1. Imunski fenotipi v mikrookolju primarnega tumorja in jetrnih zasevkov pri bolnici s silovitim razsojem vnetnega, trojno negativnega raka dojke v jetra med neoadjuvantnim zdravljenjem s citostatiki in zaviralcem imunskih kontrolnih točkMarina Mencinger, Snežana Pavlović Djokić, Vida Stegel, Srdjan Novaković, Juan Antonio Contreras, Andreja Klevišar Ivančič, 2022, published professional conference contribution abstract Keywords: onkologija, rak dojke, kemoterapija
Published in DiRROS: 03.02.2023; Views: 71; Downloads: 24
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2. Genetsko testiranje pri raku prostateVida Stegel, Srdjan Novaković, 2023, published scientific conference contribution Abstract: Rak prostate je v svetovnem merilu drugi najpogostejši rak pri moških. Genetski dejavniki lahko pomembno zvišajo tveganje za rak prostate. Genetsko testiranje na zarodne patogene različice v genih BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6 in PMS2 se izvaja za ocenjevanje ogroženosti bolnika, da zboli za drugimi raki, in za oceno ogroženosti njegovih družinskih članov. Pri metastatskem raku prostate se za zdravljenje uporabljajo tarčna zdravila, kot so zaviralci poli-ADP-riboza polimeraze (PARP) in imunoterapija. Obe vrsti zdravil sta dokazano bolj učinkoviti pri delovanju na tumorje s specifičnimi okvarami v genih, ki so soudeleženi v mehanizmih za popravljanje napak na DNA, t. j. homologne rekombinacije (HR) ali popravljanje neujemanj baz (MMR). Zato molekularnogenetsko testiranje tumorjev bolnikov z rakom prostate uporabljamo za določanje okvar HR in okvar v genih MMR. Kot pomoč pri natančnejši opredelitvi lokaliziranega raka prostate in sub-klasifikaciji glede na verjetnost napredovanja bolezni se v zadnjem času preizkušajo tudi molekularnogenetske preiskave, ki temeljijo na merjenju ekspresije različnih genov v kombinaciji z drugimi kliničnimi in histopatološkimi dejavniki.
Keywords: rak prostate, genetsko testiranje, diagnostika
Published in DiRROS: 02.02.2023; Views: 62; Downloads: 25
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4. New approach for detection of normal alternative splicing events and aberrant spliceogenic transcripts with long-range PCR and deep RNA sequencingVita Šetrajčič Dragoš, Vida Stegel, Ana Blatnik, Gašper Klančar, Mateja Krajc, Srdjan Novaković, 2021, original scientific article Abstract: RNA sequencing is a promising technique for detecting normal and aberrant RNA isoforms. Here, we present a new single-gene, straightforward 1-day hands-on protocol for detection of splicing alterations with deep RNA sequencing from blood. We have validated our method%s accuracy by detecting previously published normal splicing isoforms of STK11 gene. Additionally, the same technique was used to provide the first comprehensive catalogue of naturally occurring alternative splicing events of the NBN gene in blood. Furthermore, we demonstrate that our approach can be used for detection of splicing impairment caused by genetic variants. Therefore, we were able to reclassify three variants of uncertain significance: NBN:c.584G>A, STK11:c.863-5_863-3delCTC and STK11:c.615G>A. Due to the simplicity of our approach, it can be incorporated into any molecular diagnostics laboratory for determination of variant%s impact on splicing.
Keywords: RNA sequencing, DNA variant, splicing
Published in DiRROS: 21.09.2022; Views: 149; Downloads: 97
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5. BAP1-defficient breast cancer in a patient with BAP1 cancer syndromeAna Blatnik, Domen Ribnikar, Vita Šetrajčič Dragoš, Srdjan Novaković, Vida Stegel, Biljana Grčar-Kuzmanov, Nina Boc, Barbara Perić, Petra Škerl, Gašper Klančar, Mateja Krajc, 2022, original scientific article Abstract: BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functions, BAP1 alterations could prove useful as possible biomarkers of response to immunotherapy in patients with BAP1-associated cancers. We present a case of a patient with BAP1 cancer syndrome who developed a metastatic breast cancer with loss of BAP1 demonstrated on immunohistochemistry. She carried a germline BAP1 likely pathogenic variant (c.898_899delAG p.(Arg300Glyfs*6)). In addition, tumor tissue sequencing identified a concurrent somatic variant in BAP1 (partial deletion of exon 12) and a low tumor mutational burden. As her triple negative tumor was shown to be PD-L1 positive, the patient was treated with combination of atezolizumab and nab-paclitaxel. She had a complete and sustained response to immunotherapy even after discontinuation of nab-paclitaxel. This case strengthens the evidence for including breast cancer in the BAP1 cancer syndrome tumor spectrum with implications for future cancer prevention programs. It also indicates immune checkpoint inhibitors might prove to be an effective treatment for BAP1-deficient breast cancer.
Keywords: BAP1, breast cancer, hereditary cancer syndromes, immunotherapy
Published in DiRROS: 19.09.2022; Views: 161; Downloads: 78
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6. Identification of spliceogenic variants beyond canonical GT-AG splice sites in hereditary cancer genesVita Šetrajčič Dragoš, Ksenija Strojnik, Gašper Klančar, Petra Škerl, Vida Stegel, Ana Blatnik, Marta Banjac, Mateja Krajc, Srdjan Novaković, 2022, original scientific article Abstract: Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.
Keywords: hereditary cancer, RNA sequencing, spliceogenic
Published in DiRROS: 07.09.2022; Views: 179; Downloads: 93
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7. Real-world data on detection of germline and somatic pathogenic/likely pathogenic variants in BRCA1/2 and other susceptibility genes in ovarian cancer patients using next generation sequencingVida Stegel, Ana Blatnik, Erik Škof, Vita Šetrajčič Dragoš, Mateja Krajc, Brigita Gregorčič, Petra Škerl, Ksenija Strojnik, Gašper Klančar, Marta Banjac, Janez Žgajnar, Maja Ravnik-Oblak, Srdjan Novaković, 2022, original scientific article Abstract: Detection of germline and somatic pathogenic/likely pathogenic variants (PV/LPV) in BRCA genes is at the moment a prerequisite for use of PARP inhibitors in different treatment settings of different tumors. The aim of our study was to determine the most appropriate testing workflow in epithelial ovarian cancer (EOC) patients using germline and tumor genotyping of BRCA and other hereditary breast and/or ovarian cancer (HBOC) susceptibility genes. Consecutive patients with advanced non-mucinous EOC, who responded to platinum-based chemotherapy, were included in the study. DNA extracted from blood and FFPE tumor tissue were genotyped using NGS panels TruSightCancer/Hereditary and TruSight Tumor 170. Among 170 EOC patients, 21.8% had BRCA germline or somatic PV/LPV, and additionally 6.4% had PV/LPV in other HBOC genes. Sensitivity of tumor genotyping for detection of germline PV/LPV was 96.2% for BRCA genes and 93.3% for HBOC genes. With germline genotyping-only strategy, 58.8% of HBOC PV/LPV and 68.4% of BRCA PV/LPV were detected. By tumor genotyping-only strategy, 96.1% of HBOC PV/LPV and 97.4% of BRCA PV/LPV were detected. Genotyping of tumor first, followed by germline genotyping seems to be a reasonable approach for detection of PV/LPV in breast and/or ovarian cancer susceptibility genes in non-mucinous EOC patients.
Keywords: BRCA, ovarian cancer, tumor genotyping, HBOC
Published in DiRROS: 06.09.2022; Views: 189; Downloads: 103
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8. Klinična pot genetske obravnave bolnic z epitelijskim nemucinoznim rakom jajčnikov/jajcevodov/primarnim peritonealnim seroznim karcinomomErik Škof, Ksenija Strojnik, Marta Banjac, Ana Blatnik, Vida Stegel, Natalija Klopčič, Simona Hotujec, Srdjan Novaković, Mateja Krajc, 2021, dictionary, encyclopaedia, lexicon, manual, atlas, map Keywords: rak jajčnikov, genetika, zdravljenje, klinične poti
Published in DiRROS: 16.03.2022; Views: 327; Downloads: 172
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10. Dokazovanje mutacij v BRCA1 genu z analizo talitvene krivulje PCR produktovSrdjan Novaković, Vida Stegel, Mateja Krajc, Janez Žgajnar, Nikola Bešić, Marko Hočevar, Cvetka Bilban-Jakopin, Katarina Lokar, 2006, published scientific conference contribution Published in DiRROS: 17.09.2019; Views: 1931; Downloads: 499
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