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

Text Analytics and Mixed Feature Extraction in Ovarian Cancer Clinical and Genetic Data

Developments of richer integrative analysis methods for oncological studies are needed for efficiently leveraging the amount of clinical and genetic data available to provide the clinicians with better information. However, analyses of this nature often require mixing data of different types, which are not immediate to address jointly with classical methods. In this work, our aim is to find relationships between clinical and genetic features of different types (metric, categorical, and text) and the ovarian cancer (OC) disease progression. To this end, we first propose a univariate statistical method for text type applying bootstrap resampling to Bag of Words and Latent Dirichlet Allocation in order to include as features the free-text fields of the health recordings. Secondly, we extend bootstrap resampling for metric and categorical feature extraction with Principal Component Analysis (PCA) and Multiple Correspondence Analysis (MCA), respectively. We subsequently formulate a novel and integrative method for jointly considering metric, categorical, and text features. Results obtained in text analysis indicate individual differences in some words between two OC patients groups categorised according to their sensitivity to platinum drugs. These results indicate separability between both groups for text features. Also, regarding the multivariate analysis, clinical data results showed separability patterns for the three methods analysed according to the platinum-sensitivity degree. The use of these analytical tools in our OC cohort has allowed us to demonstrate their strengths by confirming the predictive and prognostic role of widely-known clinical and genetic variables (BRCA status, value of adjuvant therapy and optimal resection, or family history) and demonstrating significant associations in other variables whose role in OC development has been studied to a lesser extent (such as PMS1, GPC3, and SLX4 genes). These results highlight the value of implementing these approaches for the identification of novel biomarkers in the context of OC

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC

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: 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

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

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 [HGSC], endometrioid [EC] and clear cell carcinomas [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6678 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, cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93% (4630/4957) 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 (HR=2.18, 95% CI 1.36-3.47, p=0.0011) as well as with CCC (HR=1.57, 95% CI 1.11-2.22, p=0.012). Abnormal p53 was also associated with shorter overall survival in FIGO 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.CRU