p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC

Das Expressionsmuster von CA-125 und Mesothelin in Primärtumor und Metastasen des high-grade serösen Ovarialkarzinoms : über den Einfluss dieser tumorassoziierten Antigene und tumor-infiltrierenden Lymphozyten auf die Prognose

Zielsetzung: Das Ovarialkarzinom ist der zweithäufigste gynäkologische Tumor mit der höchsten Letalitätsrate. Die epithelialen Karzinome machen fast 90% aller malignen Ovarialtumoren aus. Davon ist das high-grade seröse Ovarialkarzinom (HGSC), welches von dem low-grade serösen, dem endometrioiden, dem klarzelligen und muzinösen Karzinom unterschieden wird, der häufigste Histotyp. Das Fünfjahresüberleben bei HGSC, welches in dieser Arbeit untersucht wird, liegt derzeit bei 30-40%. Das HGSC ist mit der Expression Tumor-spezifischer Antigene, welche vom Immunsystem erkannt werden, intrinsisch immunogen. In aktuellen Studien unserer Arbeitsgruppe wurden in umfassenden proteomischen Analysen des HLA-Ligandoms CA-125 und Mesothelin als die am häufigsten überexprimierten HLA-Liganden identifiziert. In dieser Arbeit haben wir deshalb zum einen das Expressionsmuster von CA-125 und Mesothelin, sowie die CD3+ und CD8+ tumor infiltrierenden Lymphozyten (TILs) in Primärtumor und Metastasen, und zum anderen deren prognostische Bedeutung, untersucht. Material und Methoden: Es wurde ein retrospektives Patientinnenkollektiv von 1999-2008, bestehend aus 154 Patientinnen mit HGSC mit Follow-Up Daten von bis zu 10 Jahren erstellt. Von diesem Kollektiv haben wir Tissue-microarrays (TMAs) erstellt und immunhistochemische Färbungen von CA-125, Mesothelin, CD3+ und CD8+ Lymphozyten angefertigt, welche nach einem semiquantitativen Scoring-System, bzw. Anzahl der Lymphozyten pro HPF, ausgewertet wurden. Ergebnisse: In dieser Arbeit konnten wir zeigen, dass das Expressionsprofil von CA-125 und Mesothelin in HGSC, kombiniert mit der Tumor-infiltration von epithelialen CD3+ Lymphozyten (CD3E), einen wesentlichen Einfluss auf die Prognose der Patientinnen hat. In über 85% der Primärtumoren und Metastasen war das CA-125 hoch exprimiert, wohingegen die Mesothelinexpression in deutlich weniger Fällen, in 40,2%, hoch ausfiel. Außerdem haben wir, in unterschiedlichen Bereichen innerhalb des Primärtumors und der Netzmetastasen, eine homogene Expression von CA-125 und Mesothelin festgestellt. Wird die Expression dieser zwei Antigene in allen Tumorabsiedlungen verglichen, lässt sich eine teilweise Heterogenität in 27,9% bzw. 35,9% der Fälle zeigen. Diese Tumorantigene zeigten, für sich alleine, keine prognostische Relevanz. Eine hohe Infiltration von CD3E-Lymphozyten im Primärtumor, in 21,2% der Fälle, hingegen zeigte eine deutlich verbesserte Fünfjahresüberlebensrate von 58,1% im Gegensatz zu 27,9% bei Patientinnen mit niedriger Lymphozyteninfiltration (p=0,003). Diese prognostisch günstigere Gruppe mit hoher Lymphozyteninfiltration haben wir nach Antigenexpressionsstatus weiter aufgeteilt: Die Fünfjahresüberlebensrate verbesserte sich nochmals, wenn zusätzlich zu hohen TILs noch eine Überexpression von CA-125 (Fünfjahresüberlebensrate 66,8%) hinzukam. Im Vergleich dazu lag bei gleichzeitig niedriger CA-125-Expression das Fünfjahresüberleben bei 25,0% (nicht signifikant mit p=0,183). Bei niedriger Mesothelinexpression verbessert sich die Prognose der Gruppe mit hohen TILs nochmals, mit einer Fünfjahresüberlebensrate von 76,0% im Vergleich zu 0% bei hoher Mesothelinexpression (signifikant mit p=0,000). Schlussfolgerung: Aus unserer Arbeit geht hervor, dass Proben aus unterschiedlichen Bereichen im Netz und Ovar zuverlässig vergleichbar sind. Proben aus den Metastasen können jedoch nicht zuverlässig mit Proben aus dem Ovar verglichen werden, da wir eine Heterogenität der Antigenexpression in einem Teil der Fälle zeigen konnten (bei 27,9% für CA-125 bzw. 35,9% für Mesothelin). Diese Heterogenität ist von Bedeutung, wenn es darum geht mögliche Angriffspunkte einer Immuntherapie festzustellen. Um den Tumor einer Patientin ausreichend zu charakterisieren, sollten mehrere Lokalisationen untersucht werden. Aus unseren Ergebnissen schließen wir weiterhin, dass eine hohe Infiltration von CD3-positiven Lymphozyten mit einer signifikant besseren Prognose einhergeht. Durch die zusätzlich hohe Expression von CA-125 verbessert sich die Prognose nochmals (jedoch ohne statistische Signifikanz), vermutlich durch die damit verbundene Immunstimulation. Eine zusätzlich hohe Mesothelinexpression zeigte sich als negativer Prognoseparameter (statistisch signifikant), da es vermutlich durch erhöhte Zellmotilität und Chemoresistenz die Metastasierung und Krankheitsprogredienz begünstigt. Eine Heterogenität dieser Parameter in der Expression zwischen Primärtumoren und Metastasen könnte die Aussagekraft dieser Biomarker beeinflussen, zum Beispiel im Hinblick auf die Entwicklung und den Einsatz von personalisierten Multipeptidvakzinen. An diese Ergebnisse können weitere Arbeiten anknüpfen, um zur personalisierten Immuntherapie gegen das high-grade seröse Ovarialkarzinom einen Beitrag zu leisten

The immunopeptidomic landscape of ovarian carcinomas

Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to exhaustively characterize the immunopeptidomic landscape of epithelial ovarian cancers (EOCs). Additional comparative profiling with the immunopeptidome of a variety of benign sources has unveiled a multitude of ovarian cancer antigens (MUC16, MSLN, LGALS1, IDO1, KLK10) to be presented by HLA class I and class II molecules exclusively on ovarian cancer cells. Most strikingly, ligands derived from mucin 16 and mesothelin, a molecular axis of prognostic importance in EOC, are prominent in a majority of patients. Differential gene-expression analysis has allowed us to confirm the relevance of these targets for EOC and further provided important insights into the relationship between gene transcript levels and HLA ligand presentation

Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study.

Funder: Funder: Calgary Laboratory Services (research support fund) Grant reference number: RS19-612Funder: Funder: National Cancer Institute: National Institutes of Health Grant reference number: R01CA172404BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p 35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Funder: Cancer Council Victoria; Id: http://dx.doi.org/10.13039/501100000951Funder: Queensland Cancer FundFunder: Cancer Council New South Wales; Id: http://dx.doi.org/10.13039/501100001102Funder: Cancer Council South Australia; Id: http://dx.doi.org/10.13039/501100000950Funder: Cancer Foundation of Western AustraliaFunder: Cancer Council Tasmania; Id: http://dx.doi.org/10.13039/501100001169Funder: Peter MacCallum Foundation; Id: http://dx.doi.org/10.13039/501100022084Funder: Ovarian Cancer Australia; Id: http://dx.doi.org/10.13039/100011928Funder: ELAN Funds of the University of Erlangen‐NurembergFunder: Breast Cancer Now; Id: http://dx.doi.org/10.13039/100009794Funder: Institute of Cancer ResearchFunder: NHSFunder: Biomedical Research CentreFunder: Fondo Europeo de Desarrollo Regional; Id: http://dx.doi.org/10.13039/501100008530Funder: German Cancer Research Center; Id: http://dx.doi.org/10.13039/100008658Funder: Mayo Foundation; Id: http://dx.doi.org/10.13039/100007048Funder: Minnesota Ovarian Cancer Alliance; Id: http://dx.doi.org/10.13039/100003135Funder: Fred C. and Katherine B. Andersen Foundation; Id: http://dx.doi.org/10.13039/100017909Funder: Pomeranian Medical University; Id: http://dx.doi.org/10.13039/501100008781Funder: UK National Institute for Health ResearchFunder: University of Cambridge; Id: http://dx.doi.org/10.13039/501100000735Funder: Clinical Academic ReserveFunder: Oak Foundation; Id: http://dx.doi.org/10.13039/100001275Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272Funder: University College London Hospitals Biomedical Research CentreFunder: The BC Cancer FoundationFunder: VGH and UBC Hospital Foundation; Id: http://dx.doi.org/10.13039/100014823Funder: Cancer Institute NSW; Id: http://dx.doi.org/10.13039/501100001171Funder: Sydney West Translational Cancer Research Centre; Id: http://dx.doi.org/10.13039/100013121Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Funder: Biomedical Research CentreFunder: European Regional Development FundFunder: Mayo Foundation for Medical Education and ResearchFunder: Pomeranian Medical UniversityFunder: Pomorski Uniwersytet Medyczny W SzczecinieFunder: Cancer Council NSWFunder: Cancer Institute NSWFunder: Deutsches KrebsforschungszentrumFunder: The BC Cancer FoundationFunder: University College London Hospitals Biomedical Research CentreFunder: Breast Cancer NowFunder: Cancer Council TasmaniaFunder: Clinical Academic ReserveFunder: ELAN Funds of the University of Erlangen-NurembergFunder: Fondo Europeo de Desarrollo RegionalFunder: National Institute for Health Research (NIHR)Funder: National Institute for Health and Care ResearchFunder: Ovarian Cancer AustraliaFunder: Queensland Cancer FundFunder: Cancer Council New South WalesFunder: Fred C. and Katherine B. Andersen FoundationFunder: German Cancer Research CenterFunder: Institute of Cancer ResearchFunder: Mayo FoundationFunder: Minnesota Ovarian Cancer AllianceFunder: Peter MacCallum FoundationFunder: University of CambridgeFunder: Cancer Foundation of Western AustraliaFunder: VGH and UBC Hospital FoundationFunder: Cancer Council VictoriaFunder: NHSFunder: UK National Institute for Health ResearchFunder: Cancer Council South AustraliaFunder: Oak FoundationFunder: Sydney West Translational Cancer Research CentreOur objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC