Françoise Descotes

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Epithelial-myoepithelial carcinoma (EMC) is a rare malignant tumor of the salivary glands, often characterized by HRAS mutations. The present study aimed to better define the molecular and transcriptomic landscape of EMC and explore its relationship with other head and neck neoplasms, particularly basal cell adenoma (BCA). We retrospectively analyzed 14 EMC cases using histology, immunohistochemistry, and whole-exome capture RNA sequencing. HRAS mutations were identified in 57.0% (8/14) of EMC, predominantly at p.Gly61Arg. Additional mutations identified included PIK3CA , STAT5B , and NOTCH1 , as well as gene fusions such as HMGA2 :: WIF1 and FBXO32 :: PLAG1 . A comparative analysis with 54 RAS -mutated head and neck tumors revealed that HRAS mutations were not exclusive to EMC, as they were also found in benign entities such as BCAs. Transcriptomic profiling found that EMC and BCA shared significant gene expression similarities, clustering closely. Differential expression analysis found upregulation of GATA3 , CHI3L1 , GRIA2 , and MME in EMC, while BCAs had enrichment of Wnt-beta-catenin signaling. In contrast, EMCs had activation of the Ras-Raf-MAPK and PI3K-Akt pathways, supported by upregulation of E2F and G2-M checkpoint targets. Immunohistochemistry confirmed GATA3 positivity in HRAS -mutated EMCs. The frequent RAS mutations and overlapping transcriptomic profiles raise important diagnostic considerations and highlight the need for integrated molecular analyses to differentiate these entities. The EMCs displayed a recurrent HRAS mutation, also observed in other head and neck tumors, and were partially clustered with the cases of BCA, suggesting potential biological similarities.

Since the histogenesis of heterologous elements within Sertoli-Leydig cell tumors (SLCTs) is poorly understood, we aimed to study the molecular relationship between Sertoli cells and the heterologous elements in 16 ovarian SLCTs. We performed a comprehensive molecular study on both SLCT and heterologous components, separately. Eleven tumors (68.7%) had one heterologous element and 5/16 (31.3%) had 2. Heterologous elements were epithelial (7/21 [81%]) (benign mucinous epithelium [9/21, 42.9%], borderline mucinous tumor [1/21, 4.8%], infiltrative mucinous adenocarcinoma [3/21, 14.3%], carcinoid tumor [3/21, 14.3%], and hepatocytes [1/21,4.8%]) or mesenchymal (4/21, 19%) (rhabdomyosarcoma [3/21,14.3%] and chondrosarcoma [1/21, 4.8%]). A DICER1 pathogenic variant was shared between SLCT and the heterologous elements in all cases with interpretable results (15/15), and other common likely-pathogenic/pathogenic variants were shared between SLCTs and heterologous components (3/16, 18.75%), favoring a clonal relationship. In contrast, the identification of distinct variants between components favored a different evolution. The molecular profile of heterologous elements differed from that of their ovarian counterparts occurring without SLCT (eg, mucinous heterologous elements were KRAS wild-type). Chromosome 8 gains, TERT and NRAS/KRAS variants, and absence of fusion transcript, were the hallmark of rhabdomyosarcoma components (3/3, 100%). The progression-free survival rate was significantly shorter for patients with TERT pathogenic variant ( P =0.0029). One patient had pleomorphic Sertoli cells associated with TP53 variants and very poor prognosis with early recurrence after complete initial surgery of a stage IA tumor. These data highlight the biological relationship between SLCTs and their heterologous elements, and the clinical usefulness of identifying pathogenic variants (ie, TERT and TP53 ), although this last point needs to be confirmed in a larger series.

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Non-Negative Matrix factorization has become an essential tool for feature extraction in a wide spectrum of applications. In the present work, our objective is to extend the applicability of the method to the case of missing and/or corrupted data due to outliers. An essential property for missing data imputation and detection of outliers is that the uncorrupted data matrix is low rank, i.e. has only a small number of degrees of freedom. We devise a new version of the Bregman proximal idea which preserves nonnegativity and mix it with the Augmented Lagrangian approach for simultaneous reconstruction of the features of interest and detection of the outliers using a sparsity promoting ℓ 1 penality. An application to the analysis of gene expression data of patients with bladder cancer is finally proposed.

Introduction: The gene quiescin/sulfhydryl oxidase 1, QSOX1, encodes an enzyme directed to the secretory pathway and excreted into the extracellular space. QSOX1 participates in the folding and stability of proteins and thus could regulate the biological activity of its substrates in the secretory pathway and/or outside the cell. The involvement of QSOX1 in oncogenesis has been studied primarily in terms of its differential expression in systemic studies. QSOX1 is overexpressed in prostate cancers and in pancreatic adenocarcinoma. In contrast, QSOX1 gene expression is repressed in endothelial tumors. In the present study, we investigated the role of QSOX1 in breast cancer. Methods: We analyzed QSOX1 mRNA expression in a cohort of 217 invasive ductal carcinomas of the breast. Moreover, we investigated QSOX1's potential role in regulating tumor growth and metastasis using cellular models in which we overexpressed or extinguished QSOX1 and xenograft experiments. Results: We showed that the QSOX1 expression level is inversely correlated to the aggressiveness of breast tumors. Our results show that QSOX1 leads to a decrease in cell proliferation, clonogenic capacities and promotes adhesion to the extracellular matrix. QSOX1 also reduces the invasive potential of cells by reducing cell migration and decreases the activity of the matrix metalloproteinase, MMP-2, involved in these mechanisms. Moreover, in vivo experiments show that QSOX1 drastically reduces the tumor development. Conclusions: Together, these results suggest that QSOX1 could be posited as a new biomarker of good prognosis in breast cancer and demonstrate that QSOX1 inhibits human breast cancer tumorogenesis.

We used a 2D-electrophoresis (2-DE) proteomic approach to identify novel biomarkers in node-negative breast cancers. This retrospective study focused on a population of patients with ductal pN0M0 tumours. A subset of patients who developed metastases and in whose tumours were found high levels of uPA and PAI-1 (metastatic relapse, MR: n=20) were compared to another subset in whom no metastatic relapse occurred and whose tumours were found to have low levels of uPA and PAI-1 (no relapse, NR: n=21). We used a 2-DE coupled with MS approach to screen cytosol fractions using two pH-gradient scales, a broad scale (3.0-11.0) and a narrower scale focussing in on a protein rich region (5.0-8.0). This study was conducted on 41 cytosol specimens analyzed in duplicate on two platforms. The differential analysis of more than 2,000 spots in 2-DE gels, obtained on the two platforms, allowed the identification of 13 proteins which were confirmed by western blotting. Two proteins, GPDA and FABP4 were down-regulated in the MR subset whereas all the others were up-regulated. An in silico analysis revealed that GMPS (GUAA), GAPDH (G3P), CFL1 (COF1) and FTL (FRIL), the most informative genes, displayed a proliferation profile (high expression in basal-like, HER2+ and luminal B molecular subtypes). Inversely, similar to FABP4, GPD1 [GPDA] displayed a high expression in luminal A subtype, a profile characteristic of tumour suppressor genes. Despite the small size of our cohort, the 2-DE analysis gave interesting results which were confirmed by the in silico analysis showing that some of the corresponding genes had a strong prognostic impact in breast cancer, mostly because of their link with proliferation: GMPS, GAPDH, FTL and GPD1. A validation phase on a larger cohort is now needed before these biomarkers could be considered for use in clinical practice.

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