Can TP53 variant negative be high-grade serous ovarian carcinoma? A case series.
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ABSTRACT:
SUBMITTER: Kasherman L
PROVIDER: S-EPMC7910505 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Can <i>TP53</i> variant negative be high-grade serous ovarian carcinoma? A case series.
Kasherman Lawrence L Garg Swati S Tchrakian Nairi N Clarke Blaise B Karakasis Katherine K Kim Raymond H RH Stockley Tracy L TL Dhani Neesha N Oza Amit M AM Lheureux Stephanie S
Gynecologic oncology reports 20210212
•<i>TP53</i> variant negative high-grade serous ovarian cancer is rare and can still show p53 abnormal immunohistochemistry.•Diagnostic and therapeutic considerations include pathologic, molecular and clinical domains.•Genetic reassessment through more comprehensive assays should be considered to ensure no missed rare or complex variants.•Presence of <i>BRCA</i> mutations can occur in <i>TP53</i> variant high-grade serous ovarian cancer. ...[more]
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Project description:BackgroundHigh grade serous ovarian cancer is characterised by high initial response to chemotherapy but poor outcome in the long term due to acquired resistance. One of the main genetic features of this disease is TP53 mutation. The majority of TP53 mutated tumors harbor missense mutations in this gene, correlated with p53 accumulation. TP53 null tumors constitute a specific subgroup characterised by nonsense, frameshift or splice-site mutations associated to complete absence of p53 expression. Different studies show that this kind of tumors may have a worse prognosis than other TP53 mutated HGSC.MethodsIn this study, we sought to characterise the intra-tumor heterogeneity of a TP53 null HGSC consisting of six primary tumor samples, two intra-pelvic and four extra-pelvic recurrences using exome sequencing and comparative genome hybridisation.ResultsSignificant heterogeneity was found among the different tumor samples, both at the mutational and copy number levels. Exome sequencing identified 102 variants, of which only 42 were common to all three samples; whereas 7 of the 18 copy number changes found by CGH analysis were presented in all samples. Sanger validation of 20 variants found by exome sequencing in additional regions of the primary tumor and the recurrence allowed us to establish a sequence of the tumor clonal evolution, identifying those populations that most likely gave rise to recurrences and genes potentially involved in this process, like GPNMB and TFDP1. Using functional annotation and network analysis, we identified those biological functions most significantly altered in this tumor. Remarkably, unexpected functions such as microtubule-based movement and lipid metabolism emerged as important for tumor development and progression, suggesting its potential interest as therapeutic targets.ConclusionsAltogether, our results shed light on the clonal evolution of the distinct tumor regions identifying the most aggressive subpopulations and at least some of the genes that may be implicated in its progression and recurrence, and highlights the importance of considering intra-tumor heterogeneity when carrying out genetic and genomic studies, especially when these are aimed to diagnostic procedures or to uncover possible therapeutic strategies.
| S-EPMC4666042 | biostudies-literature
Project description:While TP53 mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rare TP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25 TP53-wildtype tubo-ovarian HGSCs, constituting 2.5% of 987 HGSCs profiled by the MSK-IMPACT sequencing platform. Consistent with serous differentiation, positive staining for Pax8 and WT1 was present in virtually all TP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations of CCNE1 and BRCA1/2 were identified in these tumors, furthering supporting their classification as bona fide HGSC, despite lacking TP53 mutations. Overall, the level of chromosomal instability of TP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) and TP53-mutated HGSC. Morphologic assessment by observers blinded to mutation status revealed a significant subset of tumors with Grade 2 nuclear atypia (which exceeds the degree of atypia allowed for LGSC, but less than typically encountered for HGSC) combined with micropapillary features (6/19, 32%, chemotherapy-naive TP53-wildtype HGSCs compared to 0/21, 0%, TP53-mutated HGSCs; p = 0.007). Some TP53-wildtype HGSCs harbored driver mutations in KRAS (n = 3), BRAF (n = 1) or NRAS (n = 2). Overall, 10 (40%) cases had "LGSC-like" morphology (i.e., Grade 2 nuclear atypia and micropapillary features) and/or RAS/RAF mutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remaining TP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventional TP53-mutated HGSC. Despite lacking genetic alterations of TP53, these "usual HGSC-like" tumors often showed evidence of p53 dysfunction, including downregulation of expression ('null' or equivocal p53 staining in 9/14, 64%) or MDM2 amplification (n = 2). Our results support the existence of TP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms.
| S-EPMC8409220 | biostudies-literature
Project description:The current World Health Organization classification does not distinguish transitional cell carcinoma of the ovary (TCC) from conventional tubo-ovarian high-grade serous carcinoma (HGSC), despite evidence suggesting improved prognosis for patients with TCC; instead, it is considered a morphologic variant of HGSC. The immunohistochemical (IHC) markers applied to date do not distinguish between TCC and HGSC. Therefore, we sought to compare the proteomic profiles of TCC and conventional HGSC to identify proteins enriched in TCC. Prognostic biomarkers in HGSC have proven to be elusive, and our aim was to identify biomarkers of TCC as a way of reliably and reproducibly identifying patients with a favorable prognosis and better response to chemotherapy compared with those with conventional HGSC. Quantitative global proteome analysis was performed on archival material of 12 cases of TCC and 16 cases of HGSC using SP3 (single-pot, solid phase-enhanced, sample preparation)-Clinical Tissue Proteomics, a recently described protocol for full-proteome analysis from formalin-fixed paraffin-embedded tissues. We identified 430 proteins that were significantly enriched in TCC over HGSC. Unsupervised co-clustering perfectly distinguished TCC from HGSC based on protein expression. Pathway analysis showed that proteins associated with cell death, necrosis, and apoptosis were highly expressed in TCCs, whereas proteins associated with DNA homologous recombination, cell mitosis, proliferation and survival, and cell cycle progression pathways had reduced expression. From the proteomic analysis, three potential biomarkers for TCC were identified, claudin-4 (CLDN4), ubiquitin carboxyl-terminal esterase L1 (UCHL1), and minichromosome maintenance protein 7 (MCM7), and tested by IHC analysis on tissue microarrays. In agreement with the proteomic analysis, IHC expression of those proteins was stronger in TCC than in HGSC (p < 0.0001). Using global proteomic analysis, we are able to distinguish TCC from conventional HGSC. Follow-up studies will be necessary to confirm that these molecular and morphologic differences are clinically significant.
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Project description:BackgroundMutation of TP53 is the most frequent genetic alteration in high-grade serous ovarian cancer (HGSOC). The impact of hotspot mutations of TP53 and protein levels on patient outcomes in HGSOC has not been fully elucidated.MethodsThe study population (n = 791) comprised of HGSOC samples with TP53 mutation from TCGA and other publicly available data. Univariate and multivariate cox proportional hazards regression analyses were used to select variables that were correlated with patient survival.ResultsWe assessed the effects of TP53 mutations based on type and individual hotspot mutations on patient outcomes in HGSOC. Only hotspot mutations were associated with outcomes. Three hotspot mutations: G266, Y163C, and R282, in aggregate were associated with a worsened overall and recurrence-free survival compared with other hotspot mutations (p < 0.0001 and p = 0.001), other non-hotspot missense mutations (p < 0.0001 and p = 0.008), truncated mutations (p < 0.0001 and p = 0.001), and all other mutations (p < 0.0001 and p = 0.001). Specific hotspot mutations were associated with different protein expression patterns consistent with different functions.ConclusionsThis study provides evidence that individual TP53 hotspot mutations have different impact on HGSOC patient outcomes and potentially TP53 function. Thus the status of particular TP53 aberrations could influence response to therapy and selection of therapeutic agents.
| S-EPMC7000721 | biostudies-literature
Project description:Bulk and single-cell RNA sequencing do not provide full characterization of tissue spatial diversity in cancer samples, and currently available in situ techniques (multiplex immunohistochemistry and imaging mass cytometry) allow for only limited analysis of a small number of targets. The current study represents the first comprehensive approach to spatial transcriptomics of high-grade serous ovarian carcinoma using intact tumor tissue. We selected a small cohort of patients with highly annotated high-grade serous ovarian carcinoma, categorized them by response to neoadjuvant chemotherapy (poor or excellent), and analyzed pre-treatment tumor tissue specimens. Our study uncovered extensive differences in tumor composition between the poor responders and excellent responders to chemotherapy, related to cell cluster organization and localization. This in-depth characterization of high-grade serous ovarian carcinoma tumor tissue from poor and excellent responders showed that spatial interactions between cell clusters may influence chemo-responsiveness more than cluster composition alone.
| S-EPMC8891954 | biostudies-literature
Project description:Objective: Mutations in TP53 lead to loss of function (LOF) or gain of function (GOF) of the corresponding protein p53 and produce a different effect on the tumor. Our goal was to determine the spectrum of somatic TP53 variants in BRCA1/2 associated high-grade serous ovarian cancer (HGSOC). Methods: The population under study comprised of HGSOCs with pathogenic variants in BRCA1 (n = 78) or BRCA2 (n = 21). Only chemo-naive and platinum-sensitive patients were included in this study. The case group of the IARC database (n = 1249) with HGSOC not stratified by BRCA status was used as a reference. A custom NGS panel was used for sequencing TP53 and mutational hot-spots of other genes, and p53 expression was evaluated by immunohistochemistry for 68 cases of HGSOCs. Results: Somatic TP53 variants (95) or inhibition of wild-type p53 expression (3) were observed in 98 cases. The sample with normal p53 had CDKNA1 variants. The frequency of truncating variants was significantly higher than in the reference cohort (30.3 vs. 21.0%, p = 0.01). Most of the samples (41/68) demonstrated low (or absent) expression of p53, and 17 samples overexpressed p53. LOH was typical for TP53 nonsense variants (14/15). In total, 68/95 samples were LOH positive and showed LOH in all tumorous cells, thus indicating the driver effect of TP53 mutations. Three specimens had KRAS, BAX, APC, and CTNNB1 subclones variants. Conclusion: High frequency of TP53 truncating variants, the low expression of mutant p53, and low incidence of oncogene mutations show potential GOF properties of p53 to be poorly represented in BRCA1/2 associated HGSOC.
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Project description:In the early 2000s a two-tier grading system was introduced for serous ovarian cancer. Since then, we have increasingly come to accept that low-grade serous ovarian carcinoma (LGSOC) is a separate entity with a unique mutational landscape and clinical behaviour. As less than 10% of serous carcinomas of the ovary are low-grade, they are present in only a small number of patients in clinical trials for ovarian cancer. Therefore the current treatment of LGSOC is based on smaller trials, retrospective series, and subgroup analysis of large clinical trials on ovarian cancer. Surgery plays a major role in the treatment of patients with LGSOC. In the systemic treatment of LGSOC, hormonal treatment and targeted therapies seem to play an important role.
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Project description:Purpose: The majority of ovarian carcinomas are of high-grade serous histology, which is associated with poor prognosis. Surgery and chemotherapy are the mainstay of treatment, and molecular characterization is necessary to lead the way to targeted therapeutic options. To this end, various computational methods for gene expression-based subtyping of high-grade serous ovarian carcinoma (HGSOC) have been proposed, but their overlap and robustness remain unknown.Experimental Design: We assess three major subtype classifiers by meta-analysis of publicly available expression data, and assess statistical criteria of subtype robustness and classifier concordance. We develop a consensus classifier that represents the subtype classifications of tumors based on the consensus of multiple methods, and outputs a confidence score. Using our compendium of expression data, we examine the possibility that a subset of tumors is unclassifiable based on currently proposed subtypes.Results: HGSOC subtyping classifiers exhibit moderate pairwise concordance across our data compendium (58.9%-70.9%; P < 10-5) and are associated with overall survival in a meta-analysis across datasets (P < 10-5). Current subtypes do not meet statistical criteria for robustness to reclustering across multiple datasets (prediction strength < 0.6). A new subtype classifier is trained on concordantly classified samples to yield a consensus classification of patient tumors that correlates with patient age, survival, tumor purity, and lymphocyte infiltration.Conclusions: A new consensus ovarian subtype classifier represents the consensus of methods and demonstrates the importance of classification approaches for cancer that do not require all tumors to be assigned to a distinct subtype. Clin Cancer Res; 24(20); 5037-47. ©2018 AACR.
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Project description:Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a prognostic model of HGS-OvCa classification, named "Classification of Ovarian Cancer" (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens.
| S-EPMC3533304 | biostudies-literature
Project description:The secretomes of tumor cells, and macrophages from high grade serous ovarian carcinoma from the ascites of patients undergoing primary surgery were analysed after 24h culture (ex vivo) via obitrap.
2017-11-17 | PXD008047 | Pride