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PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
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Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
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BACKGROUND: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. METHODS: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves. RESULTS: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. CONCLUSION: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estadiamento de Neoplasias , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Cistadenocarcinoma Seroso/cirurgia , Cistadenocarcinoma Seroso/tratamento farmacológico , Estimativa de Kaplan-MeierRESUMO
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.
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Carcinoma Endometrioide , Neoplasias Ovarianas , Humanos , Feminino , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário , Carcinoma Endometrioide/metabolismoRESUMO
BACKGROUND: 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 < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >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.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Prognóstico , Análise de Sobrevida , RNA Mensageiro/genética , Cistadenocarcinoma Seroso/patologia , Biomarcadores Tumorais/análise , Fatores de Transcrição Forkhead/genéticaRESUMO
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.
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Antígeno B7-H1 , Neoplasias Ovarianas , Humanos , Feminino , Antígeno B7-H1/genética , Carcinoma Epitelial do Ovário/patologia , Neoplasias Ovarianas/tratamento farmacológico , Linfócitos T CD8-Positivos , Fatores de Transcrição Forkhead/uso terapêutico , Linfócitos do Interstício Tumoral , Microambiente TumoralRESUMO
Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.
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Genômica , Neoplasias Ovarianas , Feminino , Humanos , Sobreviventes , Neoplasias Ovarianas/genéticaRESUMO
PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
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Adenocarcinoma Mucinoso , Neoplasias Gastrointestinais , Neoplasias Ovarianas , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Carcinoma Epitelial do Ovário/patologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/diagnóstico , Prognóstico , Neoplasias Gastrointestinais/metabolismoRESUMO
PURPOSE: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. EXPERIMENTAL DESIGN: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. RESULTS: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. CONCLUSIONS: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.
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Adenocarcinoma de Células Claras , Endometriose , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Mutação , Endometriose/genética , Endometriose/patologiaRESUMO
ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.
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Carcinoma , Endometriose , Neoplasias Ovarianas , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Encefálicas , Linfócitos T CD8-Positivos/patologia , Canadá , Neoplasias Colorretais , Proteínas de Ligação a DNA/genética , Endometriose/genética , Endometriose/patologia , Feminino , Humanos , Síndromes Neoplásicas Hereditárias , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Prognóstico , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. METHODS: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. RESULTS: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10-4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10-6). CONCLUSIONS: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. IMPACT: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.
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Adenocarcinoma de Células Claras/genética , Metilação de DNA , Neoplasias Ovarianas/genética , Adenocarcinoma de Células Claras/etnologia , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Classe I de Fosfatidilinositol 3-Quinases/genética , Ilhas de CpG/genética , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/patologia , Prognóstico , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
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Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Imuno-Histoquímica , Mutação , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Ovarianas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Austrália , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , América do Norte , Variações Dependentes do Observador , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Análise Serial de Tecidos , Reino UnidoRESUMO
Epithelial ovarian cancer (EOC) is a complex disease comprising discrete histological and molecular subtypes, for which survival rates remain unacceptably low. Tailored approaches for this deadly heterogeneous disease are urgently needed. Efflux pumps belonging to the ATP-binding cassette (ABC) family of transporters are known for roles in both drug resistance and cancer biology and are also highly targetable. Here we have investigated the association of ABCC4/MRP4 expression to clinical outcome and its biological function in endometrioid and serous tumors, common histological subtypes of EOC. We found high expression of ABCC4/MRP4, previously shown to be directly regulated by c-Myc/N-Myc, was associated with poor prognosis in endometrioid EOC (P = .001) as well as in a subset of serous EOC with a "high-MYCN" profile (C5/proliferative; P = .019). Transient siRNA-mediated suppression of MRP4 in EOC cells led to reduced growth, migration and invasion, with the effects being most pronounced in endometrioid and C5-like serous cells compared to non-C5 serous EOC cells. Sustained knockdown of MRP4 also sensitized endometrioid cells to MRP4 substrate drugs. Furthermore, suppression of MRP4 decreased the growth of patient-derived EOC cells in vivo. Together, our findings provide the first evidence that MRP4 plays an important role in the biology of Myc-associated ovarian tumors and highlight this transporter as a potential therapeutic target for EOC.
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Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Genes myc/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Prognóstico , RNA Interferente Pequeno/genética , Taxa de SobrevidaRESUMO
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
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Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/terapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Idoso , Estudos de Coortes , Reparo de Erro de Pareamento de DNA , Feminino , Recombinação Homóloga , Humanos , Imuno-Histoquímica , Mutação , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptor ErbB-2/genética , Receptor ErbB-3/genéticaRESUMO
BACKGROUND: ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. METHODS: In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). RESULTS: ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. CONCLUSION: FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.
Assuntos
Carcinoma Epitelial do Ovário/patologia , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/patologia , Neoplasias Ovarianas/patologia , Peptídeos/farmacologia , Proteínas de Ligação a Tacrolimo , Animais , Carcinoma Epitelial do Ovário/irrigação sanguínea , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Receptores de Hialuronatos/efeitos dos fármacos , Receptores de Hialuronatos/metabolismo , Técnicas In Vitro , Interleucina-6/metabolismo , Camundongos , Camundongos SCID , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteínas de Ligação a Tacrolimo/efeitos dos fármacos , Proteínas de Ligação a Tacrolimo/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.
Assuntos
Adenocarcinoma Mucinoso/genética , Carcinoma Epitelial do Ovário/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Ovarianas/genética , Adenocarcinoma Mucinoso/classificação , Adenocarcinoma Mucinoso/metabolismo , Carcinoma Epitelial do Ovário/classificação , Carcinoma Epitelial do Ovário/metabolismo , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/metabolismo , Análise de Sequência de DNA/métodos , Análise de SobrevidaRESUMO
OBJECTIVE: Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. METHODS: Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1â¯mg daily until progression or unacceptable toxicity. RESULTS: Thirty-six patients were enrolled. Clinical benefit at 3â¯months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%-78%) and was similar at 6â¯months (61%, 95% CI 43%-75%). The median duration of clinical benefit was 9.5â¯months (95% CI 8.3-25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1â¯months (95% CI 3.2-11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3â¯months reported less pain, fatigue, and improved physical and role functioning as early as 1â¯month of commencing treatment. CONCLUSIONS: Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6â¯months with acceptable toxicity.
Assuntos
Anastrozol/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Pós-Menopausa , Intervalo Livre de Progressão , Estudos Prospectivos , Qualidade de Vida , Receptores de Progesterona/metabolismo , Adulto JovemRESUMO
Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.
Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Biomarcadores Tumorais/análise , Queratina-7/análise , Proteínas de Ligação à Região de Interação com a Matriz/análise , Neoplasias Ovarianas/diagnóstico , Fatores de Transcrição/análise , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metástase Neoplásica/diagnóstico , Sensibilidade e EspecificidadeRESUMO
We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
Assuntos
Adenocarcinoma Mucinoso/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/patologia , Prognóstico , Taxa de SobrevidaRESUMO
Background: Chemoresistance is a major challenge in ovarian cancer treatment, resulting in poor survival rates. Identifying markers of treatment response is imperative for improving outcome while minimizing unnecessary side effects. We have previously demonstrated that expression of transducin-like enhancer of split 3 (TLE3) is associated with favorable progression-free survival in taxane-treated ovarian cancer patients with nonserous histology. The purpose of this study was to perform an independent evaluation of the association of TLE3 expression with response to taxane-based chemotherapy in nonserous ovarian cancer, to validate its role as a potential therapeutic response marker for taxane-based chemotherapy.Methods: We performed immunohistochemical staining of TLE3 on ovarian cancer specimens from the Australian Ovarian Cancer Study, the Westmead Gynaecological Oncology Biobank, and Memorial Sloan Kettering Cancer Center. Progression-free survival and overall survival were assessed to validate an association between TLE3 expression and response to taxane therapy that we previously observed in a smaller study.Results: Expression of TLE3 was associated with favorable outcome only in patients who had received paclitaxel as part of their treatment regimen for both 3-year progression-free survival (n = 160; HR, 0.56; P = 0.03) and 5-year overall survival (HR, 0.53; P = 0.04). Further analysis revealed that the predictive association between TLE3 expression and outcome was strongest in tumors with clear cell histology.Conclusions: The association between high TLE3 expression and a favorable response to taxane-containing chemotherapy regimens was validated in patients with nonserous ovarian cancer.Impact: TLE3 expression may serve as a marker of chemosensitivity in taxane-treated patients with nonserous histologies. Cancer Epidemiol Biomarkers Prev; 27(6); 680-8. ©2018 AACR.