Papers by Maria Debiec-Rychter
Proceedings of the National Academy of Sciences, 2012
14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including pr... more 14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE-FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE-FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE-FAM22 maintains a structurally and functionally intact 14-3-3ε (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE-FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE-FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions.
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Modern Pathology, 2006
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Clinical neuropathology
An unusual posterior fossa neoplasm in a 26-year-old woman with short history of the cerebellar s... more An unusual posterior fossa neoplasm in a 26-year-old woman with short history of the cerebellar symptoms is presented. CT and MR images showed the tumor within the cerebellopontine angle, suspected as meningioma. At surgery, the tumor was dura-attached and did not infiltrate the arachnoid. Histologically, the neoplasm was a small blue cell tumor with solid and microcystic pattern, consistent with primitive neuroectodermal tumor (PNET). Immunohistochemically the cells were strongly positive for NCAM and GFAP. Fluorescence in situ hybridization (FISH) was performed with the cosmids G9 and F7 (flanking EWSR1/22q12 region) DNA probes and dual-color spectrum-orange LSI HER-2/neu (17q11.2)/spectrum green CEP17 (17p11.1-q11.1) DNA probe. The presence of isochromosome 17q within neoplastic cells was found. The tumor was classified as a medulloblastoma. We demonstrate the utility of a multidisciplinary approach to nervous system tumor diagnosis. The clinical features together with histologic...
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Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society, 2004
Four cases of primitive neuroectodermal tumors (PNETs) with unusual localization (three intraspin... more Four cases of primitive neuroectodermal tumors (PNETs) with unusual localization (three intraspinal extramedullary and one pontocerebellar) are reviewed. Histologically, they were small round blue cell tumors with diverse patterns. Immunohistochemically, all tumors were positive for at least two neuronal markers, two cases were Mic-2 positive and one showed glial differentiation. The paraffin-embedded tumor specimens were examined by interphase FISH using dual-color probes specific for EWS, HER-2 and BCR loci. Molecular cytogenetic study revealed the presence of EWS rearrangement in two cases and the presence of i(17q) in one tumor. Three tumors exhibited 22 disomy and one was 22 polyploid. Extraparenchymal PNETs within craniospinal axis are heterogeneous from the clinical, histological, immunohistochemical and molecular point of view. These PNETs can be of a central or peripheral type. Multidisciplinary approach is of a basic importance in differential diagnosis of such cases.
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Molecular pharmacology, Jan 24, 2015
The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the infl... more The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the influx transporter SLC22A1 (OCT1). We recently hypothesized that alternative uptake and/or retention mechanisms exist that determine intracellular imatinib levels. Here we systematically investigate the nature of these mechanisms. Imatinib uptake in cells was quantitatively determined by LC-MS-MS. Fluorescent microscopy was used to establish subcellular localization of imatinib. Immunoblotting, cell cycle analyses and apoptosis assays were done to evaluate functional consequences of imatinib sequestration. Uptake experiments revealed high intracellular imatinib concentrations in HEK293, the leukemic cell lines K562, SD-1, and a gastrointestinal stromal tumor cell line GIST-T1. We demonstrated that imatinib IUR is time, dose, temperature and energy dependent and provide evidence that SLC22A1 and other potential imatinib transporters do not substantially contribute to the IUR of imatinib. Praz...
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Genes, chromosomes & cancer, Jan 22, 2015
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European Journal of Human Genetics, 2015
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Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences, 2003
Fluorescence in situ hybridisation (FISH) analysis using total chromosome 22 painting and locus s... more Fluorescence in situ hybridisation (FISH) analysis using total chromosome 22 painting and locus specific 22q11.2 (bcr locus) probes was performed on sections from archival paraffin-embedded tumours obtained from 28 patients diagnosed with either ependymoma, WHO grade 11 (18 cases) or anaplastic ependymoma, WHO grade 111 (10 cases). The Ki-67 labelling index (LI) analysis was carried out in parallel to estimate the tumours' proliferative potential. Loss of chromosome 22 was revealed in eleven (39%) ependymomas, seven (39%) WHO grade II and four (40%) anaplastic variants. Concurrent cytogenetic analysis was performed on 11 tumours to confirm the loss of chromosome 22 in four cases; clones with a loss of chromosome 22, which was identified by FISH, were not detected by standard cytogenetics in two samples. The loss of chromosome 22 was restricted either to the tumours' site or to sex or age of the patients studied. The Ki-67 LI ranged from 0.1 to 32.0% (mean 4.3%). Low-grade tu...
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European Journal of Cancer Supplements, 2009
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Oncotarget, Jan 10, 2015
Hepatic angiosarcoma is a rare and aggressive vascular neoplasm. Pathogenic driver mutations are ... more Hepatic angiosarcoma is a rare and aggressive vascular neoplasm. Pathogenic driver mutations are largely unknown. We present the case of a patient with recurrent hepatic angiosarcoma, who initially showed good response to sunitinib, followed by progression. Using comprehensive molecular techniques, we explored the potential mechanisms of resistance. By low-read-depth whole-genome sequencing, the comparison of copy number aberrations (CNAs) of the primary tumor to the skin metastatic lesion that developed after progression on sunitinib, revealed high-level amplification of the 4q11-q13.1 region (containing KIT, PDGFRA and VEGFR2 genes) that was sustained in both lesions. Whole exome sequencing on the germline, primary and metastatic tumor DNAs, resulted in 27 confirmed mutations, 19 of which (including TP53 mutation) presented in both primary and metastatic lesions. One mutation, ZNF331 frameshift deletion, was detected only in the primary tumor. In contrast, seven other mutations, i...
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European Clinics in Obstetrics and Gynaecology, 2005
The aims of the study were (1) to increase the limited knowledge on molecular markers contributin... more The aims of the study were (1) to increase the limited knowledge on molecular markers contributing to uterine leiomyosarcoma (LMS) tumorigenesis and (2) to test the ability to predict the clinical course of smooth muscle tumors of low malignancy (SMTLM). Retrospectively, 2,360 uterine smooth muscle tumors were classified according to the Stanford criteria. After central review, the clinical course of
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Clinical cancer research : an official journal of the American Association for Cancer Research, 2014
Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response... more Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST. Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months. On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size >10 cm, mitotic index >10 mitoses per 50 high power field, and the KIT exon 9 duplication [hazard rat...
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Human pathology, 2009
Low-grade fibromyxoid sarcoma is a soft tissue sarcoma with recurrent and low metastatic potentia... more Low-grade fibromyxoid sarcoma is a soft tissue sarcoma with recurrent and low metastatic potential, which has characteristic FUS-CREB3L2 or FUS-CREB3L1 fusions. Perineurioma is a peripheral nerve sheath neoplasm, which is usually benign. Low-grade fibromyxoid sarcoma and perineurioma can appear morphologically similar, particularly in small biopsy specimens, and distinction between the 2 entities is important for appropriate treatment. Low-grade fibromyxoid sarcoma is negative for most immunohistochemical markers, whereas perineuriomas stain variably for epithelial membrane antigen, CD34 and claudin-1, a tight-junction associated protein. We studied 15 cases of genetically proven low-grade fibromyxoid sarcoma that at least focally resembled perineurioma, with antibodies to claudin-1 and epithelial membrane antigen. Of these, 11 showed positivity for epithelial membrane antigen and all 15 were positive for claudin-1; in all cases, expression of claudin-1 was equal to or greater than ...
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British journal of cancer, Jan 26, 2008
The management of localised and advanced gastrointestinal stromal tumours (GISTs) in terms of his... more The management of localised and advanced gastrointestinal stromal tumours (GISTs) in terms of histological diagnosis, surgery, imaging, medical treatment and molecular biology has rapidly changed since introduction of imatinib mesylate for molecularly targeted therapy in 2000. In this minireview, we briefly summarise and discuss the current data relevant to the increasing role of molecular characterisation of GISTs in the diagnosis, risk assessment and effective targeted therapy.
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Histopathology, 2015
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European Journal of Cancer Supplements, 2004
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Mutation research, Jan 12, 1997
The genotoxicity of N-substituted aryl compounds is dependent on their conversion to reactive met... more The genotoxicity of N-substituted aryl compounds is dependent on their conversion to reactive metabolites, frequently through the production of reactive N-acetoxyarylamines. This activation is accomplished by acetyltransferases that are widely distributed. In the rat, the production of N-acetoxyarylamines has been most clearly related to the induction of tumors in the mammary gland, but this pathway also appears to be an important factor in the production of tumors in the liver, Zymbal gland and gastrointestinal tract. Expression of rat acetyltransferases responsible for acetylation of the nitrogen and the oxygen of arylamine derivatives (i.e., acetyltransferases 1 and 2) in bacterial cells has now permitted experiments which demonstrate that these enzymes exhibit good affinities for and N-acetylation of the endogenous arylalkylamines derived from tryptophan, i.e., tryptamine, 5-hydroxytryptamine (serotonin) and 5-methoxytryptamine, the immediate metabolic precursor of melatonin. Ev...
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Cancer research, 1996
Rat acetyltransferases (ATs) can acetylate the endogenous arylalkylamines tryptamine, 5-hydroxytr... more Rat acetyltransferases (ATs) can acetylate the endogenous arylalkylamines tryptamine, 5-hydroxytryptamine (serotonin), and 5-methoxytryptamine, the immediate precursor of melatonin. The same enzymes also acetylate and activate exogenous, carcinogenic arylamines, thereby being immediately responsible for the generation of DNA adducts. Localization of AT transcripts in the pineal gland and in specific cells of the intestine, cerebral cortex, pituitary, and lung identifies cells that may be important to the neurotransmitter and hormonal roles of the tryptamine derivatives. Transcript localization i liver, mammary gland, Zymbal gland, kidney, forestomach, and bladder, as well as intestine and lung, identifies cells that may be at increased carcinogenic risk because they can convert N-hydroxylated arylamines to genotoxic metabolites. Highly specific expression is also observed in the reproductive organs of both the male and female, including the testes, epididymis, uterus, ovary, and fal...
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British journal of cancer, 1993
Restriction fragment length polymorphism (RFLP) analysis, comparative marker chromosome analysis,... more Restriction fragment length polymorphism (RFLP) analysis, comparative marker chromosome analysis, and polymorphic enzyme analysis was carried out on a total of eight human urothelial cell lines and sublines selected according to our knowledge of their HLA-A,B phenotype. RFLP analysis and cytogenetic analysis showed that the cell lines Hu1703He, Hu1922, and T24 are genuine cell lines of different origin. The identity of Hu1703He could not be confirmed by its isozyme phenotype which was identical to the T24 phenotype. RFLP analysis and isozyme analysis revealed that three cell lines, Hu456, Hu549, and Hu961a, and two transformed sublines, HCV-29Tmv and Hu609Tmv, are sublines of T24. A common origin of Hu456, Hu549, Hu961a, HCV-29Tmv, and Hu609Tmv was confirmed by marker chromosome analysis. However, the T24 origin of these cytogenetically related cell lines was not supported by chromosome analysis of T24. RFLP analysis and HLA phenotyping of two tumorigenic and invasive sublines isola...
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Human Pathology, 2006
Inflammatory myofibroblastic tumor is a rare spindle cell lesion of indeterminate malignant poten... more Inflammatory myofibroblastic tumor is a rare spindle cell lesion of indeterminate malignant potential occurring in both pulmonary and extrapulmonary tissues. This report describes an unusual presentation of an unusual tumor at an unusual location: an intramural ileal case of inflammatory myofibroblastic tumor presenting with intussusception in a 29-year-old woman. We characterize this tumor through microscopic and ultrastructural analysis, extensive immunohistochemical analysis, ploidy analysis, and Epstein-Barr virus in situ hybridization, and we report the finding of an ALK/TPM3 fusion using fluorescence in situ hybridization.
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Papers by Maria Debiec-Rychter