The self-limited nature of nodular fasciitis (NF) is well-known but its precise mechanism has not yet been clarified. We observed that “young” NF (preoperative duration <1 month) consistently contains a higher percentage (~80%) of USP6 break-apart FISH signals than “old” NF (preoperative duration >3 months) (~20%). Thus, we hypothesized that our original observation may reflect a connection with the self-limited nature of NF. Seventeen cases with reliable data concerning the onset were selected, thus approximating the lifetime of each tumor. Besides the USP6 interphase FISH examination, we also checked the most common MYH9-USP6 fusion using RT-PCR. Because of the known pathways of the tumorigenesis of NF, the mRNA level of USP6, TRAIL, IFN-beta, JAK1, STAT1, STAT3, JUN, and CDKN2A was measured using qRT-PCR. Regarding proteins, USP6, p16, p27, TRAIL, and IFN-beta were examined using immunohistochemistry. Targeted gene panel next-generation sequencing (NGS) of three cases was additionally performed. We found a strong negative correlation (p = 0.000) between the lifetime and percentage of USP6 break-apart signals and a strong positive relationship (p = 0.000) between USP6 break-apart signals and mitotic counts. Results of immunostainings, along with qRT-PCR results, favored the previously-suggested USP6-induced negative feedback mechanism through activation of TRAIL and IFN-beta, likely resulting in apoptosis and senescence of tumor cells harboring USP6 fusions. Targeted-NGS resulted in the detection of several variants, but no additional recurrent changes in the pathogenesis of these tumors. We revealed on a cellular level the USP6-induced negative feedback mechanism. In conclusion, we emphasize that in “old” NF, the percentage of USP6 break-apart FISH signals can be as low as 14–27% which can be very important from a differential diagnostic point of view. We emphasize that a careful examination and interpretation of the NGS data is needed before clinical decision-making on treatment.
Due to the relatively high recurrence rate and the destructive nature of the tumor, the treatment of giant cell tumor is still a challenge. Denosumab appeared to be a promising candidate as a therapeutic drug. However, several studies have reported that tumors can recur during/after treatment with denosumab. Based on activated receptor tyrosine kinase signaling pattern of the stromal/tumor cells, a combination treatment with denosumab and sunitinib has recently been proposed to inhibit recurrences. This prompted us to investigate the PDGFRβ expression of five denosumab treated cases using both primary and recurrent tumors during and after denosumab treatment. In addition, to recognise morphological changes, immunohistochemical analysis of H3F3A and PDGFRβ was also performed. As an effect of denosumab treatment, the permanent absence of giant cells associated with severe to mild fibrosis was the most consistent morphological change, but H3F3A positive stromal/tumor cells were observed in all cases. Furthermore, an increased immunopositivity of PDGFRβ in stromal/tumor cells was evident in all recurrent cases during denosumab treatment. Upon tumor recurrence (after the discontinuation of denosumab treatment) the intensity of PDGFRβ immunostaining in stromal/tumor cells was restored/decreased. Our results confirm (for the first time) the activation of PDGFRβ on mononuclear stromal/tumor cells at protein level as an effect of denosumab treatment, which has so far only been demonstrated by phosphoprotein array analysis (protein lysates). The decreased PDGFRβ activity after the discontinuation of denosumab treatmeant and the increased PDGFRβ activity during denosumab treatment underlines the need for denosumab and sunitinib combination therapy.
Although the Human Genome Project discovered the sequence of the human genetic information 15 years ago, genetic background of the diseases - primarily that of complex disorders - is still not known. The sum of the not yet discovered inherited risk factors is termed the missing heritability; the identification of these genetic components is, however, essential, as it is the base of the understanding of the molecular pathomechanism of diseases. It is not only of theoretical importance: this knowledge can be used in the clinical practice, as it offers the possibility of improvement of diagnostics, prevention as well as targeted and individualized therapy. Application of novel and more efficient molecular biological tools contribute to the discovery of unknown genetic factors, the complete goal can only be achieved, however, by re-conceptualization of several clinical and genetic points. Our knowledge was established by genome-wide studies, however, further knowledge must be acquired according to the following points: (1) genotype and association analysis of repeat variations (VNTRs and CNVs) besides SNPs, (2) investigation of gene-gene and gene-environment interactions, (3) epigenetic studies, (4) assessing the biological function of polymorphisms, (5) application of biologically relevant diagnostic categories and endophenotypes. Although it is only 1.2% of the whole genome that codes for proteins, however, as much as 90% is transcribed to RNA, consequently it can be hypothesized that gene expression analyses might offer promising starting points for further studies, as they can shed light on the molecular processes that contribute to the development of diseases. Orv Hetil. 2018; 159(31): 1254-1261.
Absztrakt: A neurotrofikus tropomiozin receptor-tirozin-kináz (NTRK-) géncsalád tagjai (NTRK1, NTRK2, NTRK3) által kódolt tropomiozin receptor-tirozin-kináz fehérjék (TrkA, TrkB, TrkC) fiziológiásan elsősorban az idegsejtek fejlődéséért, éréséért, működéséért felelősek. Az NTRK-géncsaládot érintő genetikai eltérések, melyek a leggyakrabban kromoszomális transzlokáció következtében jönnek létre, számos rosszindulatú daganat kialakulásához vezethetnek. Egyes, kifejezetten ritka daganatokban nagyon nagy gyakorisággal fedezhető fel valamelyik NTRK-fúziós gén létrejötte, mint például az infantilis fibrosarcoma, a congenitalis mesoblastos nephroma vagy a secretoros carcinoma, míg egyes gyakori daganatokban – vastagbélrák, tüdőrák – bár kisebb frekvenciával, de szintén megjelenhet. Az utóbbi időben vizsgált, rendkívül magas válaszadási aránnyal alkalmazott ’target’ terápia miatt az NTRK-fúziós gének diagnosztikája még nagyobb jelentőségűvé vált. A cikk összegzi mindazokat a diagnosztikai eljárásokat s azok előnyeit, illetve hátrányait, melyeknek szerepük van az NTRK-géneltérések felderítésében, valamint ezek alapján további diagnosztikai megfontolásokat fogalmaz meg, melyek segíthetnek egy adott esetben a megfelelő diagnosztikai módszer megválasztásában. Orv Hetil. 2020; 161(41): 1753–1763.
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