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Povzetek: V Sloveniji od leta 2008 deluje Državni presejalni program za raka dojk DORA, začetki za izvajanje programa pa segajo v leto 2003. Leta 2007 so na Zdravstvenem svetu sprejeli predlog organiziranega in centralizirano vodenega presejalnega programa, v katerem so ženske vabljene na mamografijo v specializiranih presejalnih centrih in po potrebi opravljajo dodatno diagnostiko v dveh presejalno-diagnostičnih centrih. Program DORA se je postopno širil po državi, od začetne širitve v ljubljanski in mariborski regiji (2010–2013), do končne širitve po celi državi (2014–2018). V programu DORA so ženske v starosti 50–69 let vsaki dve leti pisno povabljene na presejalni pregled z mamografijo, ki omogoča odkrivanje še netipnih sprememb v dojki. Ob sumljivih spremembah na mamografiji so ženske vabljenje na nadaljnjo obravnavo, če je odkrit rak dojk, pa tudi na zdravljenje. Od 2018 v okviru programa deluje 22 mamografov v 16 stacionarnih in 3 mobilnih presejalnih enotah ter dva presejalno-diagnostična centra za nadaljnjo obravnavo žensk in zdravljenje v presejanju odkritih rakov. Program DORA deluje v skladu z visokimi standardi evropskih smernic kakovosti in zagotavlja enako obravnavo za vse udeleženke v katerikoli presejalni enoti v Sloveniji. Cilj presejalnega programa je ob vsaj 70-odstotni udeležbi žensk doseči znižanje umrljivosti za rakom dojk v ciljni populaciji za 25–30 %. Program s 74-odstotno udeležbo v zadnjih desetih letih letno opravi več kot 110.000 mamografij in odkrije okrog 650 primerov raka dojk. Zaradi svoje organizacije, informacijske podpore, izobraževalnih in komunikacijskih aktivnosti ter strokovnega nadzora vseh korakov presejanja je evropski primer dobre prakse presejalnega programa.
Ključne besede: rak dojke, preventivni programi, javno zdravje
Objavljeno v DiRROS: 22.12.2022; Ogledov: 421; Prenosov: 132
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Povzetek: Background: Medullary thyroid cancer (MTC) is a rare endocrine tumour that is sporadic in 75% of cases and occurs as a part of inherited cancer syndromes in approximately 25% of cases. The aim of this study was to determine the frequency and type of RET pathogenic variants (PVs) in the Slovenian MTC patient population diagnosed between 1995 and 2021 and to elucidate the full range of associated endocrinopathies. Methods: A retrospective analysis of medical records of 266 MTC patients and their relatives seen in a tertiary centre between 1995 and 2021 was performed. Sequence analysis of exons 10, 11, 13, 14, 15, and 16 of the RET gene was analysed in most patients using Sanger sequencing. From 2017, the entire sequence of RET gene was analysed in most patients using targeted next-generation sequencing. Results: Germline PVs in the RET proto-oncogene were identified in 21.6% probands from 21 different MTC families. Of their tested relatives, 65% (67/103) were RET-positive and 35% (36/103) were RET-negative. PVs were detected in codon 618 and codon 634 in 28.6%, and in codon 790 in 23.8%. The RET-positive group consisted of 52 MTC patients, 13 patients with C cell hyperplasia and 2 individuals with neither. Associated endocrinopathies were diagnosed in 8/21 families: primary hyperparathyroidism (PHPT) in six families and pheochromocytoma (PHEO) in five families. In 62% of RET-positive families (13/21), no associated endocrinopathies were diagnosed. PHEO was most commonly associated with C634R (6/13) and PHPT with C634R (4/7). Hirschsprung’s disease appeared in one patient with RET PV in codon 618. Based on data from the Cancer Registry of Republic of Slovenia, only individual cases of common cancers with well understood environmental risk factors were discovered; lung cancer in 2/21 of families, papillary thyroid cancer in 3/21 of families, cutaneous melanoma in 2/21 of families, cervical cancer in 1/21 families, and lymphoma in 1/21 families. Conclusions: Analysis of prospectively collected MTC cases during a 27-year period revealed that 21.6% of Slovenian patients are RET PV carriers. Sixty-two percent of families had none of the associated endocrinopathies, confirming the thesis that FMTC is the most common presentation. This could suggest using risk-stratified management approaches when screening for PHEO and PHPT in RET PV carriers. However, more studies are needed to evaluate potential genetic risk modifiers as well as safety, improved quality of life, and medical cost reduction in the case of a patient-oriented approach.
Ključne besede: medullary thyroid carcinoma, multiple endocrine neoplasia, primary hyperparathyroidism
Objavljeno v DiRROS: 23.09.2022; Ogledov: 517; Prenosov: 244
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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: 438; Prenosov: 245
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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: 463; Prenosov: 238
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Ključne besede: rak debelega črevesa, rak danke, bolniki, zdravljenje
Objavljeno v DiRROS: 18.03.2022; Ogledov: 788; Prenosov: 428
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