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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: 468; Prenosov: 186
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Povzetek: 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.
Ključne besede: hereditary cancer, RNA sequencing, spliceogenic
Objavljeno v DiRROS: 07.09.2022; Ogledov: 491; Prenosov: 252
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Povzetek: 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.
Ključne besede: BRCA, ovarian cancer, tumor genotyping, HBOC
Objavljeno v DiRROS: 06.09.2022; Ogledov: 535; Prenosov: 284
Celotno besedilo (2,35 MB)
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Povzetek: Izhodišča: Bolniki s plevralnim izlivom pogosto potrebujejo razbremenilno plevralno punkcijo (RPP), po kateri navajajo bolj ali manj izrazito olajšanje dispneje. Zaradi varnosti se priporoča, da se med RPP odstrani do 1.500 mL tekočine. Metode: V raziskavo smo vključili 96 bolnikov, pri katerih je bila potrebna RPP. Zbirali smo ocene stopnje dispneje na lestvici VAS pred, takoj po in 2 uri po RPP, pri 73 bolnikih pa še 24 ur po RPP ter beležili količino odstranjene tekočine. Med RPP smo z vodnim manometrom merili plevralne tlake, iz katerih smo izračunali elastanco plevralnega prostora in na podlagi meritev bolnike razdelili v skupine z različnimi elastančnimi krivuljami. Rezultati: Med začetnim plevralnim tlakom in količino odstranjene tekočine ter olajšanjem dispneje po opravljeni RPP smo ugotovili statistično značilno povezanost. Pri največjem deležu bolnikov smo RPP zaključili zaradi pojava simptomov, zaradi meritev plevralnega tlaka pa smo RPP prekinili pri 16 bolnikih (16,7 %). V skupino z normalno elastančno krivuljo smo uvrstili 74 bolnikov, nezmožnost razpenjanja pljuč pa smo ugotovili pri 22 bolnikih. Med RPP ni bilo pomembnih zapletov, kljub temu da smo več kot 1.500 mL izliva odstranili pri 32 (33 %) bolnikih. Zaključek: Višji začetni plevralni tlak je šibko povezan z višjo začetno stopnjo dispneje in večjim olajšanjem dispneje po opravljeni RPP. Najbolj uporabna je dinamika sprememb plevralnega tlaka, s katero lahko že med RPP prepoznamo nezmožnost razpenjanja pljuč. Med RPP s plevralno manometrijo lahko varno odstranimo tudi več kot 1.500 mL tekočine
Ključne besede: pljuča, dispneja, vizualna analogna lestvica, elastančne krivulje, nezmožnost razpenjanja pljuč
Objavljeno v DiRROS: 29.08.2022; Ogledov: 441; Prenosov: 172
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Povzetek: Owing to their anoxic environment, peatlands play an important role in the preservation of records documenting past atmospheric depositions. To determine past records, data on peat stratigraphy and bog development are needed. Ground penetrating radar (GPR) was used to determine the peat thickness and morphology of the Šijec bog on the Pokljuka plateau in Slovenia, which will serve as a basis for further geochemical studies. Information on the stratigraphy below the peat/clay boundary was acquired by applying electrical resistivity tomography (ERT). The GPR results reveal four depressions within the peat bog, which are separated by elevated ridges. Within the depressions the peat reaches a depth of 6–9 m. The edges of the bog are flat, with peat thickness ranging from 2 to 4 m. The reach of the GPR was complemented with manual peat probing. A comparison of the depths obtained using GPR and the peat probe reveals that the results of both methods correspond well in most locations. The ERT indicated similar peat depths; peat responds with high electrical resistivity. In contrast, clayey sediments with low resistivity are found below the peat. The peat depressions are underlain with larger clayey depressions reaching more than 20 m in thickness and represent lake sediments. The complementary geophysical methods proved to be an efficient approach with which we can delineate the peat morphology and the underlying stratigraphy. Both indicate bog formation from a lake with four deeper depressions, that are separated by glacial deposits. The results presented here show the potential for geophysical methods to infer formational processes in peatlands, showing the presence of a series of isolated basins that later coalesced into a single peat landform. This interpretation is consistent with previous conceptual models from studies in boreal regions.
Ključne besede: peatland, ground penetrating radar, electrical resistivity tomography, peat probing, peat thickness
Objavljeno v DiRROS: 07.07.2022; Ogledov: 597; Prenosov: 399
Celotno besedilo (23,80 MB)