38 results on '"Nina N Nupponen"'
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2. The Peptide–Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death
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Ken Flanagan, Romika Kumari, Juho J. Miettinen, Staci L. Haney, Michelle L. Varney, Jacob T. Williams, Muntasir M. Majumder, Minna Suvela, Ana Slipicevic, Fredrik Lehmann, Nina N. Nupponen, Sarah A. Holstein, and Caroline A. Heckman
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by clonal plasma cell secretion of misfolded light chains that assemble as toxic amyloid fibrils, depositing in vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell–directed therapeutics are expected to reduce production of toxic light chain by eliminating amyloidogenic cells in bone marrow, thereby diminishing amyloid fibril deposition and providing the potential for organ recovery. Melphalan flufenamide (melflufen) is a first-in-class peptide–drug conjugate that targets aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen is highly lipophilic, permitting rapid uptake by cells, where it is enzymatically hydrolyzed by aminopeptidases, resulting in intracellular accumulation of the alkylating agents, including melphalan. Previous data demonstrating sensitivity of myeloma cells to melflufen suggest that the drug might be useful in AL amyloidosis. We describe the effects of melflufen on amyloidogenic plasma cells in vitro and ex vivo, demonstrating enhanced cytotoxic effects in comparison to melphalan, as well as novel mechanisms of action through the unfolded protein response (UPR) pathway. These findings provide evidence that melflufen-mediated cytotoxicity extends to amyloidogenic plasma cells, and support the rationale for the evaluation of melflufen in patients with AL amyloidosis.
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- 2022
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3. Growth Response and Differentiation of Bone Marrow-Derived Mesenchymal Stem/Stromal Cells in the Presence of Novel Multiple Myeloma Drug Melflufen
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Arjen Gebraad, Roope Ohlsbom, Juho J. Miettinen, Promise Emeh, Toni-Karri Pakarinen, Mikko Manninen, Antti Eskelinen, Kirsi Kuismanen, Ana Slipicevic, Fredrik Lehmann, Nina N. Nupponen, Caroline A. Heckman, and Susanna Miettinen
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melflufen ,melphalan flufenamide ,peptide–drug conjugate ,mesenchymal stem/stromal cells ,multiple myeloma ,bone marrow ,Cytology ,QH573-671 - Abstract
Mesenchymal stem/stromal cells (MSCs) are self-renewing and multipotent progenitors, which constitute the main cellular compartment of the bone marrow stroma. Because MSCs have an important role in the pathogenesis of multiple myeloma, it is essential to know if novel drugs target MSCs. Melflufen is a novel anticancer peptide–drug conjugate compound for patients with relapsed refractory multiple myeloma. Here, we studied the cytotoxicity of melflufen, melphalan and doxorubicin in healthy human bone marrow-derived MSCs (BMSCs) and how these drugs affect BMSC proliferation. We established co-cultures of BMSCs with MM.1S myeloma cells to see if BMSCs increase or decrease the cytotoxicity of melflufen, melphalan, bortezomib and doxorubicin. We evaluated how the drugs affect BMSC differentiation into adipocytes and osteoblasts and the BMSC-supported formation of vascular networks. Our results showed that BMSCs were more sensitive to melflufen than to melphalan. The cytotoxicity of melflufen in myeloma cells was not affected by the co-culture with BMSCs, as was the case for melphalan, bortezomib and doxorubicin. Adipogenesis, osteogenesis and BMSC-mediated angiogenesis were all affected by melflufen. Melphalan and doxorubicin affected BMSC differentiation in similar ways. The effects on adipogenesis and osteogenesis were not solely because of effects on proliferation, seen from the differential expression of differentiation markers normalized by cell number. Overall, our results indicate that melflufen has a significant impact on BMSCs, which could possibly affect therapy outcome.
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- 2022
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4. Prognostic significance of esterase gene expression in multiple myeloma
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Muntasir Mamun Majumder, Romika Kumari, Nina N. Nupponen, Raija Silvennoinen, Pekka Anttila, Juha Lievonen, Fredrik Lehmann, Caroline A. Heckman, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, Digital Precision Cancer Medicine (iCAN), Hematologian yksikkö, HUS Comprehensive Cancer Center, Department of Oncology, and University of Helsinki
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Esterase Gene ,3122 Cancers ,Esterase ,Article ,Cohort Studies ,Tumour biomarkers ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Exome Sequencing ,medicine ,Humans ,Finland ,Multiple myeloma ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Sequence Analysis, RNA ,business.industry ,Gene Expression Profiling ,Esterases ,High-Throughput Nucleotide Sequencing ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,PON1 ,Molecular medicine ,3. Good health ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Bone marrow ,Multiple Myeloma ,business - Abstract
Background Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM). Methods For gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). CD138+ plasma cells were enriched and used for RNA sequencing and analysis, and to evaluate genomic variation. The Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) dataset was used for validation of the findings from FIMM. Results MM patients (NDMM, n = 56; RRMM, n = 78) provided 171 bone marrow aspirates (NDMM, n = 56; RRMM, n = 115). Specific esterases exhibited relatively high or low expression in MM, and expression of specific esterases (UCHL5, SIAE, ESD, PAFAH1B3, PNPLA4 and PON1) was significantly altered on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, SIAE and USP4, and low expression of PCED1B, were identified as poor prognostic markers (P PAFAH1B3 and SIAE, and lower expression of PCED1B, were associated with poor prognosis. Conclusions Esterase gene expression levels change as patients progress from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology.
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- 2021
5. Single Cell RNA Sequencing Identifies Potential Molecular Indicators of Response to Melflufen in Multiple Myeloma
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Ana Slipicevic, Caroline A. Heckman, Sadiksha Adhikari, Nina N. Nupponen, Philipp Sergeev, Minna Suvela, Fredrik Lehmann, Maiju-Emilia Huppunen, and Juho J. Miettinen
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0303 health sciences ,Immunology ,Cell ,RNA ,Cell Biology ,Hematology ,Computational biology ,Biology ,medicine.disease ,Biochemistry ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,Multiple myeloma ,030304 developmental biology ,030215 immunology - Abstract
Introduction Melphalan flufenamide (melflufen), is a novel peptide-drug conjugate that targets aminopeptidases and selectively delivers alkylating agents in tumors. Melflufen was recently FDA approved for the treatment of relapsed/refractory multiple myeloma (MM) patients. Considering the challenges in treating this group of patients, and the availability of several new drugs for MM, information that can support treatment selection is urgently needed. To identify potential indicators of response and mechanism of resistance to melflufen, we applied a multiparametric drug sensitivity assay to MM patient samples ex vivo and analyzed the samples by single cell RNA sequencing (scRNAseq). Ex vivo drug testing identified MM samples that were distinctly sensitive or resistant to melflufen, while differential gene expression analysis revealed pathways associated with response. Methods Bone marrow (BM) aspirates from 24 MM patients were obtained after written informed consent following approved protocols in compliance with the Declaration of Helsinki. BM mononuclear cells from 12 newly diagnosed (ND) and 12 relapsed/refractory (RR) patients were used for multi-parametric flow cytometry-based drug sensitivity and resistance testing (DSRT) evaluation to melflufen and melphalan, and for scRNAseq. Based on the results from the DSRT tests and drug sensitivity scores (DSS), we divided the samples into three groups - high sensitivity (HS, DSS > 40 (melflufen) or DSS > 16 (melphalan)), intermediate sensitivity (IS, 31 ≤ DSS ≤ 40 (melflufen) or 10 ≤ DSS ≤ 16 (melphalan)), and low sensitivity (LS, DSS < 31 (melflufen) or DSS < 10 (melphalan)). To identify genes, responsible for the general sensitivity to melphalan-based drugs we conducted differential gene expression (DGE) analyses separately for melphalan and melflufen focusing on the plasma cell populations, comparing gene expression between HS and LS samples for both drugs ("HS vs. LS melphalan" and "HS vs. LS for melflufen", respectively). In addition, to explain the increased sensitivity of RR samples, we conducted the DGE analysis for ND vs. RR samples and searched for similarities between these three datasets. Results DSRT data indicated that samples from RRMM patients were significantly more sensitive to melflufen compared to samples from NDMM (Fig. 1A). In addition, we observed that samples with a gain of 1q (+1q) were more sensitive to melflufen while those with deletion of 13q (del13q) appeared to be less sensitive, although these results lacked significance (Fig. 1A). After separating the samples into different drug sensitivity groups (HS, IS, LS), DGE analysis showed significant downregulation of the drug efflux and multidrug resistance protein family member ABCB9 in the melflufen HS group opposed to the LS group (2.2-fold, p < 0.001). A similar pattern was detected for the melphalan HS vs. LS comparison suggesting that this alteration might be a common indicator of sensitivity to melphalan-based drugs. Furthermore, in the melflufen HS group we observed downregulation of the matrix metallopeptidase inhibitors TIMP1 and TIMP2 (3-fold and 1.6-fold, p < 0.001, respectively), and cathepsin inhibitors CST3 and CSTB (3.2-fold and 1.3-fold, p < 0.001, respectively) (Fig. 1B). This effect was observed in both "ND vs. RR" and "HS vs. LS for melflufen" comparisons, but not for melphalan, suggesting that these changes are associated with disease progression and specific indicators of sensitivity to melflufen. Moreover, gene set enrichment analysis (GSEA) showed activation of pathways related to protein synthesis, as well as amino acid starvation for malignant and normal cell populations in the HS group. Conclusion In summary, our results indicate that melflufen is more active in RRMM compared to NDMM. In addition, samples from MM patients with +1q, which is considered an indicator of high-risk disease, tended to be more sensitive to melflufen. Based on differential GSEA and pathway enrichment, several synergizing mechanisms could potentially explain the higher sensitivity to melflufen, such as decreased drug efflux and increased drug uptake. Although these results indicate potential indicators of response and mechanisms of drug efficacy, further validation of these findings is required using data from melflufen treated patients. Figure 1 Figure 1. Disclosures Slipicevic: Oncopeptides AB: Current Employment. Nupponen: Oncopeptides AB: Consultancy. Lehmann: Oncopeptides AB: Current Employment. Heckman: Orion Pharma: Research Funding; Oncopeptides: Consultancy, Research Funding; Novartis: Research Funding; Celgene/BMS: Research Funding; Kronos Bio, Inc.: Research Funding.
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- 2021
6. Combination of Melphalan Flufenamide and Anti-PD-L1 or Anti-CD38 Antibodies Enhances Anti-Myeloma Immunity
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Nina N. Nupponen, Kenneth C. Anderson, Paul G. Richardson, Joachim Gullbo, Dharminder Chauhan, Fredrik Lehmann, Arghya Ray, Ting Du, and Jakob Lindberg
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biology ,business.industry ,Immunology ,Anti pd 1 ,Cell Biology ,Hematology ,CD38 ,Biochemistry ,Melphalan-flufenamide ,Immunity ,Cancer research ,biology.protein ,Medicine ,Antibody ,business - Abstract
Introduction Melphalan flufenamide (Melflufen; Oncopeptides AB) is a novel enzyme-activated analogue of melphalan that enables a more rapid and higher intracellular accumulation of melphalan in tumor cells than is achievable by direct exposure to equimolar doses of melphalan. Our preclinical study showed that melflufen is a more potent anti-myeloma (MM) agent than melphalan, overcomes drug-resistance, and induces synergistic anti-MM activity in combination with bortezomib, lenalidomide, or dexamethasone (Chauhan et al, Clinical Cancer Res 2013;19:3019). However, the effect of melflufen on the immunosuppressive and tumor-promoting MM-host bone marrow (BM) accessory cells such as immunologically dysfunctional plasmacytoid dendritic cells (pDCs; CD123/IL-3Rα) remains unclear. Here, we utilized our coculture models of pDCs, T-, and NK cells with autologous patient MM cells to examine whether a combination of melflufen and immune checkpoint inhibitor anti-PD-L1 Ab, or daratumumab (anti-CD38 Ab), restores anti-MM immunity. Methods MM patient BM and PB samples (N=10; obtained after informed consent), and cell lines were used for the study. Minimally cytotoxic concentration of melflufen (0.1 µM) was used to assess immune functions. CTL/NK activity assays MM CD8 + T- or NK-cells were cultured with autologous pDCs (1:10 pDC:T/NK ratio) with melflufen (0.1 μM) alone, and with anti-PD-L1 (5 μg/ml) or anti-CD38 (0.5 μg/ml) Abs for 3-5 days; cells were washed to remove the drugs, and then cultured for another 24h with pre-stained target MM cells (10:1 E/T ratio; T/NK:MM), followed by quantification of viable MM cells by flow. Results 1) Both MM tumor cells and pDCs showed higher PD-L1 and CD38 levels vs normal plasma cells; 2) Treatment of MM patient total BM mononuclear cells or purified MM cells with melflufen (0.1 µM) increased PD-L1 expression on MM cells (1.84-fold, treated vs untreated; p Conclusions The combination of melflufen and anti-PD-L1 increases pDC-induced T- and NK cell-mediated cytolytic activities against MM. Moreover, combined melflufen and anti-CD38 Abs modestly enhance pDC-induced NK cell-mediated MM-specific cytolytic activity. Our preclinical data suggest targeting PD-L1 in combination with melflufen as well as support an ongoing clinical trial of melflufen with anti-CD38 Abs to enhance anti-MM immunity. Disclosures Nupponen: Oncopeptides AB: Consultancy. Lehmann: Oncopeptides AB: Current Employment. Lindberg: Oncopeptides: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Camurus: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Affibody: Membership on an entity's Board of Directors or advisory committees. Gullbo: Oncopeptides AB: Consultancy. Richardson: Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; AstraZeneca: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Chauhan: C4 Therapeutics: Current equity holder in publicly-traded company; Oncopeptides: Consultancy; Stemline Therapeutics: Consultancy. Anderson: Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.
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- 2021
7. Abstract 1843: Melflufen efficacy in multiple myeloma with TP53 aberrations
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Caroline A. Heckman, Thorsten Stühmer, Juho J. Miettinen, Maria-Victoria Mateos, Johan Aschan, Paul G. Richardson, Nina N. Nupponen, Ralf C. Bargou, Paula Rodriguez Otero, Maiju-Emilia Huppunen, Fredrik Lehmann, Ana Slipicevic, and Umair Munawar
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0301 basic medicine ,Melphalan ,Cancer Research ,medicine.diagnostic_test ,business.industry ,Cancer ,Phases of clinical research ,Plasma cell ,medicine.disease ,3. Good health ,Flow cytometry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,business ,Ex vivo ,Multiple myeloma ,medicine.drug - Abstract
Introduction Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by clonal evolution and heterogeneous genetic abnormalities. Deletion of the short arm of chromosome 17 (del17p) harboring TP53 is a high-risk abnormality associated with aggressive disease and therapy resistance. Here, we tested in vitro and ex vivo efficacy of a peptide-drug conjugate melflufen, currently in phase 3 clinical trials for relapsed/refractory multiple myeloma (RRMM), in an isogenic myeloma p53-abrogated cell line model and patient samples. Methods Efficacy of melflufen versus melphalan was tested in the AMO-1 cell line, which displays biallelic wildtype TP53 and retains aspects of a functional p53 system, and AMO-1 clones with either complete loss of p53 or expressing point-mutated p53 protein (R282W hotspot mutation), created using the CRISPR/Cas9 system and modified via Sleeping Beauty vectors. We assessed toxicity and apoptosis using Annexin V and Alamar blue assays. Ex vivo sensitivity to the drugs was examined by flow cytometry in CD138+ plasma cells isolated from MM patients with confirmed del17p or TP53 mutations. We also analyzed response rates in a subpopulation of patients with confirmed del17p from OP-106 HORIZON, an ongoing phase 2 study evaluating the efficacy of melflufen plus dexamethasone in patients with RRMM (NCT02963493). Results Whereas loss of p53 functionality strongly impaired melphalan induced cytotoxicity in the AMO-1 MM cell line model system, treatment with melflufen showed superior efficacy in the parental cells, and was effective independent of the respective TP53 status. Although at low dosages wild-type cells were still more sensitive, in contrast to melphalan this effect was overcome by slight dose increases of melflufen, due to the much steeper dose-effect relationships in the p53 deficient sublines. In contrast to melphalan, the melflufen effect was only partially blocked by combined pre-treatment with inhibitors of apoptosis and necroptosis. Similar results were observed in patient-derived material with melflufen displaying superior activity towards TP53 mutated plasma cells. Analysis of OP-106 HORIZON trial data showed comparable ORR of 20% (CI 95% 4.3-48.1) in the del17p subpopulation (n=15) to 26.2% (CI 95% 18.8-34.6) in the total population (n=136). Conclusions Melflufen is able to trigger myeloma cell death regardless of p53 status, and thus overcome p53-deficiency-mediated melphalan resistance. It demonstrates better ex vivo efficacy in MM patient derived plasma cells harboring del17p or TP53 mutations. Melflufen response rates in the del17p Citation Format: Ana Slipicevic, Umair Munawar, Thorsten Stühmer, Johan Aschan, Fredrik Lehmann, Nina N. Nupponen, Juho Miettinen, Maiju-Emilia Huppunen, Caroline A. Heckman, María-Victoria Mateos, Paula Rodríguez Otero, Paul Richardson, Ralf Bargou. Melflufen efficacy in multiple myeloma with TP53 aberrations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1843.
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- 2020
8. Abstract 190: Prognostic significance of esterase gene expression in multiple myeloma
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Raija Silvennoinen, Caroline A. Heckman, Pekka Anttila, Juha Lievonen, Romika Kumari, Fredrik Lehmann, Mamun Majumder, and Nina N. Nupponen
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Cancer Research ,Oncology ,Esterase Gene ,Cancer research ,medicine ,Biology ,medicine.disease ,Multiple myeloma - Abstract
Introduction: The esterase enzyme family is a subclass of the hydrolase enzyme superfamily that functions to split ester bonds. Several esterases have been identified, which differ in substrate specificity and biological function, and the expression of specific esterases may be dysregulated in cancer. Limited information is available regarding the expression of esterases in multiple myeloma (MM), despite potential for exploitation in novel therapeutic approaches such as peptide-drug conjugates (e.g. melflufen). We evaluated the biological significance of esterase enzyme expression in MM. Methods: For gene expression profiling, bone marrow aspirates were obtained from MM patients (pts) or healthy donors after obtaining written informed consent and following approved protocols in compliance with the Declaration of Helsinki. CD138+ plasma cells were enriched and used for RNA preparation. Illumina-compatible RNA sequencing libraries were prepared and sequenced. A cut-off value of >1 Reads Per Kilobase of transcript per Million mapped reads (RPKM) was used to filter expressed genes. The Welch two-sample t-test was used to identify significant variation in gene expression. Contribution of esterase gene expression to survival outcome was estimated by Kaplan-Meier analysis; significance between two groups was deduced using a Mantel-Cox log rank test. Results: Of 123 pts with MM, bone marrow aspirates were collected from 41 pts with newly diagnosed (ND) MM, 81 pts with relapsed/refractory (RR) MM, and 1 pt with stable disease. Samples were also obtained from two healthy donors. The most abundant esterases in MM samples were OVCA2, PAFAH1B2, NXPE3, UCHL3, LIPA, ABHD10, UCHL5, CASD1, ABHD13, and USP4 (median log2[RPKM] range: 3.9 to 2.1). The least abundant esterases were NLGN1, NLGN2, PON1, CEL, PON3, NLGN4Y, IL17A, AADAC, CES5A, and ASPG (median log2[RPKM]: -5.1 to -10.7). The expression levels of OVCA2, PAFAH1B2, NXPE3, UCHL5, SIAE, ESD, PNPLA6, and PAFAH1B3 were significantly higher (P Conclusion: Esterase expression levels in MM change on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, CES4A, and PNPLA6, and low expression of NXPE4 and GZMA, were identified as poor prognostic markers in pts with MM, suggesting a role for these esterases in myeloma biology. Citation Format: Romika Kumari, M. Mamun Majumder, Juha Lievonen, Raija Silvennoinen, Pekka Anttila, Nina N. Nupponen, Fredrik Lehmann, Caroline A. Heckman. Prognostic significance of esterase gene expression in multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 190.
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- 2020
9. In Vitro and inVivo Activity of Melflufen in Amyloidosis
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Caroline A. Heckman, Minna Suvela, Muntasir Mamun Majumder, Fredrik Lehmann, Sarah A. Holstein, Ana Slipicevic, Ken Flanagan, Juho J. Miettinen, Romika Kumari, Michelle L. Varney, and Nina N. Nupponen
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0301 basic medicine ,Melphalan ,Immunology ,Plasma cell ,Immunoglobulin light chain ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,AL amyloidosis ,Multiple myeloma ,biology ,Chemistry ,Amyloidosis ,Cell Biology ,Hematology ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Cancer research ,Bone marrow ,Antibody ,030215 immunology ,medicine.drug - Abstract
Background: Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by plasma cell secretion of misfolded light chains that assemble as amyloid fibrils and deposit on vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell directed therapeutics, aimed at preferentially eliminating the clonal population of amyloidogenic cells in bone marrow are expected to reduce production of toxic light chain and alleviate deposition of amyloid thereby restoring healthy organ function. Melphalan flufenamide ethyl ester, melflufen, is a peptidase potentiated alkylating agent with potent toxicity in myeloma cells. Melflufen is highly lipophilic, permitting rapid cellular uptake, and is subsequently enzymatically cleaved by aminopeptidases within cells resulting in augmented intracellular concentrations of toxic molecules, providing a more targeted and localized treatment. Previous data demonstrating multiple myeloma plasma cell sensitivity for melflufen suggests that the drug might be useful to directly eliminate amyloidogenic plasma cells, thereby reducing the amyloid load in patients. Furthermore, the increased intracellular concentrations of melflufen in myeloma cells indicates a potential reduction in systemic toxicity in patients, an important factor in the fragile amyloidosis patient population. To assess potential efficacy in amyloidosis patients and to explore the mechanism of action, we examined effects of melflufen on amyloidogenic plasma cells invitro and invivo. Methods: Cellular toxicity and apoptosis were measured in response to either melflufen or melphalan in multiple malignant human plasma cell lines, including the amyloidosis patient derived light chain secreting ALMC-1 and ALMC-2 cells, as well as primary bone marrow cells from AL amyloidosis patients, using annexin V and live/dead cell staining by multicolor flow cytometry, and measurement of cleaved caspases. Lambda light chain was measured in supernatant by ELISA, and intracellular levels were detected by flow cytometry. To assess efficacy of melflufen in vivo, the light chain secreting human myeloma cell line, JJN3, was transduced with luciferase and adoptively transferred into NSG mice. Cell death in response to melflufen or melphalan was measured by in vivo bioluminescence, and serum light chain was monitored. Results: Melflufen demonstrated increased potency against multiple myeloma cell lines compared to melphalan, inducing malignant plasma cell death at lower doses on established light chain secreting plasma cell lines. While ALMC-1 cells were sensitive to both melphalan and melflufen, the IC50 for melphalan at 960 nM was approximately 3-fold higher than melflufen (334 nM). However, ALMC-2 cells were relatively insensitive to melphalan (12600 nM), but maintained a 100-fold increase in sensitivity to melflufen (121 nM). Furthermore, while 40% of primary CD138+ plasma cells from patients with diagnosed AL amyloidosis responded to melflufen treatment in vitro, only 20% responded to melphalan with consistently superior IC50 values for melflufen (Figure 1). Light chain secreting cell lines and AL amyloidosis patient samples were further analyzed by single cell sequencing. We further examined differential effects on apoptosis and the unfolded protein response in vitro in response to either melflufen or melphalan. This is of particular interest in amyloidosis, where malignant antibody producing plasma cells possess an increased requirement for mechanisms to cope with the amplified load of unfolded protein and associated ER stress. As AL amyloidosis is ultimately a disease mediated by secretion of toxic immunoglobulin, we assessed the effects of melflufen on the production of light chain invitro, measuring a decrease in production of light chain in response to melflufen treatment. Finally, we took advantage of a recently described adoptive transfer mouse model of amyloidosis to assess the efficacy of melflufen and melphalan in eliminating amyloidogenic clones and reducing the levels of toxic serum light chain in vivo. Conclusions: These findings provide evidence that melflufen mediated toxicity, previously described in myeloma cells, extends to amyloidogenic plasma cells and further affects the ability of these cells to produce and secrete toxic light chain. This data supports the rationale for the evaluation of melflufen in patients with AL amyloidosis. Figure 1 Disclosures Flanagan: Oncopeptides AB: Employment. Slipicevic:Oncopeptides AB: Employment. Holstein:Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy. Lehmann:Oncopeptides AB: Employment. Nupponen:Oncopeptides AB: Employment. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding.
- Published
- 2019
10. KIT overexpression induces proliferation in astrocytes in an imatinib-responsive manner and associates with proliferation index in gliomas
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Nina N. Nupponen, Kirmo Wartiovaara, Tea Blom, Heli Fox, Hannu Haapasalo, Alexandre Angers-Loustau, Laura Kerosuo, Olli A. Jänne, Karita Peltonen, Panu E. Kovanen, and Marika J. Linja
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0303 health sciences ,Cancer Research ,Proliferation index ,medicine.drug_class ,Cell growth ,Biology ,Gene mutation ,Tyrosine-kinase inhibitor ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Imatinib mesylate ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Proto-Oncogene Proteins c-kit ,Receptor Tyrosine Kinase Gene ,Signal transduction ,030304 developmental biology - Abstract
Activating gene mutations, gene amplifications and overexpressed proteins may be useful as targets for novel therapies. Alterations at chromosome locus 4q12 are associated with gliomas and the region harbors the receptor tyrosine kinase gene KIT, which is frequently amplified in gliomas, and also overexpressed in a subset of gliomas. KIT and its ligand stem cell factor are widely expressed in embryonic and adult mouse brain, and they play a role in many signal transduction pathways involved in cellular proliferation, differentiation and cancer cell metastasis. However, the function of KIT in gliomagenesis or disease progression remains unresolved as well as its role in neural and brain tumor development. In this study, we utilized lentivirus-mediated gene transfer to deliver the KIT gene into mouse astrocytes. The growth properties of KIT overexpressing cells were analyzed using several in vitro functional assays. The effect of receptor tyrosine kinase inhibitor imatinib on astrocyte growth was also investigated. Our results indicate that overexpression of KIT in mouse astrocytes promotes cell proliferation, and the increased proliferation is partly inhibited by imatinib treatment. Furthermore, KIT overexpression induces phenotypic changes in the cells suggesting that KIT may play a role in astrocyte growth regulation.
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- 2008
11. Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas
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Janna Paulsson, Nina N. Nupponen, Johannes E. A. Wolff, Werner Paulus, Arne Östman, Minna Tanner, Brigitte Wrede, Martin Hasselblatt, and Astrid Jeibmann
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Male ,Choroid Plexus Neoplasms ,Pathology ,medicine.medical_specialty ,Receptor, Platelet-Derived Growth Factor alpha ,PDGFRB ,PDGFRA ,Biology ,Pathology and Forensic Medicine ,Receptor, Platelet-Derived Growth Factor beta ,03 medical and health sciences ,0302 clinical medicine ,Biomarkers, Tumor ,medicine ,Humans ,CISH ,Receptor ,030304 developmental biology ,0303 health sciences ,Carcinoma ,Gene Amplification ,Infant ,Choroid plexus carcinoma ,Prognosis ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Imatinib mesylate ,Child, Preschool ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Choroid plexus ,Platelet-derived growth factor receptor - Abstract
Platelet-derived growth factor (PDGF) receptor signaling has been implicated in the development of glial tumors, but not yet been examined in choroid plexus carcinomas, pediatric tumors with dismal prognosis for which novel treatment options would be desirable. Therefore, protein expression of PDGF receptors alpha and beta as well as amplification status of the respective genes, PDGFRA and PDGFRB, were examined in a series of 22 patients harboring choroid plexus carcinoma using immunohistochemistry and chromogenic in situ hybridization (CISH). The majority of choroid plexus carcinomas expressed PDGF receptors with 6 cases (27%) displaying high staining scores for PDGF receptor alpha and 13 cases (59%) showing high staining scores for PDGF receptor beta. Correspondingly, copy-number gains of PDGFRA were observed in 8 cases out of 12 cases available for CISH and 1 case displayed amplification (six or more signals per nucleus). The proportion of choroid plexus carcinomas with amplification of PDGFRB was even higher (5/12 cases). PDGFRB amplification status and PDGF receptor beta protein expression scores were significantly correlated (P=0.01, Spearman). Expression status of PDGF receptor alpha or PDGF receptor beta was not significantly associated with progression-free survival. To conclude, expression and amplification of PDGF receptors, particularly PDGF receptor beta, are frequent in choroid plexus carcinomas, providing a first rationale for the development of treatments targeting PDGF receptor signaling in these rare malignant pediatric tumors.
- Published
- 2008
12. Gene amplification, mutation, and protein expression of EGFR and mutations of ERBB2 in serous ovarian carcinoma
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Heini Lassus, Heikki Joensuu, Jorma Isola, Nina N. Nupponen, Ralf Bützow, Harri Sihto, and Arto Leminen
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Ovarian Neoplasms ,Proliferation index ,Receptor, ErbB-2 ,Serous carcinoma ,Gene Dosage ,Chromogenic in situ hybridization ,Middle Aged ,Biology ,medicine.disease ,Cystadenocarcinoma, Serous ,ErbB Receptors ,Serous fluid ,Ovarian carcinoma ,Mutation ,Drug Discovery ,medicine ,Cancer research ,Humans ,Molecular Medicine ,Female ,CISH ,Ovarian cancer ,In Situ Hybridization ,Genetics (clinical) ,EGFR inhibitors - Abstract
EGFR and erbB-2 are targets for specific cancer therapy. The purpose of this study was to examine the frequency and clinicopathological correlations of gene amplification, protein expression, and mutations of EGFR and ERBB2 in serous carcinoma, the most common and aggressive type of ovarian cancer. Tissue microarray constructed of 398 carcinomas was examined by chromogenic in situ hybridization (CISH) and by immunohistochemistry. Cases with amplification of EGFR by CISH were further analyzed by fluorescence in situ hybridization. One hundred ninety-eight samples were analyzed for mutations in exons 18, 19, or 21 of EGFR and in exon 20 of ERBB2 using denaturating high-performance liquid chromatography and direct sequencing. Amplification of EGFR was present in 12% (41/333), low-level gain in 43% (144/333), and protein overexpression in 17% (66/379) of the tumors. Both increased copy number and overexpression of EGFR were associated with high tumor grade, greater patient age, large residual tumor size, high proliferation index, aberrant p53, and poor patient outcome. Furthermore, increased copy number of EGFR was associated with increased copy number of ERBB2. No mutations were identified in EGFR, whereas one tumor had an insertion mutation in exon 20 of ERBB2. Both amplification and protein overexpression of EGFR occur in serous ovarian carcinoma, but EGFR copy number has a stronger prognostic value. This makes EGFR amplification a potentially useful criterion for selecting patients in clinical trials testing the effect of EGFR inhibitors in serous ovarian carcinoma.
- Published
- 2006
13. Epidermal growth factor receptor domain II, IV, and kinase domain mutations in human solid tumors
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Heikki Joensuu, Marjut Puputti, Olli Tynninen, Laura Pulli, Walter J. Koskinen, Aija Knuuttila, Minna Tanner, Nina N. Nupponen, Ralf Bützow, Harri Sihto, Tapio Visakorpi, Tom Böhling, and Leena-Maija Aaltonen
- Subjects
Lung Neoplasms ,Molecular Sequence Data ,medicine.disease_cause ,Polymerase Chain Reaction ,Receptor tyrosine kinase ,Growth factor receptor ,Carcinoma, Non-Small-Cell Lung ,Drug Discovery ,medicine ,Humans ,Amino Acid Sequence ,Epidermal growth factor receptor ,Lung cancer ,Chromatography, High Pressure Liquid ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Mutation ,biology ,Kinase ,Receptor Protein-Tyrosine Kinases ,Exons ,Sequence Analysis, DNA ,medicine.disease ,Protein Structure, Tertiary ,ErbB Receptors ,Protein kinase domain ,Cancer research ,biology.protein ,Molecular Medicine ,Adenocarcinoma ,Glioblastoma - Abstract
Mutations that may predict response to adenosine 5'-triphosphate (ATP)-mimetic epidermal growth factor receptor (EGFR) inhibitors occur in the EGFR kinase domain in lung adenocarcinomas and bronchioloalveolar carcinomas (BACs). Data on the frequency of EGFR mutations are sparse in other human tumors. Apart from the deletion mutant EGFRvIII, little is known about the frequency of mutations that encode for the EGFR extracellular domains II and IV that participate in receptor dimerization and formation of the tethered (autoinhibited) receptor conformation. We investigated 566 human neoplasms consisting of various histological types for mutations in exons 6, 7 (encode domain II), 14, 15 (domain IV), 18, 19, and 21 (the kinase domain) using denaturing high-performance liquid chromatography (DHPLC). Approximately 4,500 EGFR exons were screened for the presence of a mutation, and samples with an abnormal finding in DHPLC were sequenced. Only one mutation was found in the extracellular domain IV (glioblastoma), and none in domain II. Eight (11%) out of the 40 lung adenocarcinomas, or 33 BACs, investigated had exon 19 or 21 mutation in the kinase domain, but no mutations were found in other tumor types. Most of the lung cancers with mutated EGFR had three to six copies of the mutated gene in fluorescence in situ hybridization. We conclude that mutations of the EGFR kinase domain and the cysteine-rich extracellular domains are infrequent in most types of human cancer apart from lung adenocarcinoma. Mutated EGFR is usually not amplified in lung cancer.
- Published
- 2005
14. Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy
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Kristiina Aittomäki, Jodie N. Painter, Anne Ropponen, Miia Savander, Nina N. Nupponen, Anna-Elina Lehesjoki, Seija Riikonen, and Olavi Ylikorkala
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Male ,Heterozygote ,Genotype ,Genetic Linkage ,Physiology ,Cholestasis, Intrahepatic ,Biology ,Genetic Heterogeneity ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Cholestasis ,Pregnancy ,Polymorphism (computer science) ,Genetics ,medicine ,Humans ,Genetics (clinical) ,030304 developmental biology ,Adenosine Triphosphatases ,0303 health sciences ,integumentary system ,musculoskeletal, neural, and ocular physiology ,Haplotype ,Progressive familial intrahepatic cholestasis ,Exons ,ABCB4 ,medicine.disease ,nervous system diseases ,3. Good health ,Pregnancy Complications ,Haplotypes ,Female ,030211 gastroenterology & hepatology ,sense organs ,Cholestasis of pregnancy - Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic condition that may affect women during the third trimester of pregnancy. Symptoms experienced by these women generally resolve spontaneously following delivery, but prior to delivery the fetus is at increased risk of intrauterine distress and sudden intrauterine death. The genetic etiology of most cases of ICP is unknown, although heterozygous carriers of mutations causing progressive familial intrahepatic cholestasis (PFIC) diseases may experience ICP. When examining linkage to known cholestasis genes, affected members of four Finnish ICP families shared haplotypes around ATP8B1, the gene responsible for PFIC1. This gene was subsequently screened in 176 familial and sporadic ICP patients. A total of 17 sequence changes were detected, five exonic and 12 intronic. No intronic change was associated with ICP in sporadic cases. Four intronic changes segregated with ICP in three families, a different change in each of two families and three changes in another family, although the significance of this is currently unknown. Three exonic changes were nonsynonymous, one (in exon 23) is probably a polymorphism while two predict novel amino-acid replacements (N45T and K203R). These changes, in exons 2 and 7, were detected in one individual each, and may have predisposed these individuals to ICP. In conclusion, although the exon 2 and 7 changes may have functioned as risk alleles, ATP8B1 is probably not a major gene contributing to the occurrence of ICP.
- Published
- 2005
15. Early-Onset Renal Cell Carcinoma as a Novel Extraparaganglial Component of SDHB-Associated Heritable Paraganglioma
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Maija Ht Kiuru, Charis Eng, Heikki Järvinen, Eero Pukkala, Andrzej Januszewicz, Riitta Herva, Mary Buchta, Mariola Pęczkowska, Matti Juhola, Lauri A. Aaltonen, Nina N. Nupponen, Carl Morrison, Rainer Lehtonen, Sarah R. McWhinney, Sanna K. Virta, Jukka-Pekka Mecklin, Sakari Vanharanta, and Hartmut P. H. Neumann
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Adult ,Iron-Sulfur Proteins ,Male ,medicine.medical_specialty ,Adolescent ,SDHB ,Population ,Mutation, Missense ,Biology ,Germline ,Pheochromocytoma ,Paraganglioma ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Internal medicine ,Report ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,Age of Onset ,education ,Carcinoma, Renal Cell ,Genetics (clinical) ,Germ-Line Mutation ,030304 developmental biology ,Sequence Deletion ,0303 health sciences ,education.field_of_study ,Hereditary Paraganglioma ,Base Sequence ,Siblings ,medicine.disease ,Kidney Neoplasms ,3. Good health ,Pedigree ,Succinate Dehydrogenase ,Protein Subunits ,Endocrinology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,SDHD - Abstract
Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.
- Published
- 2004
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16. Human pHyde is not a classical tumor suppressor gene in prostate cancer
- Author
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Teuvo L.J. Tammela, Kati P. Porkka, Tapio Visakorpi, Robert L. Vessella, and Nina N. Nupponen
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Male ,PCA3 ,Cancer Research ,Pathology ,medicine.medical_specialty ,Neoplasms, Hormone-Dependent ,Tumor suppressor gene ,DNA Mutational Analysis ,Transplantation, Heterologous ,Prostatic Hyperplasia ,Cell Cycle Proteins ,Biology ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,DU145 ,Prostate ,LNCaP ,Gene expression ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,RNA, Messenger ,In Situ Hybridization, Fluorescence ,DNA Primers ,030304 developmental biology ,Oncogene Proteins ,0303 health sciences ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Prostatic Neoplasms ,DNA ,Blotting, Northern ,medicine.disease ,Rats ,3. Good health ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Oxidoreductases ,Fluorescence in situ hybridization - Abstract
A novel putative tumor suppressor gene, pHyde, was recently cloned from rat prostate. The rat gene has been shown to inhibit prostate cancer cell proliferation both in vitro and in vivo. However, the role of human pHyde in prostate cancer has not been studied before. Here, we analyzed human prostate cancer cell lines (LNCaP, DU145, PC-3, 22Rv1), xenografts (LuCaP 23.1, 35, 41, 49, 58, 69, 70 and 73) and clinical prostate carcinomas for genetic alterations and expression of pHyde. The expression of pHyde in normal human tissues as well as in prostate cancer was studied by Northern analysis and real-time quantitative RT-PCR. It was ubiquitously expressed in all normal tissues analyzed. Although, the expression was significantly (p=0.007) lower in poorly differentiated than in well and moderately differentiated carcinomas, there were no differences in the expression levels between benign prostate hyperplasia, untreated primary and recurrent hormone-refractory prostate carcinomas (p=0.607). Altogether, missense mutations were detected in 2 out of 68 samples studied (∼3%) by denaturing high-performance liquid chromatography (DHPLC) and sequencing. One of the samples with the mutation also exhibited a loss of a gene copy by fluorescence in situ hybridization (FISH). This was the only sample that exhibited a genetic alteration in both alleles, suggesting that the human pHyde is not a classical prostate tumor suppressor gene. The reduced expression of the gene found in some tumors warrant further studies. © 2003 Wiley-Liss, Inc.
- Published
- 2003
17. Little evidence for involvement ofMLH3in colorectal cancer predisposition
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Reijo Salovaara, Heikki Järvinen, Pertti Sistonen, Virpi Launonen, Jukka-Pekka Mecklin, Auli Karhu, Nina N. Nupponen, Lauri A. Aaltonen, Rainer Lehtonen, Päivi Peltomäki, Tuija Hienonen, and Päivi Laiho
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,0303 health sciences ,Cancer Research ,MLH3 ,Biology ,MLH1 ,digestive system diseases ,3. Good health ,Frameshift mutation ,MSH6 ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Oncology ,MSH2 ,030220 oncology & carcinogenesis ,PMS2 ,Missense mutation ,neoplasms ,030304 developmental biology - Abstract
Mutations in the DNA MMR genes MSH2, MLH1, MSH6 and PMS2 underlie a large subset of HNPCC cases, and a hallmark of the tumors is MSI. In many HNPCC families, however, a causative mutation has not been found. Therefore, the involvement of additional, thus far unknown, genes in MSI as well as MSS colorectal tumor predisposition is possible. The role of a relatively recently cloned MMR gene, MLH3, in familial CRC has been studied; but the results appear somewhat conflicting. To further evaluate the role of MLH3 in CRC predisposition, we analyzed 30 Finnish CRC cases for germline mutations by sequencing. These cases were selected from a large series of Finnish CRC patients, to match features previously proposed to associate with MLH3 germline defects. We found 5 missense variants, 4 of which were also found in Finnish cancer-free controls. The only remaining variant does not appear to be an attractive candidate for a disease-associated mutation because the amino acid change is located outside the conserved residues. We also screened for the previously reported variants, including a frameshift change, the most likely pathogenic MLH3 mutation observed so far. The frameshift was not present in the 30 CRC cases or in 700 cancer-free controls. While it is a difficult task to exclude a role of MLH3 in HNPCC, our study could not confirm a role for MLH3 in CRC predisposition. © 2003 Wiley-Liss, Inc.
- Published
- 2003
18. Germline Alterations of the RNASEL Gene, a Candidate HPC1 Gene at 1q25, in Patients and Families with Prostate Cancer
- Author
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Tarja Ikonen, Annika Rökman, Olli Kallioniemi, Nina Mononen, Pasi A. Koivisto, Teuvo L.J. Tammela, Eija H. Seppälä, Mika P. Matikainen, John D. Carpten, Jeffrey M. Trent, Nina N. Nupponen, Ville Autio, Joan E. Bailey-Wilson, and Johanna Schleutker
- Subjects
Male ,DNA Mutational Analysis ,Mutation, Missense ,Biology ,urologic and male genital diseases ,MSR1 ,Prostate cancer ,Germline mutation ,Gene Frequency ,Endoribonucleases ,Genetics ,medicine ,Humans ,Missense mutation ,Genetics(clinical) ,Age of Onset ,Mutation frequency ,Allele frequency ,Finland ,Germ-Line Mutation ,Polymorphism, Single-Stranded Conformational ,Genetics (clinical) ,Prostatic Neoplasms ,RNASEL Gene ,Articles ,medicine.disease ,Pedigree ,Chromosomes, Human, Pair 1 ,Female ,Age of onset - Abstract
The RNASEL gene (2',5'-oligoisoadenylate-synthetase dependent) encodes a ribonuclease that mediates the antiviral and apoptotic activities of interferons. The RNASEL gene maps to the hereditary-prostate-cancer (HPC)-predisposition locus at 1q24-q25 (HPC1) and was recently shown to harbor truncating mutations in two families with linkage to HPC1. Here, we screened for RNASEL germline mutations in 66 Finnish patients with HPC, and we determined the frequency of the changes in the index patients from 116 families with HPC, in 492 patients with unselected prostate cancer (PRCA), in 223 patients with benign prostatic hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X, was found in 5 (4.3%) of the 116 patients from families with HPC. This was significantly higher (odds ratio [OR] =4.56; P=.04) than the frequency of E265X in controls (1.8%). The highest mutation frequency (9.5%) was found in patients from families with four or more affected members. Possible segregation was detected only in a single family. However, the median age at disease onset for E265X carriers was 11 years less than that for noncarriers in the same families. In addition, of the four missense variants found, R462Q showed an association with HPC (OR=1.96; P=.07). None of the variants showed any differences between controls and either patients with BPH or patients with PRCA. We conclude that, although RNASEL mutations do not explain disease segregation in Finnish families with HPC, the variants are enriched in families with HPC that include more than two affected members and may also be associated with the age at disease onset. This suggests a possible modifying role in cancer predisposition. The impact that the RNASEL sequence variants have on PRCA burden at the population level seems small but deserves further study.
- Published
- 2002
19. Amplification of EIF3S3 Gene Is Associated with Advanced Stage in Prostate Cancer
- Author
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Outi R. Saramäki, Nina N. Nupponen, Ola Bratt, Lukas Bubendorf, Niels Willi, Tapio Visakorpi, Thomas C. Gasser, and Pasi A. Koivisto
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Eukaryotic Initiation Factor-3 ,Gene Dosage ,Biology ,Gene dosage ,Pathology and Forensic Medicine ,Prostate cancer ,Peptide Initiation Factors ,Prostate ,medicine ,Humans ,In Situ Hybridization, Fluorescence ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Tissue microarray ,medicine.diagnostic_test ,Gene Amplification ,Prostatic Neoplasms ,Regular Article ,Middle Aged ,medicine.disease ,Survival Analysis ,Survival Rate ,medicine.anatomical_structure ,Cancer research ,Adenocarcinoma ,Oncogene MYC ,Comparative genomic hybridization ,Fluorescence in situ hybridization - Abstract
Gain of the long arm of chromosome 8 (8q) is one of the most common gains found in the advanced prostate cancer by comparative genomic hybridization. We have previously identified a putative target gene for the 8q gain, EIF3S3, that encodes a p40 subunit of eukaryotic translation initiation factor 3 (eIF3). Here, we studied the frequency of the EIF3S3 amplification in different stages of prostate cancer and co-amplification of EIF3S3 and oncogene MYC. In addition, prognostic utility of the EIF3S3 copy number alteration was evaluated. The analyses were done with fluorescence in situ hybridization and tissue microarray technology. High-level amplification of EIF3S3 was found in 11 of 125 (9%) of pT1/pT2 tumors, 12 of 44 (27%) of pT3/pT4 tumors, and 8 of 37 (22%) of lymph node metastases as well as in 26 of 78 (33%) and 15 of 30 (50%) of hormone refractory locally recurrent tumors and metastases, respectively. The amplification was associated with high Gleason score (P < 0.001). One of the 79 tumors with EIF3S3 amplification had only two copies of MYC, whereas all tumors with amplification of MYC had also amplification of EIF3S3 indicating common co-amplification of the genes. Gain of EIF3S3 was associated with poor cancer-specific survival in incidentally found prostate carcinomas (P = 0.023). In the analyses of prostatectomy-treated patients, the amplification was not statistically significantly associated with progression-free time. In conclusion, amplification of EIF3S3 gene is common in late-stage prostate cancer suggesting that it may be functionally involved in the progression of the disease.
- Published
- 2001
20. Vol. 35, 1999
- Author
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Colin W. Bayne, Yves Fradet, Polly Feigl, A.R. Zlotta, Peter Boyle, Roxann M. Neumann, Junqi Qian, Ronald A. Lubet, Levy Kopelovitch, Thomas Putz, C.C. Schulman, B. Têtu, Donna M. Peehl, Gary J. Kelloff, Don W. W. Newling, Margaret Ross, Ferran Algaba, Peter Whelan, Judd W. Moul, D. Altshuler, B.E. Henderson, M. Marshall, James A. Crowell, David L. McCormick, Jagat Ghosh, C.L. Pearce, Gianluca Severi, E. Lander, R.K. Ross, Vinicius Duval da Silva, T.H. Van Der Kwast, G. Daley, K. Griffiths, Andrew C.B. Cato, Rodolfo Montironi, Nina N. Nupponen, Alfred Hobisch, Ramak Shadmani, M. Markiewicz, Peter W. Hamilton, Georg Bartsch, E.D. Crawford, Wim J. Kirkels, Lynne Moore, Iris E. Eder, Charles W. Boone, L. Denis, Liang Cheng, J.K.V. Reichardt, Ian M. Thompson, Helmut Klocker, P. Bretsky, Marina Scarpelli, Charles E. Myers, David J. Waters, Marion J.G. Bussemakers, R. Lieberman, Robert B. Jenkins, Caroline C. Sigman, K.V.N. Rao, Isabelle Bairati, Vernon E. Steele, Zoran Culig, M. Studen, U. Manne, Fritz H. Schröder, D. Perkins, G.A. Coetzee, Peter H. Bartels, David G. Bostwick, A. Reissigl, Wael Sakr, W. Grizzle, D. Urban, Peter Ekman, François Meyer, Claudia Nessler-Menardi, L.N. Kolonel, Hubert G. Bartels, Deborah Thompson, M.S. Morton, H. Volgger, Michael B. Sporn, W. Horninger, C.A. Coltman, G. Bartsch, Heike Peterziel, R. Myers, H. Klocker, Adrian P.M. van der Meijden, J. Mohler, F. Labrie, Ronald Lieberman, H. Rogatsch, John Rietbergen, Fouad K. Habib, G. Kelloff, Richard Sylvester, Laurence Collette, Maarten C. Bosland, Winfred A. Malone, H. Weiss, Ries Kranse, Robert F. Hoedemaeker, Tapio Visakorpi, and Linda Vaught
- Subjects
business.industry ,Urology ,Library science ,Medicine ,business - Published
- 1999
21. Genetic Aberrations in Hypodiploid Breast Cancer
- Author
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Jorma Isola, Minna Tanner, Tanja Pejovic, Ritva Karhu, Nina N. Nupponen, Mårten Fernö, Åke Borg, Dick Killander, and Bo Baldetorp
- Subjects
medicine.diagnostic_test ,Biology ,medicine.disease ,Molecular biology ,Pathology and Forensic Medicine ,Cyclin D1 ,Breast cancer ,Gene duplication ,medicine ,Hypodiploidy ,Hyperdiploidy ,Ploidy ,Comparative genomic hybridization ,Fluorescence in situ hybridization - Abstract
The evolution of somatic genetic aberrations in breast cancer has remained poorly understood. The most common chromosomal abnormality is hyperdiploidy, which is thought to arise via a transient hypodiploid state. However, hypodiploidy persists in 1 to 2% of breast tumors, which are characterized by a poor prognosis. We studied the genetic aberrations in 15 flow cytometrically hypodiploid breast cancers by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). Surprisingly, numerous copy number gains were detected in addition to the copy number losses. The number of gains per tumor was 4.3 +/- 3.2 and that of losses was 4.5 +/- 3.3 (mean +/- SD), which is similar to that previously observed in hyperdiploid breast cancers. Gains at chromosomes or chromosomal regions at 11q13, 1q, 19, and 16p and losses of 2q, 4, 6q, 9p, 13, and 18 were most commonly observed. Compared with unselected breast carcinomas, hypodiploid tumors showed certain differences. Loss of chromosome 4 (53%) and gain of 11q13 (60%) were significantly more common in hypodiploid tumors. The gain at 11q13 was found by FISH to harbor amplification of the Cyclin D1 oncogene, which is therefore three to four times more common in hypodiploid than in unselected breast cancers (15 to 20%). Structural chromosomal aberrations (such as Cyclin D1 amplification) were present both in diploid and hypodiploid tumor cell populations, as assessed by FISH and CGH after flow cytometric sorting. Together these results indicate that hypodiploid tumors form a distinct genetic entity of invasive breast cancer, although they probably share a common genetic evolution pathway where structural chromosomal aberrations precede gross DNA ploidy changes.
- Published
- 1998
22. Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma
- Author
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Päivi Peltomäki, Nina N. Nupponen, Wael M. Abdel-Rahman, Annette Gylling, Ralf Bützow, Marjut Puputti, and Miina Ollikainen
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Class I Phosphatidylinositol 3-Kinases ,Gene mutation ,medicine.disease_cause ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Germline mutation ,Internal medicine ,Proto-Oncogene Proteins ,medicine ,PTEN ,Humans ,neoplasms ,PI3K/AKT/mTOR pathway ,Polymorphism, Single-Stranded Conformational ,030304 developmental biology ,Aged ,0303 health sciences ,biology ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Endometrial cancer ,Gene Amplification ,PTEN Phosphohydrolase ,Membrane Proteins ,Middle Aged ,medicine.disease ,digestive system diseases ,Lynch syndrome ,3. Good health ,Endometrial Neoplasms ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,ras Proteins ,Female ,KRAS ,business ,Carcinogenesis ,Colorectal Neoplasms - Abstract
While the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is known to be activated in multiple sporadic cancers, the role of this pathway in familial tumors is mostly unknown. We searched for alterations in the catalytic domain of PI3K (PIK3CA), PTEN and KRAS, all of which may contribute to PI3K/AKT pathway activation, in a total of 160-familial colorectal (CRC) and endometrial carcinomas (EC), stratified by the presence vs. absence of germline mutations in DNA mismatch repair (MMR) genes. PIK3CA alterations (consisting of point mutations or low-level amplification, which were mutually exclusive with 1 exception) occurred in 10/70 (14%) of CRCs and 19/90 (21%) of ECs. Within ECs, amplification was significantly associated with the subgroup lacking germline mutations in MMR genes (familial site-specific endometrial cancer) (p = 0.015). Decreased or lost PTEN expression was characteristic of endometrial tumourigenesis (51/81, 63%, in EC compared with 24/62, 39%, in CRC, p = 0.004) and KRAS mutations of colorectal tumourigenesis (19/70, 27% in CRC vs. 9/89, 10%, in EC, p = 0.006) regardless of the MMR gene mutation status. PIK3CA alterations frequently coexisted with PTEN or KRAS changes. Combined with published studies on sporadic tumors, our data broaden the understanding of the role for PI3K pathway genes in human tumorigenesis. © 2007 Wiley-Liss, Inc.
- Published
- 2007
23. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas
- Author
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Hanna Mäenpää, Jorma Isola, Olli Tynninen, Heikki Joensuu, Nina N. Nupponen, Tea Blom, Marjut Puputti, Anders Paetau, and Harri Sihto
- Subjects
Cancer Research ,Receptor, Platelet-Derived Growth Factor alpha ,Chromogenic in situ hybridization ,Gene Expression ,PDGFRA ,03 medical and health sciences ,0302 clinical medicine ,Glioma ,Medicine ,Humans ,neoplasms ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Gene Amplification ,Amplicon ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,nervous system diseases ,3. Good health ,ErbB Receptors ,Proto-Oncogene Proteins c-kit ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,business ,Tyrosine kinase ,Anaplastic astrocytoma ,Fluorescence in situ hybridization - Abstract
Receptor tyrosine kinase aberrations are implicated in the genesis of gliomas. We investigated expression and amplification of KIT, PDGFRA, VEGFR2, and EGFR in 87 gliomas consisting of astrocytomas, anaplastic astrocytomas, oligodendrogliomas, or oligoastrocytomas in tumor samples collected at the time of the diagnosis and in samples of the same tumors at tumor recurrence. Gene amplifications were investigated using either chromogenic in situ hybridization or fluorescence in situ hybridization, and protein expression using immunohistochemistry. In samples collected at glioma diagnosis, KIT and PDGFRA amplifications were more frequent in anaplastic astrocytomas than in astrocytomas, oligodendrogliomas, and oligoastrocytomas [28% versus 5% (P = 0.012) and 33% versus 2% (P = 0.0008), respectively]. VEGFR2 amplifications occurred in 6% to 17% of the gliomas at diagnosis, and EGFR amplifications in 0% to 12%. Amplified KIT was more frequently present in recurrent gliomas than in newly diagnosed gliomas (P = 0.0066). KIT amplification was associated with KIT protein expression and with presence of PDGFRA and EGFR amplifications both at the time of the first glioma diagnosis and at tumor recurrence, and with VEGFR2 amplification at tumor recurrence. Three (4%) primary gliomas and 10 (14%) recurrent gliomas that were evaluable for coamplification of KIT, PDGFRA, and VEGFR2 showed amplification of at least two of these genes; the amplicon contained amplified KIT in all 13 cases. In conclusion, besides glioblastoma, amplified KIT, PDGFRA, and VEGFR may also occur in lower-grade gliomas and in their recurrent tumors. It is currently not known whether specific tyrosine kinase inhibitors are effective in the treatment of such gliomas. (Mol Cancer Res 2006;4(12):927–34)
- Published
- 2006
24. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis
- Author
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Bengt Nilsson, Lars-Gunnar Kindblom, Johanna Andersson, Jeanne M. Meis-Kindblom, Anders Odén, Nina N. Nupponen, Harri Sihto, Heikki Joensuu, Per Bümming, and Bengt Gustavsson
- Subjects
Adult ,Male ,Receptor, Platelet-Derived Growth Factor alpha ,Gastrointestinal Stromal Tumors ,Population ,DNA Mutational Analysis ,Mutation, Missense ,PDGFRA ,Biology ,medicine.disease_cause ,Risk Assessment ,Sensitivity and Specificity ,Cohort Studies ,03 medical and health sciences ,Exon ,0302 clinical medicine ,medicine ,Biomarkers, Tumor ,Missense mutation ,Humans ,Stromal tumor ,education ,030304 developmental biology ,Aged ,Probability ,Retrospective Studies ,0303 health sciences ,education.field_of_study ,Mutation ,Hepatology ,GiST ,Gastroenterology ,Exons ,Middle Aged ,Prognosis ,digestive system diseases ,3. Good health ,Gene Expression Regulation, Neoplastic ,Survival Rate ,genomic DNA ,Proto-Oncogene Proteins c-kit ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Gene Deletion - Abstract
Background & Aims: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor α ( PDGFRA ) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. Methods: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. Results:KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST ≤1 cm had mutations in 73% and 33%, respectively. KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST. KIT exon 11 deletions adversely affected outcome. KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively. Conclusions: KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST.
- Published
- 2005
25. Primary cutaneous T-cell lymphomas show a deletion or translocation affecting NAV3, the human UNC-53 homologue
- Author
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Bogusław Nedoszytko, Vesna Blazevic, Nina N. Nupponen, Hanna Nevala, Sonja Hahtola, Suvi Päivinen, Ying Zhou, Annamari Ranki, Pärt Peterson, Sanna Syrjä, Jadwiga Roszkiewicz, Ritva Karhu, Maria Pesonen, Inge Krebs, Kalle Saksela, Leena Karenko, Marketta Kähkönen, Harri Sihto, Tapio Visakorpi, Soili Kytölä, and Annemarie Poustka
- Subjects
Cancer Research ,Monosomy ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Tumor suppressor gene ,Chromosomal translocation ,Nerve Tissue Proteins ,Biology ,Translocation, Genetic ,medicine ,Humans ,Sezary Syndrome ,Gene Silencing ,Interphase ,Chromosome 12 ,Alleles ,In Situ Hybridization, Fluorescence ,Chromosome Aberrations ,Mycosis fungoides ,Chromosomes, Human, Pair 12 ,Cytogenetics ,Chromosome Mapping ,Membrane Proteins ,Chromosome Breakage ,medicine.disease ,Lymphoma ,Lymphoma, T-Cell, Cutaneous ,Oncology ,Cancer research ,Interleukin-2 ,Haploinsufficiency ,Gene Deletion - Abstract
Multicolor fluorescent in situ hybridization (FISH) was used to identify acquired chromosomal aberrations in 12 patients with mycosis fungoides or Sézary syndrome, the most common forms of primary cutaneous T-cell lymphoma (CTCL). The most frequently affected chromosome was 12, which showed clonal deletions or translocations with a break point in 12q21 or 12q22 in five of seven consecutive Sézary syndrome patients and a clonal monosomy in the sixth patient. The break point of a balanced translocation t(12;18)(q21;q21.2), mapped in the minimal common region of two deletions, fine mapped to 12q2. By locus-specific FISH, the translocation disrupted one gene, NAV3 (POMFIL1), a human homologue of unc-53 in Caenorhabditis elegans. A missense mutation in the remaining NAV3 allele was found in one of six cases with a deletion or translocation. With locus-specific FISH, NAV3 deletions were found in the skin lesions of four of eight (50%) patients with early mycosis fungoides (stages IA-IIA) and in the skin or lymph node of 11 of 13 (85%) patients with advanced mycosis fungoides or Sézary syndrome. Preliminary functional studies with lentiviral small interfering RNA-based NAV3 silencing in Jurkat cells and in primary lymphocytes showed enhanced interleukin 2 expression (but not CD25 expression). Thus, NAV3 may contribute to the growth, differentiation, and apoptosis of CTCL cells as well as to the skewing from Th1-type to Th2-type phenotype during disease progression. NAV3, a novel putative haploinsufficient tumor suppressor gene, is disrupted in most cases of the commonest types of CTCL and may thus provide a new diagnostic tool.
- Published
- 2005
26. Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers
- Author
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Virpi Launonen, Heikki Järvinen, Tuija Hienonen, Pia Alhopuro, Nina N. Nupponen, Heli J. Lehtonen, Bert Vogelstein, Auli Karhu, Susa Enholm, Reijo Salovaara, Diego Arango, Jukka-Pekka Mecklin, Lauri A. Aaltonen, Riitta Koistinen, Thomas D. Barber, Rainer Lehtonen, and Heli Sammalkorpi
- Subjects
Genome instability ,Cancer Research ,DNA Repair ,DNA repair ,Base Pair Mismatch ,Biology ,medicine.disease_cause ,Seminal Vesicle Secretory Proteins ,Genomic Instability ,Frameshift mutation ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,RNA, Messenger ,Mutation frequency ,Frameshift Mutation ,Alleles ,030304 developmental biology ,Genetics ,0303 health sciences ,Mutation ,Base Sequence ,Microsatellite instability ,DNA, Neoplasm ,medicine.disease ,Introns ,3. Good health ,Semenogelin I ,Oncology ,030220 oncology & carcinogenesis ,DNA mismatch repair ,Colorectal Neoplasms ,Microsatellite Repeats - Abstract
DNA mismatch repair (MMR)–deficient cells typically accumulate mutations in short repetitive DNA tracts. This microsatellite instability (MSI) facilitates malignant transformation when affecting genes with growth-related and caretaker functions. To date, several putative MSI target genes have been proposed mainly based on high mutation frequency within their coding regions. However, some intronic repeat mutations have also been suggested to associate with MSI tumorigenesis, indicating the need for additional analyses on noncoding repeats. Here we have analyzed an intronic T9 repeat of semenogelin I (SEMG1) and report mutation frequencies of 51% (75 of 146) and 62% (8 of 13) in MMR-deficient primary colorectal cancers and cell lines, respectively. The putative effect of the SEMG1 mutations was assessed by RNA and protein level analyses, but no differences were detected between colorectal cancer cell lines with different SEMG1 status. Subsequently, the general background mutation frequency of MSI colorectal cancers was assessed by screening for intergenic T9 repeat alterations. One of 10 examined repeats was mutated in 70% (102 of 145) of the colorectal cancers evaluated. The frequencies observed here are notably higher than previously published in noncoding repeats shorter than 10 bp in MMR-deficient primary tumors. Our results indicate that high mutation frequencies, similar or higher than those observed in proposed and approved target genes, can be detected in repeat tracts of MSI tumors without any apparent selection pressure. These data call for urgent and thorough large-scale evaluation of mutation frequencies in neutral short repetitive sequences in MMR-deficient tumors.
- Published
- 2005
27. No fumarate hydratase (FH) mutations in hereditary prostate cancer
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Johanna Schleutker, Julie M. Cunningham, Annika Rökman, Tarja Ikonen, D J Schaid, Mika P. Matikainen, Rainer Lehtonen, S. N. Thibodeau, Nina N. Nupponen, Auli Karhu, Lauri A. Aaltonen, O. P. Kallioniemi, and Maija Ht Kiuru
- Subjects
Male ,Somatic cell ,DNA Mutational Analysis ,Biology ,medicine.disease_cause ,Electronic Letter ,Germline ,Fumarate Hydratase ,Germline mutation ,Leiomyomatosis ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetics (clinical) ,Chromatography, High Pressure Liquid ,Mutation ,Papillary renal cell carcinomas ,Chromosome ,Prostatic Neoplasms ,DNA, Neoplasm ,Chromosomes, Human, Pair 1 ,Fumarase ,Cancer research ,Microsatellite Repeats - Abstract
Mutations in fumarate hydratase (fumarase, FH ), a nuclear gene encoding a mitochondrial tricarboxylic acid cycle or Krebs cycle protein also present in the cytosol, have recently been shown to predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC, OMIM 605839)1 or multiple cutaneous and uterine leiomyomatosis (MCL, OMIM 150800).2 In addition to leiomyomas of the skin and uterus, some subjects also develop papillary renal cell carcinoma of rare type II histology.3,4 Germline FH mutations were found in approximately 60% (24/42) of families segregating HLRCC.1 Mutations in FH have been recently observed in apparently sporadic tumours. In a series of lesions studied, one uterine leiomyosarcoma and one cutaneous leiomyoma harboured a germline mutation while one soft tissue sarcoma represented the first known purely somatic case.5 Homozygous germline FH mutations have been found to cause recessive fumarate hydratase deficiency (OMIM 136850).6–8 FH has been mapped to chromosome 1q43, between markers D1S2785 and D1S2842, within 500 kb of D1S2785. ### Key points
- Published
- 2003
28. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1
- Author
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P. Meltzer, A. M. De Marzo, Robert B. Jenkins, Ping Hu, Raman Sood, Katherine W. Klinger, Piroska Bujnovszky, Robert H. Silverman, Nina N. Nupponen, Galen Hostetter, Kathy E. Wiley, Tracy Moses, Joan E. Bailey-Wilson, Jeffrey R. Smith, Patrick C. Walsh, Johanna Schleutker, Deborah A. Meyers, Izabela Makalowska, Agnes Baffoe-Bonnie, Sarah D. Isaacs, E. Gillanders, Henrik Grönberg, Robert D. Burk, John D. Carpten, Jeffrey M. Trent, Ying Xiang, Dennis A. Faith, Christiane M. Robbins, Derek Gildea, Timothy D. Connors, Dietrich A. Stephan, W. Isaacs, Mike Brownstein, Mezbah U. Faruque, Zhaocheng Wang, Nickolas Papadopoulos, Brian Kelly, Mika P. Matikainen, Jianfeng Xu, O. P. Kallioniemi, and Charles M. Ewing
- Subjects
Male ,Candidate gene ,Heterozygote ,Positional cloning ,Genetic Linkage ,Nonsense mutation ,DNA Mutational Analysis ,Loss of Heterozygosity ,Biology ,urologic and male genital diseases ,Loss of heterozygosity ,Germline mutation ,Endoribonucleases ,Genetics ,Humans ,Lymphocytes ,Germ-Line Mutation ,Oligoribonucleotides ,Base Sequence ,Adenine Nucleotides ,Homozygote ,RNASEL Gene ,Prostatic Neoplasms ,DNA, Neoplasm ,Oncogenes ,Candidate Tumor Suppressor Gene ,Pedigree ,Case-Control Studies ,biology.protein ,Female ,Ribonuclease L - Abstract
Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States1,2, little is known about inherited factors that influence its genetic predisposition3,4,5. Here we report that germline mutations in the gene encoding 2′-5′-oligoadenylate(2-5A)–dependent RNase L (RNASEL)6,7,8 segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24–25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene10,11,12. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.
- Published
- 2002
29. Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer
- Author
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Christiane M. Robbins, Siqun L. Zheng, Juanita D Mestre, Tracy Moses, Dennis A. Faith, Bao Li Chang, Joan E. Bailey-Wilson, Nina N. Nupponen, John D. Carpten, Piroska Bujnovszky, Jeffrey M. Trent, Patrick C. Walsh, Kathleen E. Wiley, Jianfeng Xu, William B. Isaacs, Deborah A. Meyers, Sarah D. Isaacs, Brian Kelly, Eugene R. Bleecker, and Charles M. Ewing
- Subjects
Proband ,Male ,Genotype ,Genetic Linkage ,Population ,DNA Mutational Analysis ,Penetrance ,Biology ,Polymorphism, Single Nucleotide ,White People ,Prostate cancer ,Gene Frequency ,medicine ,Genetics ,Humans ,Genetics(clinical) ,Genetic Predisposition to Disease ,Genetic Testing ,Allele ,Age of Onset ,education ,Allele frequency ,Genetics (clinical) ,Alleles ,Genetic association ,education.field_of_study ,Genetic heterogeneity ,Prostatic Neoplasms ,Exons ,Articles ,medicine.disease ,Neoplasm Proteins ,Pedigree ,Amino Acid Substitution ,Mutation ,Lod Score ,Chromosomes, Human, Pair 17 ,Microsatellite Repeats - Abstract
To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer–susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer–modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.
- Published
- 2000
30. Amplification and Overexpression of p40 Subunit of Eukaryotic Translation Initiation Factor 3 in Breast and Prostate Cancer
- Author
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Kati P. Porkka, Åke Borg, Minna Tanner, Nina N. Nupponen, Karin Persson, Tapio Visakorpi, Laura Kakkola, and Jorma Isola
- Subjects
Male ,Gene Dosage ,Genes, myc ,Gene Expression ,Breast Neoplasms ,Prokaryotic Initiation Factor-3 ,Biology ,medicine.disease_cause ,Gene dosage ,Pathology and Forensic Medicine ,Prostate cancer ,Eukaryotic translation ,Peptide Initiation Factors ,Gene duplication ,medicine ,Tumor Cells, Cultured ,Initiation factor ,Humans ,RNA, Messenger ,In Situ Hybridization, Fluorescence ,medicine.diagnostic_test ,Subtraction hybridization ,Carcinoma ,Gene Amplification ,Chromosome Mapping ,Prostatic Neoplasms ,medicine.disease ,Blotting, Northern ,Cancer research ,Female ,Carcinogenesis ,Fluorescence in situ hybridization ,Regular Articles ,Chromosomes, Human, Pair 8 - Abstract
Amplification at the long arm of chromosome 8 occurs in a large fraction of breast and prostate cancers. To clone the target genes for this amplification, we used suppression subtraction hybridization to identify overexpressed genes in the breast cancer cell line SK-Br-3, which harbors amplification at 8q (8q21 and 8q23-q24). A differentially expressed gene identified by SSH, the p40 subunit of eukaryotic translation initiation factor 3 (eIF3), was localized to 8q23 and found to be highly amplified and overexpressed in the breast and prostate cancer cell lines studied. High-level amplification of eIF3-p40 was found in 30% of hormone-refractory prostate tumors and in 18% of untreated primary breast tumors. In the vast majority of the cases, p40 and c-myc were amplified with equal copy numbers. Tumors with higher copy numbers of p40 than c-myc were also found. Expression of p40 mRNA was analyzed with in situ hybridization. The amplification of eIF3-p40 gene was associated with overexpression of its mRNA, as expected for a functional target gene of the amplification. These results imply that genomic aberrations of translation initiation factors, such as eIF3-p40, may contribute to the pathogenesis of breast and prostate cancer.
- Published
- 1999
31. Identification of a novel transcription factorlike gene repressed during TGF-B induced human intestinal epithelial cell differentiation
- Author
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Nina N. Nupponen, Katri Lindfors, Tapio Visakorpi, Tuula Halttunen, Markku Mäki, Mauno Vihinen, and Heikki Kainulainen
- Subjects
Hepatology ,Transcription (biology) ,Gastroenterology ,Intestinal epithelial cell differentiation ,Biology ,CDX2 ,Gene ,Cell biology - Published
- 2000
32. Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors
- Author
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Heikki Järvinen, Lauri A. Aaltonen, Leena-Maija Aaltonen, Pasi A. Koivisto, Charis Eng, Ralf Bützow, Nina N. Nupponen, Auli Karhu, Virpi Launonen, Päivi Peltomäki, Johanna Arola, Reijo Salovaara, Maija Ht Kiuru, Kristiina Aittomäki, Jukka-Pekka Mecklin, Jari Sjöberg, Jorma Isola, Rainer Lehtonen, Kirsti Husgafvel-Pursiainen, Sakari Vanharanta, and Veli Matti Wasenius
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Somatic cell ,Short Communication ,DNA Mutational Analysis ,Loss of Heterozygosity ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,Pathology and Forensic Medicine ,Fumarate Hydratase ,Loss of heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Leiomyomatosis ,Germline mutation ,medicine ,Missense mutation ,Humans ,Uterine Neoplasm ,Carcinoma, Renal Cell ,Chromatography, High Pressure Liquid ,030304 developmental biology ,0303 health sciences ,Base Sequence ,Leiomyoma ,3. Good health ,030220 oncology & carcinogenesis ,Mutation ,Uterine Neoplasms ,Hereditary leiomyomatosis and renal cell carcinoma ,Female ,Carcinogenesis - Abstract
Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.
33. Gene expression signatures for colorectal cancer microsatellite status and HNPCC
- Author
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Lise-Lotte Christensen, Mecklin Jp, Friedrik P. Wikman, Karin Birkenkamp-Demtröder, Lars Dyrskjøt, Torben F. Ørntoft, Claus L. Andersen, Flemming Brandt Sørensen, Heikki Järvinen, Mogens Kruhøffer, Matti Juhola, Diego Arango, Jens Ledet Jensen, Søren Laurberg, Bech-Knudsen F, Line Buhl, Thomas Thykjaer, Päivi Laiho, Reijo Salovaara, Nina N. Nupponen, and Lauri A. Aaltonen
- Subjects
Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,DNA Repair ,Base Pair Mismatch ,Colorectal cancer ,DNA repair ,HNPCC ,Gene Expression ,Adenocarcinoma ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Chromosomal Instability ,Chromosome instability ,medicine ,Humans ,Aged ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,Aged, 80 and over ,Genetics ,0303 health sciences ,Gene Expression Profiling ,Microsatellite instability ,Genetics and Genomics ,Middle Aged ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,3. Good health ,Gene expression profiling ,colon cancer ,Oncology ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Cancer research ,Microsatellite ,microsatellite instability ,DNA mismatch repair ,Microsatellite Repeats - Abstract
The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.
34. Melflufen, a peptide-conjugated alkylator, is an efficient anti-neo-plastic drug in breast cancer cell lines.
- Author
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Schepsky A, Traustadottir GA, Joelsson JP, Ingthorsson S, Kricker J, Bergthorsson JT, Asbjarnarson A, Gudjonsson T, Nupponen N, Slipicevic A, Lehmann F, and Gudjonsson T
- Subjects
- Animals, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, CD13 Antigens genetics, CD13 Antigens metabolism, Cell Line, Tumor, Chick Embryo, DNA Damage, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases genetics, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases metabolism, Female, Gene Expression Regulation, Neoplastic, Histones metabolism, Humans, Leucyl Aminopeptidase genetics, Leucyl Aminopeptidase metabolism, Melphalan pharmacology, Phenylalanine pharmacology, Signal Transduction, Tumor Suppressor p53-Binding Protein 1 genetics, Tumor Suppressor p53-Binding Protein 1 metabolism, Antineoplastic Agents, Alkylating pharmacology, Breast Neoplasms drug therapy, Melphalan analogs & derivatives, Phenylalanine analogs & derivatives
- Abstract
Melphalan flufenamide (hereinafter referred to as "melflufen") is a peptide-conjugated drug currently in phase 3 trials for the treatment of relapsed or refractory multiple myeloma. Due to its lipophilic nature, it readily enters cells, where it is converted to the known alkylator melphalan leading to enrichment of hydrophilic alkylator payloads. Here, we have analysed in vitro and in vivo the efficacy of melflufen on normal and cancerous breast epithelial lines. D492 is a normal-derived nontumorigenic epithelial progenitor cell line whereas D492HER2 is a tumorigenic version of D492, overexpressing the HER2 oncogene. In addition we used triple negative breast cancer cell line MDA-MB231. The tumorigenic D492HER2 and MDA-MB231 cells were more sensitive than normal-derived D492 cells when treated with melflufen. Compared to the commonly used anti-cancer drug doxorubicin, melflufen was significantly more effective in reducing cell viability in vitro while it showed comparable effects in vivo. However, melflufen was more efficient in inhibiting metastasis of MDA-MB231 cells. Melflufen induced DNA damage was confirmed by the expression of the DNA damage proteins ƴH2Ax and 53BP1. The effect of melflufen on D492HER2 was attenuated if cells were pretreated with the aminopeptidase inhibitor bestatin, which is consistent with previous reports demonstrating the importance of aminopeptidase CD13 in facilitating melflufen cleavage. Moreover, analysis of CD13
high and CD13low subpopulations of D492HER2 cells and knockdown of CD13 showed that melflufen efficacy is mediated at least in part by CD13. Knockdown of LAP3 and DPP7 aminopeptidases led to similar efficacy reduction, suggesting that also other aminopeptidases may facilitate melflufen conversion. In summary, we have shown that melflufen is a highly efficient anti-neoplastic agent in breast cancer cell lines and its efficacy is facilitated by aminopeptidases., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)- Published
- 2020
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35. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis.
- Author
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Andersson J, Bümming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, Odén A, Gustavsson B, Kindblom LG, and Nilsson B
- Subjects
- Adult, Aged, Biomarkers, Tumor, Cohort Studies, DNA Mutational Analysis, Exons genetics, Female, Gastrointestinal Stromal Tumors therapy, Gene Deletion, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Probability, Prognosis, Retrospective Studies, Risk Assessment, Sensitivity and Specificity, Survival Rate, Gastrointestinal Stromal Tumors genetics, Gastrointestinal Stromal Tumors mortality, Mutation, Missense, Proto-Oncogene Proteins c-kit genetics, Receptor, Platelet-Derived Growth Factor alpha genetics
- Abstract
Background & Aims: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up., Methods: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing., Results: KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST =1 cm had mutations in 73% and 33%, respectively. KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST. KIT exon 11 deletions adversely affected outcome. KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively., Conclusions: KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST.
- Published
- 2006
- Full Text
- View/download PDF
36. Primary cutaneous T-cell lymphomas show a deletion or translocation affecting NAV3, the human UNC-53 homologue.
- Author
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Karenko L, Hahtola S, Päivinen S, Karhu R, Syrjä S, Kähkönen M, Nedoszytko B, Kytölä S, Zhou Y, Blazevic V, Pesonen M, Nevala H, Nupponen N, Sihto H, Krebs I, Poustka A, Roszkiewicz J, Saksela K, Peterson P, Visakorpi T, and Ranki A
- Subjects
- Alleles, Chromosome Breakage, Chromosome Mapping, Chromosomes, Human, Pair 12 genetics, Gene Silencing, Humans, In Situ Hybridization, Fluorescence, Interleukin-2 biosynthesis, Interphase genetics, Lymphoma, T-Cell, Cutaneous metabolism, Membrane Proteins biosynthesis, Nerve Tissue Proteins biosynthesis, Sezary Syndrome genetics, Translocation, Genetic, Chromosome Aberrations, Gene Deletion, Lymphoma, T-Cell, Cutaneous genetics, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Skin Neoplasms genetics
- Abstract
Multicolor fluorescent in situ hybridization (FISH) was used to identify acquired chromosomal aberrations in 12 patients with mycosis fungoides or Sézary syndrome, the most common forms of primary cutaneous T-cell lymphoma (CTCL). The most frequently affected chromosome was 12, which showed clonal deletions or translocations with a break point in 12q21 or 12q22 in five of seven consecutive Sézary syndrome patients and a clonal monosomy in the sixth patient. The break point of a balanced translocation t(12;18)(q21;q21.2), mapped in the minimal common region of two deletions, fine mapped to 12q2. By locus-specific FISH, the translocation disrupted one gene, NAV3 (POMFIL1), a human homologue of unc-53 in Caenorhabditis elegans. A missense mutation in the remaining NAV3 allele was found in one of six cases with a deletion or translocation. With locus-specific FISH, NAV3 deletions were found in the skin lesions of four of eight (50%) patients with early mycosis fungoides (stages IA-IIA) and in the skin or lymph node of 11 of 13 (85%) patients with advanced mycosis fungoides or Sézary syndrome. Preliminary functional studies with lentiviral small interfering RNA-based NAV3 silencing in Jurkat cells and in primary lymphocytes showed enhanced interleukin 2 expression (but not CD25 expression). Thus, NAV3 may contribute to the growth, differentiation, and apoptosis of CTCL cells as well as to the skewing from Th1-type to Th2-type phenotype during disease progression. NAV3, a novel putative haploinsufficient tumor suppressor gene, is disrupted in most cases of the commonest types of CTCL and may thus provide a new diagnostic tool.
- Published
- 2005
- Full Text
- View/download PDF
37. Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy.
- Author
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Painter JN, Savander M, Ropponen A, Nupponen N, Riikonen S, Ylikorkala O, Lehesjoki AE, and Aittomäki K
- Subjects
- Cholestasis, Intrahepatic epidemiology, Exons, Female, Genetic Linkage genetics, Genotype, Haplotypes genetics, Heterozygote, Humans, Male, Pregnancy, Pregnancy Complications epidemiology, Adenosine Triphosphatases genetics, Cholestasis, Intrahepatic genetics, Genetic Heterogeneity, Pregnancy Complications etiology
- Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic condition that may affect women during the third trimester of pregnancy. Symptoms experienced by these women generally resolve spontaneously following delivery, but prior to delivery the fetus is at increased risk of intrauterine distress and sudden intrauterine death. The genetic etiology of most cases of ICP is unknown, although heterozygous carriers of mutations causing progressive familial intrahepatic cholestasis (PFIC) diseases may experience ICP. When examining linkage to known cholestasis genes, affected members of four Finnish ICP families shared haplotypes around ATP8B1, the gene responsible for PFIC1. This gene was subsequently screened in 176 familial and sporadic ICP patients. A total of 17 sequence changes were detected, five exonic and 12 intronic. No intronic change was associated with ICP in sporadic cases. Four intronic changes segregated with ICP in three families, a different change in each of two families and three changes in another family, although the significance of this is currently unknown. Three exonic changes were nonsynonymous, one (in exon 23) is probably a polymorphism while two predict novel amino-acid replacements (N45T and K203R). These changes, in exons 2 and 7, were detected in one individual each, and may have predisposed these individuals to ICP. In conclusion, although the exon 2 and 7 changes may have functioned as risk alleles, ATP8B1 is probably not a major gene contributing to the occurrence of ICP.
- Published
- 2005
- Full Text
- View/download PDF
38. Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer.
- Author
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Rökman A, Ikonen T, Seppälä EH, Nupponen N, Autio V, Mononen N, Bailey-Wilson J, Trent J, Carpten J, Matikainen MP, Koivisto PA, Tammela TL, Kallioniemi OP, and Schleutker J
- Subjects
- Age of Onset, DNA Mutational Analysis, Endoribonucleases chemistry, Female, Finland, Gene Frequency, Humans, Male, Mutation, Missense genetics, Pedigree, Prostatic Neoplasms enzymology, Prostatic Neoplasms epidemiology, Prostatic Neoplasms pathology, Chromosomes, Human, Pair 1 genetics, Endoribonucleases genetics, Germ-Line Mutation genetics, Polymorphism, Single-Stranded Conformational, Prostatic Neoplasms genetics
- Abstract
The RNASEL gene (2',5'-oligoisoadenylate-synthetase dependent) encodes a ribonuclease that mediates the antiviral and apoptotic activities of interferons. The RNASEL gene maps to the hereditary-prostate-cancer (HPC)-predisposition locus at 1q24-q25 (HPC1) and was recently shown to harbor truncating mutations in two families with linkage to HPC1. Here, we screened for RNASEL germline mutations in 66 Finnish patients with HPC, and we determined the frequency of the changes in the index patients from 116 families with HPC, in 492 patients with unselected prostate cancer (PRCA), in 223 patients with benign prostatic hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X, was found in 5 (4.3%) of the 116 patients from families with HPC. This was significantly higher (odds ratio [OR] =4.56; P=.04) than the frequency of E265X in controls (1.8%). The highest mutation frequency (9.5%) was found in patients from families with four or more affected members. Possible segregation was detected only in a single family. However, the median age at disease onset for E265X carriers was 11 years less than that for noncarriers in the same families. In addition, of the four missense variants found, R462Q showed an association with HPC (OR=1.96; P=.07). None of the variants showed any differences between controls and either patients with BPH or patients with PRCA. We conclude that, although RNASEL mutations do not explain disease segregation in Finnish families with HPC, the variants are enriched in families with HPC that include more than two affected members and may also be associated with the age at disease onset. This suggests a possible modifying role in cancer predisposition. The impact that the RNASEL sequence variants have on PRCA burden at the population level seems small but deserves further study.
- Published
- 2002
- Full Text
- View/download PDF
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