Adult granulosa cell tumors (AGCTs) of the ovary are characterized by their propensity for late recurrences and are primarily managed surgically due to the limited efficacy of systemic treatment. The FOXL2 p.C134W somatic mutation has been identified in ∼95% of AGCT cases, and TERT promoter alterations have been linked to worse overall survival. This study highlights the potential prognostic significance of FOXO1 mutations, suggesting that they may be associated with poorer overall survival and shorter time to recurrence. A total of 183 primary AGCTs and 44 recurrences without corresponding primary tumors were analyzed. The primary AGCTs were categorized into 3 groups: 77 nonrecurrent tumors, 18 tumors that later recurred (including 9 cases with matched primary-recurrence pairs), and 88 tumors with unknown recurrence status. Targeted next-generation sequencing was conducted on 786 cancer-related genes to investigate their genetic profile. The study aimed to identify the molecular alterations associated with AGCT pathogenesis and recurrence rate, comparing primary versus recurrent tumors, and primary recurrent versus primary nonrecurrent cases. Our findings confirmed the high prevalence (99%) of the FOXL2 p.C134W mutation in AGCTs. Secondary truncating FOXL2 mutations were observed in 5% of cases. Two cases with typical AGCT morphology were FOXL2 wild-type, harboring mutations in KRAS or KMT2D instead, suggesting alternative genetic pathways. TERT promoter mutations were found in 43% of cases, more frequently in recurrences. Other recurrent mutations detected in the cohort included KMT2D (10%), FOXO1 (7%), CHEK2 (5%), TP53 (3.5%), PIK3CA (3.5%), and AKT1 (3%). Two recurrent, FOXL2-mutated cases also carried DICER1 mutations. One tumor exhibited MSI-high status and a tumor mutation burden of 19 mut/Mb.Our results indicate the need for further investigation into the role of FOXO1 as a potential prognostic marker in AGCTs.

• MeSH
• Adult MeSH
• Forkhead Box Protein O1 * genetics   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * genetics   MeSH
• Mutation * MeSH
• Granulosa Cell Tumor * genetics   pathology   MeSH
• Ovarian Neoplasms * genetics   pathology   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Forkhead Box Protein L2 genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Telomerase genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

INTRODUCTION: Prader-Willi syndrome (PWS) is primarily caused by a paternal microdeletion of the 15q11-q13 region, maternal uniparental disomy (mUPD) or unbalanced translocations. The MKRN3 gene, located within 15q11-q13, is a master regulator of pubertal initiation. We aimed to compare variant pubertal onset and progression with recent normative data and to correlate it with abnormal MKRN3 gene status. METHODS: Age at pubarche, gonadarche, subsequent pubertal progression and bone age (BA) at gonadarche were investigated in 37 PWS patients (18 females) who already entered pubarche and/or gonadarche with median age 11.1 (95% CI: 6.4 - 18.8) years. All patients were re-tested to confirm genetic subtypes of PWS. The MKRN3 gene was analyzed using single gene sequencing. RESULTS: Out of 37 subjects, 22 had microdeletion and 15 mUPD. Regardless of genetic subtypes and MKRN3 gene status, no correlation between genotypes and the pubertal pattern was found. They initiated pubarche early - girls at 7.4 (95%CI:6.4-8.4), and boys at 9.2 (8.2-10.2) years. The subsequent progression from PH2 to PH4 (pubic hair development) was prolonged to 3.7 years in girls (1.5-5.9;p<0.05), and 2.9 in boys (2.2-3.6;p<0.001). The age at gonadarche was adequate - 10.0 years in girls (8.8-11.2), and 11.0 in boys (9.8-12.1). Progression rate of breast development from B2 to B4 was 3.9 (0.2-7.5) years in girls and of testicular volume from 4 ml to 15ml was 3.8 (0.0-8.1) years in boys. The BA at gonadarche is advanced by 0.6 ± 1.1 years (p<0.001). CONCLUSIONS: Children with PWS, regardless of the genetic subtype and/or MKRN3 status, had an early pubarche and normally timed gonadarche. Pubarche progression was slower. Advanced BA was significantly correlated with gonadarche.

• MeSH
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Prader-Willi Syndrome * genetics   physiopathology   MeSH
• Disease Progression MeSH
• Puberty * physiology   genetics   MeSH
• Ribonucleoproteins genetics   MeSH
• Ubiquitin-Protein Ligases genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Retinitis pigmentosa (RP) is a hereditary disorder caused by mutations in more than 70 different genes including those that encode proteins important for pre-mRNA splicing. Most RP-associated mutations in splicing factors reduce either their expression, stability or incorporation into functional splicing complexes. However, we have previously shown that two RP mutations in PRPF8 (F2314L and Y2334N) and two in SNRNP200 (S1087L and R1090L) behaved differently, and it was still unclear how these mutations affect the functions of both proteins. To investigate this in the context of functional spliceosomes, we used iCLIP in HeLa and retinal pigment epithelial (RPE) cells. We found that both mutations in the RNA helicase SNRNP200 change its interaction with U4 and U6 snRNAs. The significantly broader binding profile of mutated SNRNP200 within the U4 region upstream of the U4/U6 stem I strongly suggests that its activity to unwind snRNAs is impaired. This was confirmed by FRAP measurements and helicase activity assays comparing mutant and WT protein. The RP variants of PRPF8 did not affect snRNAs, but showed a reduced binding to pre-mRNAs, which resulted in the slower splicing of introns and altered expression of hundreds of genes in RPE cells. This suggests that changes in the expression and splicing of specific genes are the main driver of retinal degeneration in PRPF8-linked RP.

• MeSH
• HeLa Cells MeSH
• Humans MeSH
• Ribonucleoprotein, U4-U6 Small Nuclear metabolism   genetics   MeSH
• Mutation * MeSH
• Eye Proteins genetics   metabolism   MeSH
• RNA Precursors * metabolism   genetics   MeSH
• RNA-Binding Proteins metabolism   genetics   MeSH
• Retinal Pigment Epithelium metabolism   pathology   MeSH
• Retinitis Pigmentosa * genetics   metabolism   pathology   MeSH
• Ribonucleoproteins, Small Nuclear metabolism   genetics   MeSH
• RNA, Small Nuclear genetics   metabolism   MeSH
• RNA Splicing * genetics   MeSH
• Spliceosomes metabolism   genetics   MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Telomeres, essential for maintaining genomic stability, are typically preserved through the action of telomerase, a ribonucleoprotein complex that synthesizes telomeric DNA. One of its two core components, telomerase RNA (TR), serves as the template for this synthesis, and its evolution across different species is both complex and diverse. This review discusses recent advancements in understanding TR evolution, with a focus on plants (Viridiplantae). Utilizing novel bioinformatic tools and accumulating genomic and transcriptomic data, combined with corresponding experimental validation, researchers have begun to unravel the intricate pathways of TR evolution and telomere maintenance mechanisms. Contrary to previous beliefs, a monophyletic origin of TR has been demonstrated first in land plants and subsequently across the broader phylogenetic megagroup Diaphoretickes. Conversely, the discovery of plant-type TRs in insects challenges assumptions about the monophyletic origin of TRs in animals, suggesting evolutionary innovations coinciding with arthropod divergence. The review also highlights key challenges in TR identification and provides examples of how these have been addressed. Overall, this work underscores the importance of expanding beyond model organisms to comprehend the full complexity of telomerase evolution, with potential applications in agriculture and biotechnology.

• MeSH
• Phylogeny MeSH
• Evolution, Molecular * MeSH
• RNA * genetics   metabolism   MeSH
• Plants genetics   MeSH
• Telomerase * genetics   metabolism   MeSH
• Telomere * metabolism   genetics   MeSH
• Viridiplantae genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Differences in survival according to the pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT). A retrospective cross-sectional study including 684 patients was designed, and a Partial Least-Squares Discriminant Analysis (PLS-DA) was performed. After the PSL-DA, it was observed that the tandem -138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the -124C > T and the -138_139 CC > TT subtypes were associated with fast-growing melanomas (OR 0.5, CI 0.29-0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37-0.97, p = .037), compared to the -146C > T mutation. Finally, the -124C > T appeared to be more associated with the presence of TILs (non-brisk) than the -146C > T (OR 0.6, CI 0.40-1.01, p = .05). These findings confirmed that the -124C > T and the tandem -138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the -124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem -138_139CC > TT mutations.

• MeSH
• Humans MeSH
• Melanoma * genetics   pathology   mortality   MeSH
• Mutation MeSH
• Skin Neoplasms genetics   pathology   mortality   MeSH
• Promoter Regions, Genetic * genetics   MeSH
• Cross-Sectional Studies MeSH
• Retrospective Studies MeSH
• Telomerase * genetics   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

AIMS: Spindle-cell/sclerosing rhabdomyosarcomas (SS-RMS) are clinically and genetically heterogeneous. They include three well-defined molecular subtypes, of which those with EWSR1/FUS::TFCP2 rearrangements were described only recently. This study aimed to evaluate five new cases of SS-RMS and to perform a clinicopathological and statistical analysis of all TFCP2-rearranged SS-RMS described in the English literature to more comprehensively characterize this rare tumour type. METHODS AND RESULTS: Cases were retrospectively selected and studied by immunohistochemistry, fluorescence in situ hybridization with EWSR1/FUS and TFCP2 break-apart probes, next-generation sequencing (Archer FusionPlex Sarcoma kit and TruSight RNA Pan-Cancer Panel). The PubMed database was searched for relevant peer-reviewed English reports. Five cases of SS-RMS were found. Three cases were TFCP2 rearranged SS-RMS, having FUSex6::TFCP2ex2 gene fusion in two cases and triple gene fusion EWSR1ex5::TFCP2ex2, VAX2ex2::ALKex2 and VAX2intron2::ALKex2 in one case. Two cases showed rhabdomyoblastic differentiation and spindle-round cell/sclerosing morphology, but were characterized by novel genetic fusions including EWSR1ex8::ZBTB41ex7 and PLOD2ex8::RBM6ex7, respectively. In the statistical analysis of all published cases, CDKN2A or ALK alterations, the use of standard chemotherapy and age at presentation in the range of 18-24 years were negatively correlated to overall survival. CONCLUSION: EWSR1/FUS::TFCP2-rearranged SS-RMS is a rare rhabdomyosarcoma subtype, affecting predominantly young adults with average age at presentation 34 years (median 29.5 years; age range 7-86 years), with a predilection for craniofacial bones, rapid clinical course with frequent bone and lung metastases, and poor prognosis (3-year overall survival rate 28%).

• MeSH
• Child MeSH
• DNA-Binding Proteins genetics   MeSH
• Adult MeSH
• Gene Fusion MeSH
• In Situ Hybridization, Fluorescence MeSH
• Middle Aged MeSH
• Humans MeSH
• Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor genetics   MeSH
• RNA-Binding Protein EWS genetics   MeSH
• RNA-Binding Proteins genetics   MeSH
• Retrospective Studies MeSH
• Rhabdomyosarcoma * genetics   pathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Transcription Factors * genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

INTRODUCTION: Papillary thyroid carcinoma (PTC) frequently harbors the BRAF V600E mutation. Recent research suggests that aggressive behavior in BRAF V600E+ PTC may be due to an undetected mutation in the TERT gene. This study aims to observe the clinicopathological features of BRAF V600+ PTC and correlate them with surgical treatment complications. METHODS: A retrospective analysis was conducted on the BRAF V600E+ PTC cohort from July 2019 to January 2023. The histopathological features and surgical treatment (total thyroidectomy - group A, total thyroidectomy + central block neck dissection - group B) complications were correlated. Patients with TERT and TP53 mutation were excluded. Next-generation sequencing and real-time PCR were used for genetic analysis. RESULTS: Out of 121 PTCs, 65 cases showed BRAF V600E mutation with the following features: intracapsular spread (13.8%), extracapsular spread (27.7%), extrathyroidal spread (15.4%), multifocality (26.2%), angioinvasion (12.3%), and local metastasis (27.7%). The incidence of surgical complications in group A/B was: reversible recurrent laryngeal nerve (RLN) paresis 3.7/7.1%, RLN paresis permanent 0/2.4%, paresthesia 6.8/23.8%, hypocalcemia 36.4/61.9% on day 1 and 27.3/33.3% on day 3, and bleeding 2.3/9.5%. There was no significant difference in clinicopathological features between the BRAF V600E+ and BRAF V600E- PTC groups. Group B had a significantly higher incidence of hypoacalcaemia on postoperative day 1 (p = 0.047). CONCLUSION: The BRAF V600E mutation will certainly remain important in the preoperative diagnosis of PTC. The more radical surgical procedures currently recommended may be abandoned in the future, particularly elective CLND, which has a higher risk of postoperative complications.

• MeSH
• Adult MeSH
• Neck Dissection adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• Tumor Suppressor Protein p53 * genetics   MeSH
• Thyroid Neoplasms * genetics   surgery   pathology   MeSH
• Thyroid Cancer, Papillary * genetics   surgery   pathology   MeSH
• Postoperative Complications epidemiology   etiology   MeSH
• Proto-Oncogene Proteins B-raf * genetics   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Telomerase * genetics   MeSH
• Thyroidectomy * adverse effects   methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Soft tissue sarcomas harboring EWSR1::PATZ1 are a recently recognized entity with variable morphology and a heterogeneous immunohistochemical profile. We studied 17 such tumors. The tumors occurred in 12 men and 5 women (median age, 50 years; range, 15-71 years), involved the thoracoabdominal soft tissues (14 cases; 82%), lower extremities (2 cases; 12%), and tongue (1 case; 6%), and ranged from 0.7 to 11.3 cm (median, 4.7 cm). All but 1 patient received complete surgical resection; 7 were also treated with neoadjuvant chemo/radiotherapy. All cases showed typical features of EWSR1::PATZ1 sarcoma, including uniform round to spindled cells, fibromyxoid matrix, fibrous bands, hyalinized vessels, and pseudoalveolar/microcystic spaces. Unusual features, seen in a subset of cases, included degenerative-appearing nuclear atypia, epithelioid cytomorphology, mature fat, abundant rhabdomyoblasts, high mitotic activity, and foci with increased cellularity and nuclear atypia. Positive immunohistochemical results were desmin (16/17, 94%), MyoD1 (13/14, 93%), myogenin (6/14, 43%), GFAP (10/10, 100%), S100 protein (15/17, 88%), SOX10 (7/13, 54%), keratin (10/17, 59%), CD99 (4/11, 36%), H3K27me3 (retained expression 9/9, 100%), p16 (absent expression 1/4, 25%), and p53 (wild type 3/3, 100%). Fusion events included EWSR1 exon 8::PATZ1 exon 1 (14/17, 82%), EWSR1 exon 9::PATZ1 exon 1 (2/17, 12%), and EWSR1 exon 7::PATZ1 exon 1 (1/17, 6%). No evaluated tumor had alterations of CDKN2A/B and/or TP53, or MDM2 amplification. Clinical follow-up (16 patients: median, 13.5 months; range, 1-77 months) showed distant metastases in 3 patients (1/3 at time of presentation) and no local recurrences. At the time of last follow-up, 14 patients were disease free, 1 was alive with disease, 1 was dead of disease (at 13 months), and 1 had an indeterminant pulmonary nodule. We conclude that the morphologic spectrum of EWSR1::PATZ1 is broader than has been previously appreciated. Although more long-term follow-up is needed, the prognosis of these very rare sarcomas may be more favorable than previously reported.

• MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Soft Tissue Neoplasms * genetics   therapy   pathology   MeSH
• Prognosis MeSH
• RNA-Binding Protein EWS genetics   MeSH
• S100 Proteins MeSH
• Repressor Proteins genetics   MeSH
• Sarcoma * genetics   therapy   pathology   MeSH
• Kruppel-Like Transcription Factors MeSH
• Transcription Factors MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far. OBJECTIVE: We aimed to deliver pilot data on the genetic landscape of ALS in our country. METHODS: A cohort of patients with ALS (n = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients - with concomitant FTD (n = 7) and with young-onset of the disease (n = 22). RESULTS: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72). Surprisingly, none of the young-onset sporadic patients harboured a pathogenic variant and we detected no pathogenic SOD1 variant in our cohort. CONCLUSION: Our findings resemble those from other European populations, with the highest prevalence of HRE in the C9orf72 gene. Further, our findings suggest a possibility of a missing genetic variability among young-onset patients.

• MeSH
• Amyotrophic Lateral Sclerosis * genetics   MeSH
• DNA-Binding Proteins genetics   MeSH
• Adult MeSH
• DNA Repeat Expansion * MeSH
• Frontotemporal Dementia * genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• C9orf72 Protein * genetics   MeSH
• RNA-Binding Protein FUS genetics   MeSH
• Protein Serine-Threonine Kinases genetics   MeSH
• Aged MeSH
• Age of Onset MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

• MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor MeSH
• Soft Tissue Neoplasms * MeSH
• RNA-Binding Protein EWS MeSH
• RNA-Binding Protein FUS MeSH
• Sarcoma * diagnosis   genetics   MeSH
• NFATC Transcription Factors MeSH
• Transcription Factors metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH