Boards for AstraZeneca and has received support from GSK to attend conferences. His institution receives funding from AstraZeneca and Aprea. UM has shares in Abcodia Ltd. Sandra Orsulic and Beth Y. Karlan have patents on predictive gene signatures in ovarian cancer (US010253368 and EU2908913). All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2020
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3. A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer.

Author

Samardzija C, Luwor RB, Volchek M, Quinn MA, Findlay JK, and Ahmed N

Subjects
Animals, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Biomarkers, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation, Cisplatin pharmacology, Cystadenocarcinoma, Serous genetics, Cystadenocarcinoma, Serous mortality, Cystadenocarcinoma, Serous pathology, Disease Models, Animal, Drug Resistance, Neoplasm genetics, Epithelial Cell Adhesion Molecule, Female, Gene Expression, Gene Knockdown Techniques, Heterografts, Humans, Hyaluronan Receptors genetics, Hyaluronan Receptors metabolism, Mice, Neoplasm Metastasis, Octamer Transcription Factor-3 metabolism, Ovarian Neoplasms mortality, Prognosis, RNA, Small Interfering genetics, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Recurrence, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Tumor Burden, Tumor Cells, Cultured, Octamer Transcription Factor-3 genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
Abstract

Background: High grade epithelial ovarian cancer (EOC) is commonly characterised by widespread peritoneal dissemination and ascites. Metastatic EOC tumour cells can attach directly to neighbouring organs or alternatively, maintain long term tumourigenicity and chemoresistance by forming cellular aggregates (spheroids). Cancer stem-like cells are proposed to facilitate this mechanism. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance., Methods: To investigate the expression of Oct4A in primary EOC tumours, IHC and qRT-PCR analyses were used. The expression of Oct4A in chemonaive and recurrent EOC patient ascites-derived tumour cells samples was investigated by qRT-PCR. The functional role of Oct4A in EOC was evaluated by generating stable knockdown Oct4A clones in the established EOC cell line HEY using shRNA-mediated silencing technology. Cellular proliferation, spheroid forming ability, migration and chemosensitivty following loss of Oct4A in HEY cells was measured by in vitro functional assays. These observations were further validated in an in vivo mouse model using intraperitoneal (IP) injection of established Oct4A KD clones into Balb/c nu/nu mice., Results: We demonstrate that, compared to normal ovaries Oct4A expression significantly increases with tumour dedifferentiation. Oct4A expression was also significantly high in the ascites-derived tumour cells of recurrent EOC patients compared to chemonaive patients. Silencing of Oct4A in HEY cells resulted in decreased cellular proliferation, migration, spheroid formation and increased chemosensitivity to cisplatin in vitro. IP injection of Oct4A knockdown cells in vivo produced significantly reduced tumour burden, tumour size and invasiveness in mice, which overall resulted in significantly increased mouse survival rates compared to mice injected with control cells., Conclusions: This data highlights a crucial role for Oct4A in the progression and metastasis of EOC. Targeting Oct4A may prove to be an effective strategy in the treatment and management of epithelial ovarian tumours.

Published
2015
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4. Prognostic gene expression signature for high-grade serous ovarian cancer

Author

Millstein, J, Budden, T, Goode, EL, Anglesio, MS, Talhouk, A, Intermaggio, MP, Leong, HS, Chen, S, Elatre, W, Gilks, B, Nazeran, T, Volchek, M, Bentley, RC, Wang, C, Chiu, DS, Kommoss, S, Leung, SCY, Senz, J, Lum, A, Chow, V, Sudderuddin, H, Mackenzie, R, George, J, AOCS Group, Fereday, S, Hendley, J, Traficante, N, Steed, H, Koziak, JM, Köbel, M, McNeish, IA, Goranova, T, Ennis, D, Macintyre, G, Silva De Silva, D, Ramón Y Cajal, T, García-Donas, J, Hernando Polo, S, Rodriguez, GC, Cushing-Haugen, KL, Harris, HR, Greene, CS, Zelaya, RA, Behrens, S, Fortner, RT, Sinn, P, Herpel, E, Lester, J, Lubiński, J, Oszurek, O, Tołoczko, A, Cybulski, C, Menkiszak, J, Pearce, CL, Pike, MC, Tseng, C, Alsop, J, Rhenius, V, Song, H, Jimenez-Linan, M, Piskorz, AM, Gentry-Maharaj, A, Karpinskyj, C, Widschwendter, M, Singh, N, Kennedy, CJ, Sharma, R, Harnett, PR, Gao, B, Johnatty, SE, Sayer, R, Boros, J, Winham, SJ, Keeney, GL, Kaufmann, SH, Larson, MC, Luk, H, Hernandez, BY, Thompson, PJ, Wilkens, LR, Carney, ME, Trabert, B, Lissowska, J, Brinton, L, Sherman, ME, Bodelon, C, Hinsley, S, Lewsley, LA, Glasspool, R, Banerjee, SN, Stronach, EA, Haluska, P, Ray-Coquard, I, Mahner, S, Winterhoff, B, Slamon, D, Levine, DA, Kelemen, LE, Benitez, J, and Chang-Claude, J

Subjects
Ovarian Neoplasms, screening and diagnosis, overall survival, Oncology and Carcinogenesis, Cystadenocarcinoma, Serous, AOCS Group, formalin-fixed paraffin-embedded, Prognosis, Survival Analysis, Ovarian Cancer, Detection, Rare Diseases, high-grade serous ovarian cancer, gene expression, Genetics, Humans, Female, Genetic Testing, 4.4 Population screening, Oncology & Carcinogenesis, Transcriptome, Proportional Hazards Models, Cancer, 4.2 Evaluation of markers and technologies
Abstract

BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Published
2020

5. Prognostic gene expression signature for high-grade serous ovarian cancer

Author

Millstein, J, Budden, T, Goode, EL, Anglesio, MS, Talhouk, A, Intermaggio, MP, Leong, HS, Chen, S, Elatre, W, Gilks, B, Nazeran, T, Volchek, M, Bentley, RC, Wang, C, Chiu, DS, Kommoss, S, Leung, SCY, Senz, J, Lum, A, Chow, V, Sudderuddin, H, Mackenzie, R, George, J, AOCS Group, Fereday, S, Hendley, J, Traficante, N, Steed, H, Koziak, JM, Köbel, M, McNeish, IA, Goranova, T, Ennis, D, Macintyre, G, Silva De Silva, D, Ramón Y Cajal, T, García-Donas, J, Hernando Polo, S, Rodriguez, GC, Cushing-Haugen, KL, Harris, HR, Greene, CS, Zelaya, RA, Behrens, S, Fortner, RT, Sinn, P, Herpel, E, Lester, J, Lubiński, J, Oszurek, O, Tołoczko, A, Cybulski, C, Menkiszak, J, Pearce, CL, Pike, MC, Tseng, C, Alsop, J, Rhenius, V, Song, H, Jimenez-Linan, M, Piskorz, AM, Gentry-Maharaj, A, Karpinskyj, C, Widschwendter, M, Singh, N, Kennedy, CJ, Sharma, R, Harnett, PR, Gao, B, Johnatty, SE, Sayer, R, Boros, J, Winham, SJ, Keeney, GL, Kaufmann, SH, Larson, MC, Luk, H, Hernandez, BY, Thompson, PJ, Wilkens, LR, Carney, ME, Trabert, B, Lissowska, J, Brinton, L, Sherman, ME, Bodelon, C, Hinsley, S, Lewsley, LA, Glasspool, R, Banerjee, SN, Stronach, EA, Haluska, P, Ray-Coquard, I, Mahner, S, Winterhoff, B, Slamon, D, Levine, DA, Kelemen, LE, Benitez, J, Chang-Claude, J, Gronwald, J, Wu, AH, Menon, U, Goodman, MT, Schildkraut, JM, Wentzensen, N, Brown, R, Berchuck, A, Chenevix-Trench, G, DeFazio, A, Gayther, SA, García, MJ, Henderson, MJ, Rossing, MA, Beeghly-Fadiel, A, Fasching, PA, Orsulic, S, Karlan, BY, Konecny, GE, Huntsman, DG, Bowtell, DD, Brenton, JD, Doherty, JA, Pharoah, PDP, and Ramus, SJ

Subjects
Ovarian Neoplasms, high-grade serous ovarian cancer, overall survival, gene expression, Humans, Female, prognosis, formalin-fixed paraffin-embedded, Transcriptome, Survival Analysis, 3. Good health, Cystadenocarcinoma, Serous, Proportional Hazards Models
Abstract

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

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