TY - JOUR AU - Prosz, Aurel AU - Sahgal, Pranshu AU - Huffman, Brandon M AU - Sztupinszki, Zsofia AU - Morris, Clare X AU - Chen, David AU - Börcsök, Judit AU - Diossy, Miklos AU - Tisza, Viktoria AU - Spisák, Sándor AU - Likasitwatanakul, Pornlada AU - Rusz, Orsolya AU - Csabai, István AU - Cecchini, Michael AU - Baca, Yasmine AU - Elliot, Andrew AU - Enzinger, Peter AU - Singh, Harshabad AU - Ubellaker, Jessalyn AU - Lazaro, Jean-Bernard AU - Cleary, James M AU - Szállási, Zoltán AU - Sethi, Nilay S TI - Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting. JF - NPJ PRECISION ONCOLOGY J2 - NPJ PRECIS ONCOL VL - 8 PY - 2024 IS - 1 PG - 14 SN - 2397-768X DO - 10.1038/s41698-024-00561-6 UR - https://m2.mtmt.hu/api/publication/34779369 ID - 34779369 AB - Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in cancer. HR-deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of HR deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Using whole exome and genome sequencing data, we found that a significant subset of GEA, but very few colorectal adenocarcinomas, show evidence of HR deficiency by mutational signature analysis (HRD score). High HRD gastric cancer cell lines demonstrated functional HR deficiency by RAD51 foci assay and increased sensitivity to platinum chemotherapy and PARP inhibitors. Of clinical relevance, analysis of three different GEA patient cohorts demonstrated that platinum treated HR deficient cancers had better outcomes. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by two photoproduct repair assays. Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors. LA - English DB - MTMT ER - TY - JOUR AU - Pipek, Orsolya Anna AU - Alpár, Donát AU - Rusz, Orsolya AU - Bödör, Csaba AU - Udvarnoki, Zoltán András AU - Medgyes-Horváth, Anna AU - Csabai, István AU - Szállási, Zoltán AU - Madaras, Lilla AU - Kahán, Zsuzsanna AU - Cserni, Gábor AU - Kővári, Bence AU - Kulka, Janina AU - Tőkés, Anna-Mária TI - Genomic Landscape of Normal and Breast Cancer Tissues in a Hungarian Pilot Cohort JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 10 PG - 19 SN - 1661-6596 DO - 10.3390/ijms24108553 UR - https://m2.mtmt.hu/api/publication/33814839 ID - 33814839 N1 - Funding Agency and Grant Number: NKFIH, Hungary [FK20-134253, K21-137948, TKP2021-EGA-24, TKP2021-NVA-15, NVKP-16-1-2016-0004]; EU's Horizon 2020 research and innovation program [739593]; Janos Bolyai Research Scholarship program of the Hungarian Academy of Sciences [BO/00125/22]; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-22-5-SE-7]; Complementary Research Excellence Program; Kerpel Talent Award of Semmelweis University [EFOP-3.6.3-VEKOP-16-2017-00009]; ELIXIR Hungary Funding text: This study was supported by the following grants: NKFIH, Hungary: FK20-134253, K21-137948, TKP2021-EGA-24, TKP2021-NVA-15 and NVKP-16-1-2016-0004. The study was also supported by the EU's Horizon 2020 research and innovation program (No. 739593), the Janos Bolyai Research Scholarship program (BO/00125/22) of the Hungarian Academy of Sciences, the UNKP-22-5-SE-7 grant of the New National Excellence Program of the Ministry for Innovation and Technology, by the Complementary Research Excellence Program, the Kerpel Talent Award of Semmelweis University (EFOP-3.6.3-VEKOP-16-2017-00009), and the ELIXIR Hungary. AB - A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. We validated a subset of the identified variants at the DNA level using the Illumina TruSight Oncology (TSO) 500 assay. Canonical breast-cancer-associated genes with pathogenic germline mutations were CHEK2 and ATM. Nearly all the observed germline mutations were as frequent in the Hungarian breast cancer cohort as in independent European populations. The majority of the detected somatic short variants were single-nucleotide polymorphisms (SNPs), and only 8% and 6% of them were deletions or insertions, respectively. The genes most frequently affected by somatic mutations were KMT2C (31%), MUC4 (34%), PIK3CA (18%), and TP53 (34%). Copy number alterations were most common in the NBN, RAD51C, BRIP1, and CDH1 genes. For many samples, the somatic mutational landscape was dominated by mutational processes associated with homologous recombination deficiency (HRD). Our study, as the first breast tumor/normal sequencing study in Hungary, revealed several aspects of the significantly mutated genes and mutational signatures, and some of the copy number variations and somatic fusion events. Multiple signs of HRD were detected, highlighting the value of the comprehensive genomic characterization of breast cancer patient populations. LA - English DB - MTMT ER - TY - JOUR AU - Szeitz, Beáta AU - Pipek, Orsolya Anna AU - Kulka, Janina AU - Szundi, Csilla AU - Rusz, Orsolya AU - Tőkés, Tímea AU - Szász, Attila Marcell AU - Kovács, Attila AU - Pesti, Adrián István AU - Ben Arie, Taya Beri AU - Gángó, Ambrus AU - Fülöp, Zsolt AU - Drágus, Emőke AU - Vári-Kakas, Stefan A. AU - Tőkés, Anna-Mária TI - Investigating the Prognostic Relevance of Tumor Immune Microenvironment and Immune Gene Assembly in Breast Carcinoma Subtypes JF - CANCERS J2 - CANCERS VL - 14 PY - 2022 IS - 8 PG - 22 SN - 2072-6694 DO - 10.3390/cancers14081942 UR - https://m2.mtmt.hu/api/publication/32793328 ID - 32793328 LA - English DB - MTMT ER - TY - JOUR AU - Kim, Jewel Ju Ea AU - Kocsmár, Ildikó AU - Buzás, György Miklós AU - Szirtes, Ildikó AU - Rusz, Orsolya AU - Diczházi, Csaba AU - Szijártó, Attila AU - Hritz, István AU - Schaff, Zsuzsa AU - Kiss, András AU - Kocsmár, Éva AU - Lotz, Gábor TI - Efficacy of Clarithromycin Depends on the Bacterial Density in Clarithromycin-Heteroresistant Helicobacter pylori Infections: An In Situ Detected Susceptibility and Quantitative Morphometry-Based Retrospective Study JF - PATHOLOGY AND ONCOLOGY RESEARCH J2 - PATHOL ONCOL RES VL - 27 PY - 2021 PG - 11 SN - 1219-4956 DO - 10.3389/pore.2021.1609863 UR - https://m2.mtmt.hu/api/publication/32110177 ID - 32110177 N1 - 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Department of Gastroenterology, Ferencváros Health Centre, Budapest, Hungary Department of Pharmacy, Péterfy Hospital - National Institute of Traumatology, Budapest, Hungary Department of Pathology, Péterfy Hospital - National Institute of Traumatology, Budapest, Hungary 1st Department of Surgery and Interventional Gastroenterology, Semmelweis University, Budapest, Hungary Cited By :5 Export Date: 15 December 2023 CODEN: POREF Correspondence Address: Kocsmár, É.; 2nd Department of Pathology, Hungary; email: kocsmar.eva@med.semmelweis-univ.hu Correspondence Address: Lotz, G.; 2nd Department of Pathology, Hungary; email: lotz.gabor@med.semmelweis-univ.hu LA - English DB - MTMT ER - TY - JOUR AU - Diossy, Miklos AU - Sztupinszki, Zsófia AU - Borcsok, Judit AU - Krzystanek, Marcin AU - Tisza, Viktoria AU - Spisák, Sándor AU - Rusz, Orsolya AU - Tímár, József AU - Csabai, István AU - Fillinger, János AU - Moldvay, Judit AU - Pedersen, Anders Gorm AU - Szüts, Dávid AU - Szállási, Zoltán TI - A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures JF - NPJ PRECISION ONCOLOGY J2 - NPJ PRECIS ONCOL VL - 5 PY - 2021 IS - 1 PG - 8 SN - 2397-768X DO - 10.1038/s41698-021-00199-8 UR - https://m2.mtmt.hu/api/publication/32076418 ID - 32076418 N1 - Funding Agency and Grant Number: Research and Technology Innovation Fund [KTIA_NAP_13-2014-0021]; Breast Cancer Research Foundation [BCRF-17-156]; Kraeftens Bekaempelse [R281-A16566]; Novo Nordisk Foundation Interdisciplinary Synergy Programme Grant [NNF15OC0016584]; Department of Defense through the Prostate Cancer Research ProgramUnited States Department of Defense [W81XWH-18-2-0056]; Det Frie Forskningsrad Sundhed og Sygdom [7016-00345B]; Velux FoundationVelux Fonden [00018310] Funding text: The results shown here are based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.This work was supported by the Research and Technology Innovation Fund (KTIA_NAP_13-2014-0021 to Z.Szallasi.), Breast Cancer Research Foundation (BCRF-17-156 to Z.Szallasi.), Kraeftens Bekaempelse (R281-A16566 to Z.Szallasi.), the Novo Nordisk Foundation Interdisciplinary Synergy Programme Grant (NNF15OC0016584 to Z.Szallasi. and I.C.), Department of Defense through the Prostate Cancer Research Program (W81XWH-18-2-0056 to Z.Szallasi.), Det Frie Forskningsrad Sundhed og Sygdom (7016-00345B to Z.Szallasi.), and the Velux Foundation (00018310 to Z.Sztupinszki. and J.B.). LA - English DB - MTMT ER - TY - JOUR AU - Börcsök, Judit AU - Sztupinszki, Zsófia AU - Bekele, Raie AU - Gao, Sizhi P AU - Diossy, Miklos AU - Samant, Amruta S AU - Dillon, Kasia M AU - Tisza, Viktoria AU - Spisák, Sándor AU - Rusz, Orsolya AU - Csabai, Istvan AU - Pappot, Helle AU - Frazier, Zoe J AU - Konieczkowski, David J AU - Liu, David AU - Vasani, Naresh AU - Rodrigues, James A AU - Solit, David B AU - Hoffman-Censits, Jean H AU - Plimack, Elizabeth R. AU - Rosenberg, Jonathan E AU - Lazaro, Jean-Bernard AU - Taplin, Mary-Ellen AU - Iyer, Gopa AU - Brunak, Søren AU - Lózsa, Rita Bernadett AU - Van Allen, Eliezer M AU - Szüts, Dávid AU - Mouw, Kent W AU - Szállási, Zoltán TI - Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer JF - CLINICAL CANCER RESEARCH J2 - CLIN CANCER RES VL - 27 PY - 2021 IS - 7 SP - 2011 EP - 2022 PG - 12 SN - 1078-0432 DO - 10.1158/1078-0432.CCR-20-3316 UR - https://m2.mtmt.hu/api/publication/31781512 ID - 31781512 N1 - Funding Agency and Grant Number: Research and Technology Innovation Fund [KTIA_NAP_13-2014-0021]; Breast Cancer Research Foundation [BCRF-17-156]; Novo Nordisk Foundation Interdisciplinary Synergy Programme grant [NNF15OC0016584]; Novo Nordisk Foundation Center for Protein Research core grant [NNF14CC0001]; Department of Defense through the Prostate Cancer Research ProgramUnited States Department of Defense [W81XWH-18-2-0056]; Det Frie Forskningsrad Sundhed og Sygdom [7016-00345]; Burroughs-Wellcome FundBurroughs Wellcome Fund; Dana-Farber Whole Foods Golf Fund; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [5K08CA219504, R01 CA227388]; Fox Chase Cancer Center NCI Core grant [P30CA00692]; Velux FoundationsVelux Fonden [00018310]; Department of DefenseUnited States Department of Defense [CA160312P2] Funding text: Results shown here are based, in part, from data generated by The Cancer Genome Atlas Research Network: http://cancergenome.nih.gov/and the International Cancer Genome Consortium: https://icgc.org/.This work was supported by the Research and Technology Innovation Fund (KTIA_NAP_13-2014-0021 to Z. Szallasi), Breast Cancer Research Foundation (BCRF-17-156 to Z. Szallasi), the Novo Nordisk Foundation Interdisciplinary Synergy Programme grant (NNF15OC0016584 to Z. Szallasi), the Novo Nordisk Foundation Center for Protein Research core grant (NNF14CC0001 to S. Brunak), Department of Defense through the Prostate Cancer Research Program (W81XWH-18-2-0056 to Z. Szallasi), Det Frie Forskningsrad Sundhed og Sygdom (7016-00345B to Z. Szallasi), Burroughs-Wellcome Fund (to K. W. Mouw), Dana-Farber Whole Foods Golf Fund (to M.-E. Taplin), the NCI (5K08CA219504 to K.W. Mouw and R01 CA227388 to E.M. Van Allen), Fox Chase Cancer Center NCI Core grant (P30CA00692 to E. R. Plimack), the Velux Foundations (00018310 to Z. Sztupinszki and J. Borcsok) and Department of Defense CA160312P2 (to J.E. Rosenberg and E.M. Van Allen). LA - English DB - MTMT ER - TY - JOUR AU - Sztupinszki, Zsófia AU - Diossy, Miklos AU - Krzystanek, Marcin AU - Börcsök, Judit AU - Pomerantz, Mark M AU - Tisza, Viktoria AU - Spisák, Sándor AU - Rusz, Orsolya AU - Csabai, István AU - Freedman, Matthew L AU - Szállási, Zoltán TI - Detection of molecular signatures of homologous recombination deficiency in prostate cancer with or without BRCA1/2 mutations JF - CLINICAL CANCER RESEARCH J2 - CLIN CANCER RES VL - 26 PY - 2020 IS - 11 SP - 2673 EP - 2680 PG - 8 SN - 1078-0432 DO - 10.1158/1078-0432.CCR-19-2135 UR - https://m2.mtmt.hu/api/publication/31194960 ID - 31194960 N1 - Z. Sztupinszki and M. Diossy contributed equally to the article LA - English DB - MTMT ER - TY - JOUR AU - Biró, Edit Magdolna AU - Kahán, Zsuzsanna AU - Kálmán, János AU - Rusz, Orsolya AU - Pákáski, Magdolna AU - Irinyi, Tamás AU - Kelemen, Gyöngyi AU - Dudás, Rita AU - Drótos, Gergely AU - Hamvai, Csaba TI - Cognitive Functioning and Psychological Well-being in Breast Cancer Patients on Endocrine Therapy JF - IN VIVO J2 - IN VIVO VL - 33 PY - 2019 IS - 4 SP - 1381 EP - 1392 PG - 12 SN - 0258-851X DO - 10.21873/invivo.11615 UR - https://m2.mtmt.hu/api/publication/31171249 ID - 31171249 LA - English DB - MTMT ER - TY - JOUR AU - Póti, Ádám AU - Gyergyák, Hella AU - Németh, Eszter AU - Rusz, Orsolya AU - Tóth, Szilárd AU - Kovácsházi, Csenger AU - Chen, Dan AU - Szikriszt, Bernadett AU - Spisák, Sándor AU - Takeda, Shunichi AU - Szakács, Gergely AU - Szállási, Zoltán AU - Richardson, Andrea L AU - Szüts, Dávid TI - Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents. JF - GENOME BIOLOGY J2 - GENOME BIOL VL - 20 PY - 2019 IS - 1 PG - 13 SN - 1474-7596 DO - 10.1186/s13059-019-1867-0 UR - https://m2.mtmt.hu/api/publication/30923894 ID - 30923894 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Budapest, H-1117, Hungary Department of Oncotherapy, University of Szeged, Szeged, Hungary Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, United States Department of Radiation Genetics, Kyoto University Medical School, Kyoto, 606-8501, Japan Institute of Cancer Research, Medical University Vienna, Vienna, Austria Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, United States Harvard Medical School, Boston, MA, United States Danish Cancer Society Research Center, Copenhagen, Denmark SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Johns Hopkins University, School of Medicine, Baltimore, MD, United States Cited By :2 Export Date: 8 April 2020 CODEN: GNBLF Correspondence Address: Szüts, D.; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Hungary; email: szuts.david@ttk.mta.hu Chemicals/CAS: Poly(ADP-ribose) Polymerase Inhibitors Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Budapest, H-1117, Hungary Department of Oncotherapy, University of Szeged, Szeged, Hungary Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, United States Department of Radiation Genetics, Kyoto University Medical School, Kyoto, 606-8501, Japan Institute of Cancer Research, Medical University Vienna, Vienna, Austria Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, United States Harvard Medical School, Boston, MA, United States Danish Cancer Society Research Center, Copenhagen, Denmark SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Johns Hopkins University, School of Medicine, Baltimore, MD, United States Cited By :3 Export Date: 10 June 2020 CODEN: GNBLF Correspondence Address: Szüts, D.; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Hungary; email: szuts.david@ttk.mta.hu Chemicals/CAS: Poly(ADP-ribose) Polymerase Inhibitors AB - Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction.Using whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity.Our results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity. LA - English DB - MTMT ER - TY - JOUR AU - Tőkés, Anna-Mária AU - Rusz, Orsolya AU - Cserni, Gábor AU - Tóth, Erika AU - Rubovszky, Gábor AU - Tőkés, Tímea AU - Vízkeleti, Laura AU - Reiniger, Lilla AU - Kószó, Renáta Lilla AU - Kahán, Zsuzsanna AU - Kulka, Janina AU - Donia, Marco AU - Vörös, András AU - Szállási, Zoltán TI - Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of residual breast cancer JF - ACTA ONCOLOGICA J2 - ACTA ONCOL VL - 58 PY - 2019 IS - 11 SP - 1603 EP - 1611 PG - 9 SN - 0284-186X DO - 10.1080/0284186X.2019.1633015 UR - https://m2.mtmt.hu/api/publication/30658783 ID - 30658783 N1 - Funding Agency and Grant Number: New National Excellence Program [UNKP-17-4-II-SE-65, UNKP-17-4-III-SE-71]; STIA [19/2017, 6800313113, 68003F0043]; Research and Technology Innovation Fund [KTIA_NAP_13-2014-0021]; Breast Cancer Research Foundation; [NVKP_16-1-2016-0004]; [NKP-2017-00002] Funding text: This work is supported by New National Excellence Program [UNKP-17-4-II-SE-65] (L.V); New National Excellence Program [UNKP-17-4-III-SE-71] (AMT); NVKP_16-1-2016-0004; STIA 19/2017, 6800313113, 68003F0043 (AMT); The Research and Technology Innovation Fund [KTIA_NAP_13-2014-0021 to Z.S.]; NKP-2017-00002 (Z.S.); Breast Cancer Research Foundation (Z.S.). LA - English DB - MTMT ER -