Genomic landscape of human melanoma progression  Page description

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Details of project

 
Identifier
112371
Type K
Principal investigator Tímár, József
Title in Hungarian Az emberi melanóma progressziójának genomikai elemzése
Title in English Genomic landscape of human melanoma progression
Keywords in Hungarian bőr melanóma, exome analízis, kópiaszám variáció, klonális fejlődés, áttétképzés
Keywords in English skin melanoma, exome analysis, copy number variation, clonal progression, metastasis
Discipline
Public health, health services, environmental and occupational medicine, epidemiology, medical ethics (Council of Medical and Biological Sciences)50 %
Ortelius classification: Oncology
Genomics, comparative genomics, functional genomics (Council of Medical and Biological Sciences)50 %
Panel Genetics, Genomics, Bioinformatics and Systems Biology
Department or equivalent Dept. of Pathology (Semmelweis University)
Participants Balázs, Margit
Bálint, Bálint László
Barbai, Tamás
Bugyik, Edina
Enyedi, Ágnes
Garay, Tamás Márton
Kenessey, István
Rásó, Erzsébet
Vízkeleti, Laura
Starting date 2015-01-01
Closing date 2019-12-31
Funding (in million HUF) 39.704
FTE (full time equivalent) 7.47
state running project





 

Final report

 
Results in Hungarian
Meghatároztuk a BRAF- (46%), NRAS- (20%) és KIT mutációs incidenciát (15%) melanómában. Melanoma metasztázis biobank elemzésével megállapítottuk hogy a BRAF (de nem az NRAS) mutáns allél frekvencia szignifikánsan magasabb az áttétekben aminek hátterében a BRAF gén kópiaszám emelkedése áll. Agyi áttétekben a DNS károsodást kijavító gének kópiaszám fokozódását észleltük. Megállapítottuk hogy az agyi áttétet képező melanómákban fokozott az AQP1 fehérje expresszió aminek hátterében a gén sokszorozódása áll. Tüdőáttétekben fokozott CCL8 expressziót észleltünk amit miR aberrációk okoznak. BRAF mutáns melanómás betegek gyakran rezisztenssé válnak BRAF inhibitorra aminek hátterében fokozott EGFR expressziót és EGFR génsokszorozódást mutattunk ki. A rezisztenciát azonban EGFR inhibitor kombinációs terápiával fel lehetett függeszteni in vitro. Azt figyeltük meg hogy az NRAS mutáns melanómák érzékenyek preniláció gátló szerek iránt (zoledronsav és BHP1222). A HIF1a konstitutívan aktív humán melanómákban. Kimutattuk hogy ZnSO4 kezeléssel blokkolni lehet a HIF1a expressziót aminek következménye az áttétképző képesség csökkenése preklinikai modellben. A melanómás betegek gyakran rezisztensek az immunterápiára aminek egyik mechanizmusa az IFN-jelpálya funkcionális zavara. Modelleztük az IFN rezisztenciát kisérleti modellben és meghatároztunk egy 32-génes IFN rezisztencia génmintázatot.
Results in English
We have identified Hungarian skin melanoma mutation incidence of BRAF (46%), NRAS (20%) and KIT (15%). We have found in metastatic melanoma that BRAF (but not NRAS) mutant allele frequency increased significantly in metastases due to the copy number gain of BRAF. Using a large metastatic melanoma biobank we were able to identify organ metastasis specific chromosomal alterations. In brain metastases we found copy number gains of genes involved in DNA damage responses. Furthermore, we found AQP1 protein overexpression in brain metastatic melanoma which was due also to copy number gain of the gene. In lung metastatic melanoma we have detected CCL8 overexpression linked to regulatory miR alteration. BRAF inhibitor resistance is a serious clinical problem in BRAF mutant melanoma patients. We found that it is partially due to EGFR overexpression (again due to CNA) which can be overcome by EGFR-inhibitor combination therapy. We have also found that NRAS mutant melanoma is sensitive to prenylation inhibitors zoledronic acid and BHP1222. HIF1a is constitutively active in melanoma. We have detected that HIF1a expression can be selectively inhibitied by ZnSO4 which results in decreased metastatic potential. Immunotherapy resistance is also a significant clinical problem frequently due to IFN-signaling abnormalities. We have established an in vitro model of IFN-resistance of human melanoma and determined a 32-gene signature.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=112371
Decision
Yes





 

List of publications

 
Doma V, Barbai T, Beleaua MA, Kovalszky I, Raso E, Tímár J.: KIT mutation incidence and pattern of melanoma in central East Europe., Pathol Oncol Res, 2019
Doma V, Karpati S, Raso E, Barbai T, Tímár J: Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma, BMC Cancer 19:786, 2019
Rittler D, Baranyi M, Molnar E, Garay T, Jalsowsky I, Varga I, Hegedus B, Aigner C, Tóvári J, Tímár J.: The antitumor effect of lipophyllic bisphosphonate PHP1222in melanoma models, Int J Mol Sci 20:e4917, 2019
Molnar E, Garay T, Donia M, Baranyi M, Rittler D, Berger W, Timar J: Long term vemurafenib exposure induced alterations of cell phenotypes in melanoma, Int J Mol Sci 20:e4484,2019, 2019
Ladanyi A, Timar J: Immunologic and immunogenomic aspects of tumor progression, Sem Cancer Biol ePUB ahead, 2019
Tímár J, Hegedűs B, Rásó E: The role of lipid signaling in the progression of malignant melanoma, CANCER METAST REV published online 28 May 2018: pp. 1-11., 2018
Kenessey I, Koi K, Horvath O, Cserepes M, Molnar D, Izsak V, Dobos J, Hegedűs B, Tovari J, Timar J: KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models, ONCOTARGET 7: (48) pp. 79503-79514., 2016
Timar J, Vizkeleti L, Doma V, Barbai T, Raso E: Genetic progression of malignant melanoma, CANCER METAST REV 35: (1) pp. 93-107., 2016
Tímár J, Hegedűs B, Rásó E: The role of lipid signaling in the progression of malignant melanoma, CANCER METAST REV published online 28 May 2018: pp. 1-11., 2018
Tímár J, Hegedűs B, Rásó E: The role of lipid signaling in the progression of malignant melanoma, CANCER METAST REV published online 28 May 2018: pp. 1-11., 2018
Kenessey I, Koi K, Horvath O, Cserepes M, Molnar D, Izsak V, Dobos J, Hegedűs B, Tovari J, Timar J: KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models, ONCOTARGET 7: (48) pp. 79503-79514., 2016
Timar J, Vizkeleti L, Doma V, Barbai T, Raso E: Genetic progression of malignant melanoma, CANCER METAST REV 35: (1) pp. 93-107., 2016
Tímár J, Hegedűs B, Rásó E: The role of lipid signaling in the progression of malignant melanoma, CANCER METAST REV published online 28 May 2018: pp. 1-11., 2018
Timar J, Vizkeleti L, Doma V, Barbai T, Raso E: Genetic progression of malignant melanoma, CANCER METAST REV 35: (1) pp. 93-107., 2016
Tímár J, Hegedűs B, Rásó E: The role of lipid signaling in the progression of malignant melanoma, CANCER METAST REV published online 28 May 2018: pp. 1-11., 2018
Timar J, Vizkeleti L, Doma V, Barbai T, Raso E: Genetic progression of malignant melanoma, CANCER METAST REV 35: (1) pp. 93-107., 2016
Tímár J, Hegedűs B, Rásó E: The role of lipid signaling in the progression of malignant melanoma, CANCER METAST REV published online 28 May 2018: pp. 1-11., 2018
Timar J, Vizkeleti L, Doma V, Barbai T, Raso E: Genetic progression of malignant melanoma, CANCER METAST REV 35: (1) pp. 93-107., 2016
Barbai T, Fejős Zs, Puskas LG, Tímár J, Rásó E.: The importance of microenvironment: the role of CCL8 in meltastasis formation of melanoma., Oncotarget 6: 29111-29128,2015, 2015
Kiss T, Ecsedi S, Vizkeleti L, Koroknai V, Emri G, Kovács N, Ádány R, Balázs M.: The role of osteopontin expression in melanoma progression., Tumor Biol 36: 7841-7847, 2015, 2015
Koroknai V, Ecsedi S, Vizkeleti L, Kiss T, Szász I, Lukács A, Papp O, Ádány R, Balázs M.: Genomic profiling of invasive melanoma cell lines by array comparative genomic hybridization., Melanoma Res 2015 (epub), 2015
Barbai T, Fejős Zs, Puskas LG, Tímár J, Rásó E.: The importance of microenvironment: the role of CCL8 in meltastasis formation of melanoma., Oncotarget 6: 29111-29128, 2015
Kiss T, Ecsedi S, Vizkeleti L, Koroknai V, Emri G, Kovács N, Ádány R, Balázs M.: The role of osteopontin expression in melanoma progression., Tumor Biol 36: 7841-7847, 2015, 2015
Koroknai V, Ecsedi S, Vizkeleti L, Kiss T, Szász I, Lukács A, Papp O, Ádány R, Balázs M.: Genomic profiling of invasive melanoma cell lines by array comparative genomic hybridization., Melanoma Res 26: 100-107, 2016
Timar J, Vizkeleti L, Doma V, Barbai T, Raso E: Genetic progression of malignant melanoma, CANCER METAST REV 35: (1) 93-107, 2016
Imrédi E, Tóth B, Doma V, Barbai T, Rásó E, Kenessey I, Tímár J: Aquaporin 1 protein expression is associated with BRAF V600 mutation and adverse prognosis in cutaneous melanoma, Melanoma Research 26: 254-260, 2016
Imredi E, Toth B, Doma V, Barbai T, Raso E, Kenessey I, Timar J: Aquaporin 1 protein expression is associated with BRAF V600 mutation and adverse prognosis in cutaneous melanoma., MELANOMA RES 26: (3) 254-260, 2016
Timar J, Vizkeleti L, Doma V, Barbai T, Raso E: Genetic progression of malignant melanoma, CANCER METAST REV 35: (1) 93-107, 2016
Barbai T, Fejos Z, Puskas LG, Timar J, Raso E: The importance of microenvironment: the role of CCL8 in metastasis formation of melanoma, ONCOTARGET 6: (30) 29111-29128, 2015
Kiss T, ecsedi S, Vizkeleti L, Koroknai V, Emri G, Kovács N, Ádány R, Balázs M.: The role of osteopontin expression in melanoma progression, Tumor Biology 36:7841-7847, 2015
Koroknai V, Ecsedi S, Vizkeleti L, Kiss T, Szász I, KLukács A, Papp O, Ádány R, Balázs M.: Genomic profiling of invasive melanoma cell lines by array comparative genomic hybridization., Melanoma Research 26:100-107, 2016
Timar J, Vizkeleti L, Doma V, Barbai T, Raso E: Genetic progression of malignant melanoma, CANCER METAST REV 35: (1) 93-107, 2016
Timar J, Hegedüs B, Rásó E.: The role of lipid signaling in the progression of malignant melanoma, Cancer Metastasis Rev 37:245-255, 2018
Kenessey I, Kramer Zs, Istvan L, Cserepes M, Garay T, Hegedus B, Dobos J, Tímár J, Tóvári J: Inhibition of EGFR imporves antitumor efficacy of vemurafenib in BRAF-mutatnt human melanoma in preclinical model, Melanoma Res 28:536-546, 2018
Imredi E, Tóth B, Doma V, barbai T, Rásó E, Kenessey I, Tímár J.: Aquaporin1 protein expression of the primary tumor may predict cerebral progression of cutaneous melanoma, Pathol Oncol Res epub, 2018
Burian Z, Ladanyi A, Barbai T, piurko V, Garay T, Raso E, Timar J.: Selective inhibition of HIF1a expression by ZnSO4 has antitumoral effects in human melanoma, Pathol Oncol Res epub, 2019
Hegedus L, Padanyi R, Molnar J, Paszty K, Varga K, Kenessey I, Sáarkozy E, Wolf M, Grusch M, Hegyi Z. Homolya L, Aigner C, Garay T, Hegedus B, Timar J, Kallay E, Enyedi A: Histone deacetylase inhibitor treatment increases the expression of the plasma membrane Ca pumpPMCA4a and inhibits migration of melanoma cells independent of ERK., Future Oncol 7:95, 2017





 

Events of the project

 
2019-05-27 15:43:11
Résztvevők változása
2017-03-14 12:47:18
Résztvevők változása




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