1. Genetic counselling, BRCA1/2 status and clinico-pathologic characteristics of patients with ovarian cancer before 50 years of ageMirjam Cvelbar, Marko Hočevar, Srdjan Novaković, Vida Stegel, Andraž Perhavec, Mateja Krajc, 2017, izvirni znanstveni članek Povzetek: In Slovenia like in other countries, till recently, personal history of epithelial ovarian cancer (EOC) has not been included among indications for genetic counselling. Recent studies reported up to 17% rate of germinal BRCA1/2 mutation (gBRCA1/2m) within the age group under 50 years at diagnosis. The original aim of this study was to invite to the genetic counselling still living patients with EOC under 45 years, to offer gBRCA1/2m testing and to perform analysis of gBRCA1/2m rate and of clinico-pathologic characteristics. Later, we added also the data of previously genetically tested patients with EOC aged 45 to 49 years. Patients and methods. All clinical data have to be interpreted in the light of many changes happened in the field of EOC just in the last few years: new hystology stage classification (FIGO), new hystology types and differentiation grades classification, new therapeutic possibilities (PARP inhibitors available, also in Slovenia) and new guidelines for genetic counselling of EOC patients (National Comprehensive Cancer Network, NCCN), together with next-generation sequencing possibilities. Results. Compliance rate at the invitation was 43.1%. In the group of 27 invited or previously tested patients with EOC diagnosed before the age of 45 years, five gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within the group was 18.5%. There were 4 gBRCA1 and 1 gBRCA2 mutations detected. In the extended group of 42 tested patients with EOC diagnosed before the age of 50 years, 14 gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within this extended, partially selected group was 33.3%. There were 11 gBRCA1 and 3 gBRCA2 mutations detected. Conclusions. The rate of gBRCA1/2 mutation in tested unselected EOC patients under the age of 50 years was higher than 10%, namely 18.5%. Considering also a direct therapeuthic benefit of PARP inhibitors for BRCA positive patients, there is a double reason to offer genetic testing to all EOC patients younger than 50 years. Regarding clinical data, it is important to perform their re-interpretation in everyday clinical practice, because this may influence therapeutic possibilities to be offered.
Ključne besede: ovarian cancer, BRCA 1/2, genetic counseling
Objavljeno v DiRROS: 24.05.2024; Ogledov: 85; Prenosov: 32
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2. Genotyping of BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes in a male patient with secondary breast cancerAna Lina Vodušek, Srdjan Novaković, Vida Stegel, Berta Jereb, 2011, izvirni znanstveni članek Objavljeno v DiRROS: 18.03.2024; Ogledov: 147; Prenosov: 43
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3. Rapid detection of most frequent Slovenian germ-line mutations in BRCA1 gene using real-time PCR and melting curve analysisSrdjan Novaković, Vida Stegel, 2005, izvirni znanstveni članek Povzetek: Background. Detection of inherited mutations in cancer susceptibility genes isof great importance in some types of cancers including the colorectal cancer(mutations of APC gene in familial adenomatous polyposis -FAP, mutationsin mismatch repair genes in hereditary nonpolyposis colorectal cancer- HNPCC), malignant melanoma (mutations in CDKN2A and CDK4 genes) and breast cancer (mutations in BRCA1 and BRCA2 genes). Methods. This article presents the technical data for the detection of five mutations in BRCA1 gene in breast cancer patients and their relatives. The mutations - 1806C>T, 300T>G, 300T>A, 310G>A, 5382insC -were determined by the real-time PCR and themelting curve analysis. Results and conclusion. In comparison to direct sequencing, this method proved to be sensitive and rapid enough for the routine daily determination of mutations in DNA isolated from the peripheral blood.
Objavljeno v DiRROS: 14.02.2024; Ogledov: 186; Prenosov: 47
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5. Molekularno genetsko testiranje pri raku telesa materniceVida Stegel, Srdjan Novaković, 2023, objavljeni znanstveni prispevek na konferenci Povzetek: V grobem tumorje telesa maternice delimo na endometrijske epitelne, mezenhimske, mešane epitelne in mezenhimske in druge. Karcinom endometrija, ki sodi med epitelne tumorje, predstavlja večino (80-90 %) vseh malignih bolezni telesa maternice. Sarkomi predstavljajo 2- 5 % vseh malignih bolezni telesa maternice. Molekularno genetske preiskave se pri obravnavi tumorjev telesa maternice uporabljajo za namen odkrivanja različic/markerjev pomembnih za diagnozo, prognozo ali zdravljenje bolezni. Pato-histološka klasifikacija karcinoma endometrija je v preteklosti temeljila predvsem na morfoloških značilnostih tumorja, v zadnjem času pa se je izoblikovala histološko-molekularna klasifikacija, ki upošteva tudi molekularne značilnosti tumorja. Upoštevajoč molekularno klasifikacijo TCGA (The Cancer Genome Atlas), pri karcinomih endometrija ločimo med POLE-ultramutirani tumorji, mikrosatelitno nestabilnimi tumorji, tumorji s številnimi spremembami v številu kopij genov in tumorji z maloštevilnimi spremembami v številu kopij genov. Molekularne podskupine karcinoma endometrija so tudi neodvisen prognostični dejavnik. Določene molekulano genetske lastnosti vplivajo tudi na izbiro zdravljenja.
Ključne besede: rak maternice, ginekološki raki, molekularna diagnostika
Objavljeno v DiRROS: 30.05.2023; Ogledov: 436; Prenosov: 146
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6. 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, objavljeni povzetek strokovnega prispevka na konferenci Ključne besede: onkologija, rak dojke, kemoterapija
Objavljeno v DiRROS: 03.02.2023; Ogledov: 426; Prenosov: 110
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7. Genetsko testiranje pri raku prostateVida Stegel, Srdjan Novaković, 2023, objavljeni znanstveni prispevek na konferenci Povzetek: 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.
Ključne besede: rak prostate, genetsko testiranje, diagnostika
Objavljeno v DiRROS: 02.02.2023; Ogledov: 544; Prenosov: 126
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9. 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, izvirni znanstveni članek Povzetek: 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.
Ključne besede: RNA sequencing, DNA variant, splicing
Objavljeno v DiRROS: 21.09.2022; Ogledov: 490; Prenosov: 270
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10. 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, izvirni znanstveni članek Povzetek: 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.
Ključne besede: BAP1, breast cancer, hereditary cancer syndromes, immunotherapy
Objavljeno v DiRROS: 19.09.2022; Ogledov: 502; Prenosov: 196
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