Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer

Nieuwenhuysen, Els Van; Busschaert, Pieter; Laenen, Annouschka; Moerman, Philippe; Han, Sileny; Neven, Patrick; Lambrechts, Diether; Vergote, Ignace

doi:10.1016/j.neo.2019.03.014

Cited by 31 publications

(35 citation statements)

References 41 publications

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“…Our findings at diagnosis where M2 TAMs are increased at metastatic sites is in line with previous literature data showing that M2 increase the invasiveness of ovarian cancer [24] and that TAM behavior, number, and composition differ according to the tumor area (demonstrated in different solid tumors, but not yet in ovarian cancer [25]). Although often treated similarly, low-grade tumors respond differently to chemotherapy compared to high-grade tumors [26], differ genetically [27], and have a different immune biology. The group of Yang et al demonstrated, based on the retrospective analysis of micro-array datasets, that the gene signature of immune cells is nearly opposite in high-grade serous ovarian cancer compared to low-grade serous ovarian cancer [28].…”

Section: Discussionmentioning

confidence: 99%

Opposite Macrophage Polarization in Different Subsets of Ovarian Cancer: Observation from a Pilot Study

Vankerckhoven

Wouters

Mathivet

et al. 2020

Cells

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The role of the innate immune system in ovarian cancer is gaining importance. The relevance of tumor-associated macrophages (TAM) is insufficiently understood. In this pilot project, comprising the immunofluorescent staining of 30 biopsies taken from 24 patients with ovarian cancer, we evaluated the presence of total TAM (cluster of differentiation (CD) 68 expression), M1 (major histocompatibility complex (MHC) II expression), and M2 (anti-mannose receptor C type 1 (MRC1) expression), and the blood vessel diameter. We observed a high M1/M2 ratio in low-grade ovarian cancer compared to high-grade tumors, more total TAM and M2 in metastatic biopsies, and a further increase in total TAM and M2 at interval debulking, without beneficial effects of bevacizumab. The blood vessel diameter was indicative for M2 tumor infiltration (Spearman correlation coefficient of 0.65). These data mainly reveal an immune beneficial environment in low-grade ovarian cancer in contrast to high-grade serous ovarian cancer, where immune suppression is not altered by neoadjuvant therapy.

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Section: Discussionmentioning

confidence: 99%

Opposite Macrophage Polarization in Different Subsets of Ovarian Cancer: Observation from a Pilot Study

Vankerckhoven

Wouters

Mathivet

et al. 2020

Cells

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“…In addition, LGSOC has a more indolent course than HGSOC, resulting in a longer overall survival (OS). However, LGSOC is more resistant to chemotherapy and has less than 5% response rate to first-line chemotherapy compared to the 80% response rate of HGSOC [ 32 , 33 ].…”

Section: Low Grade Serous Carcinomamentioning

confidence: 99%

“…The most commonly mutated genes are KRAS and BRAF , with these mutations being mutually exclusive [ 25 , 34 , 35 ]. Singer et al., in 2003, reported the first analysis of KRAS and BRAF mutations in LGSOC [ 36 ], and since then, many studies have confirmed the presence of these mutations in LGSOC [ 33 , [37] , [38] , [39] ]. The frequency of mutations ranged from 0% to 32% (mean 7.8%) for BRAF and 15.4%–54.5% (mean 24.2%) for KRAS mutations.…”

Section: Low Grade Serous Carcinomamentioning

confidence: 99%

Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications

Romero

Leskelä

Mies

et al. 2020

European Journal of Cancer Supplements

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Ovarian epithelial cancer (OEC) is the most lethal gynecologic malignancy. Despite current chemotherapeutic and surgical options, this high lethality can be attributed to multiple factors, including late-stage presentation. In order to optimize OEC treatment, it is important to highlight that it is composed of five main subtypes: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian carcinoma (EOC), ovarian clear cell carcinoma (CCOC), and mucinous ovarian carcinoma (MOC). These subtypes differ in their precursor lesions, as well as in epidemiological, morphological, molecular and clinical features. OEC is one of the tumours in which most pathogenic germline mutations have been identified. Accordingly, up to 20% OC show alterations in BRCA1/2 genes, and also, although with a lower frequency, in other low penetrance genes associated with homologous recombination deficiency (HRD), mismatch repair genes (Lynch syndrome) and TP53 . The most important prognostic factor is the 2014 FIGO staging, while older age is also associated with worse survival. HGSOC in all stages and CCC and MOC in advanced stages have the worse prognosis among histological types. Molecular markers have emerged as prognostic factors, particularly mutations in BRCA1/2, which are associated with a better outcome. Regarding treatment, whereas a proportion of HGSOC is sensible to platinum-based treatment and PARP inhibitors due to HRD, the rest of the histological types are relatively chemoresistant. New treatments based in specific molecular alterations are being tested in different histological types. In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or POLE mutations.

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“…Notably, TP53 R234H mutations were observed in two MEKi-resistant cell lines (CL-07 and CL-08) both with VAF above 96% indicating their clonal origin (Fig 1A, Supplementary Figure 1). While mutations in TP53 are rare in LGSOC tumors (8% frequency) [9,43], these cell lines (which were derived from two sequential tumor samples corresponding to the same patient) had been confirmed to be LGSOC by pathology review [44]. Furthermore, 3% of tumors in the GENIE cohort had TP53 mutations.…”

Section: -4)mentioning

confidence: 99%

“…However, in the last 5-10 years investigators have elucidated many key genomic aberrations, leading to major advancements in the molecular characterization and classification of LGSOC [3,4]. In contrast to other ovarian cancer subtypes, LGSOC are genetically characterized by high frequency of oncogenic mutations in KRAS, NRAS, and BRAF (20-40%, 7-26%, 5-33%, respectively) [5-7], a very low prevalence of TP53 mutations (<8%) [8,9], frequent copy-number deletion of CDKN2A resulting in loss of tumor suppressor protein p16 (15-53%) [10,11], and high expression of estrogen receptor (ER) and progesterone receptor (PR) (>90% and >50%, respectively) [12][13][14]. More recently, less frequent mutations in USP9X (15%) and EIF1AX (8%) have been described in a small proportion of LGSOC tumors [10,15].Traditionally, the therapeutic management of different ovarian cancer histotypes has been similar as it is now appreciated that different ovarian histological subtypes represent different diseases [16].Consequently, the most common treatment for LGSOC is based on cytoreductive surgery followed by platinum/paclitaxel chemotherapy.…”

mentioning

confidence: 99%

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

Shrestha

Fernández

Dawson

et al. 2020

Preprint

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Background: Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates. As such, there is a pressing need to develop more effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use a multiomics approach to interrogate a collection of LGSOC patient-derived cell lines to elucidate novel biomarkers and therapeutic vulnerabilities.Methods: Fourteen LGSOC cell lines were interrogated using whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics. Somatic mutation, copy-number aberrations, gene and protein expression were analyzed and integrated using different computational approaches.LGSOC cell line data was compared to publicly available LGSOC tumor data (AACR GENIE cohort), and also used for predictive biomarker identification of MEK inhibitor (MEKi) efficacy. Protein interaction databases were evaluated to identify novel therapeutic targets. Results: KRAS mutations were exclusively found in MEKi-sensitive and NRAS mutations mostly in MEKiresistant cell lines. Analysis of COSMIC mutational signatures revealed distinct patterns of nucleotide substitution mutations in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes (chromosome 9p21) were much more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. For in-vitro MEKi efficacy prediction, proteomic data provided better discrimination than gene expression data. Condensin, MCM, and RFC protein complexes were identified as potential treatment targets in MEKi-resistant cell lines.Conclusions: Our LGSOC cell lines are representative models of the most common molecular aberrations found in LGSOC tumors. This study highlights the importance of using proteomic data in multiomics assessment of drug prediction and identification of potential therapeutic targets. CDKN2A/B and MTAP deficiency offer an opportunity to find synthetically lethal candidates for novel treatments.Multiomics approaches are crucial to improving our understanding of the molecular aberrations inLGSOC, establishing effective drug prediction programs and identifying novel therapeutic targets inLGSOC. BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer with a poor prognosis. Women with LGSOC are usually diagnosed with advanced-stage disease and only 10-20% are alive 10 years after diagnosis [1,2]. Research on LGSOC is challenging due to its low prevalence, uncertain etiology, and the limited availability of research models. However, in the last 5-10 years investigators have elucidated many key genomic aberrations, leading to major advancements in the molecular characterization and classification of LGSOC [3,4]. In contrast to other ovarian cancer subtypes, LGSOC are genetically characterized by high frequency of oncogenic mutations in KRAS, NRAS, and BRAF (20-40%, 7-26%, 5-33%, respectively) [5-7], a very low prevalence of TP53 mutatio...

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Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer

Cited by 31 publications

References 41 publications

Opposite Macrophage Polarization in Different Subsets of Ovarian Cancer: Observation from a Pilot Study

Opposite Macrophage Polarization in Different Subsets of Ovarian Cancer: Observation from a Pilot Study

Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

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