PURPOSE: The field cancerization concept indicates the presence of pre-cancerous changes in clinically normal tissue surrounding the tumor. In squamous cell carcinoma of the oral tongue (SCCOT) which is infrequently linked to human papillomavirus infection, we have previously reported that clinically normal tongue contralateral to tumor (NTCT) is molecularly abnormal. Here, combining our transcriptomic and genomic data, we aimed to investigate the contribution of molecular changes in NTCT to cancer development. METHODS: Microarray gene expression data of 14 healthy controls, 23 NTCT and 29 SCCOT samples were investigated to characterize transcriptional profiles in NTCT. Whole exome sequencing and RNA-sequencing data of paired NTCT and tumor samples from 15 SCCOT patients were used to study correlation between copy number variation and differential gene expression. RESULTS: Using supervised multivariate partial least squares discriminant analysis, a total of 61 mRNAs that distinguish NTCT from healthy tongue were selected. Functional enrichment analysis of the 22 upregulated genes showed increased "positive regulation of nitrogen compound metabolic process" in NTCT. All 12 genes involved in this process have roles in apoptosis (anti- and/or pro-apoptotic). Compared to healthy controls, Zinc Finger Protein 395 (ZNF395), a pro-apoptotic tumor suppressor located on chromosome 8p, was the only gene showing increased mRNA level in NTCT whereas decreased in SCCOT. Given the frequent loss of chromosome 8p in SCCOT, the impact of ZNF395 copy number variation on gene expression was further examined, revealing a positive correlation between copy number and mRNA level (correlation coefficient = 0.572, p < 0.001). CONCLUSION: NTCT is susceptible to malignant transformation, where tissue homeostasis is maintained at least partly through regulation of apoptosis. Loss of the pro-apoptotic gene ZNF395 could thus initiate cancer development.

• Klíčová slova
• ZNF395, Apoptosis, Etiologic field effect, Field cancerization, SCCOT,
• MeSH
• apoptóza * genetika   MeSH
• dlaždicobuněčné karcinomy hlavy a krku * genetika   patologie   MeSH
• dospělí MeSH
• homeostáza genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory jazyka * genetika   patologie   MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• spinocelulární karcinom genetika   patologie   MeSH
• transkriptom MeSH
• upregulace * MeSH
• variabilita počtu kopií segmentů DNA MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

• Klíčová slova
• Molecular neuro-oncology, PLAGL1, PLAGL2, Pediatric cancer,
• MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• kojenec MeSH
• lidé MeSH
• metylace DNA MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory centrálního nervového systému * genetika   MeSH
• předškolní dítě MeSH
• primitivní neuroektodermové nádory * genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• proteiny vázající RNA genetika   MeSH
• signální dráha Wnt genetika   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• nádorové supresorové proteiny MeSH
• PLAGL1 protein, human MeSH Prohlížeč
• PLAGL2 protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• proteiny vázající RNA MeSH
• transkripční faktory MeSH

Epithelial ovarian carcinoma (EOC) is highly fatal because of the risk of resistance to therapy and recurrence. We performed whole-exome sequencing of blood and tumor tissue pairs of 50 patients with surgically resected EOC. Compared with sensitive patients, platinum-resistant patients had a significantly higher somatic mutational rate in <i>TP53</i> and lower in several genes from the Hippo pathway. We confirmed the pivotal role of somatic mutations in homologous recombination repair genes in platinum sensitivity and favorable prognosis of EOC patients. Implementing the germline homologous recombination repair profile significantly improved the prediction. In addition, distinct mutational signatures, for example, SBS6, and overall mutational load, somatic mutations in <i>PABPC1</i>, <i>PABPC3</i>, and <i>TFAM</i> co-segregated with the resistance status, high-grade serous carcinoma subtype, or overall survival of patients. We generated germline and somatic genetic landscapes of prognostically different subgroups of EOC patients for further follow-up studies focused on utilizing the observed associations in precision oncology.

• MeSH
• epiteliální ovariální karcinom farmakoterapie   genetika   MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• nádory vaječníků * farmakoterapie   genetika   MeSH
• platina * farmakologie   terapeutické užití   MeSH
• sekvenování exomu MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• platina * MeSH

• Klíčová slova
• IncRNA H19 regulation, LIN28B overexpression, pediatric leukemia,
• MeSH
• dítě MeSH
• kojenec MeSH
• leukemie genetika   metabolismus   patologie   MeSH
• lidé MeSH
• mladiství MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• předškolní dítě MeSH
• proteiny vázající RNA biosyntéza   genetika   MeSH
• regulace genové exprese u leukemie * MeSH
• RNA dlouhá nekódující genetika   metabolismus   MeSH
• RNA nádorová genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• H19 long non-coding RNA MeSH Prohlížeč
• LIN28B protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• proteiny vázající RNA MeSH
• RNA dlouhá nekódující MeSH
• RNA nádorová MeSH