Comprehensive Clinical Genetics, Molecular and Pathological Evaluation Efficiently Assist Diagnostics and Therapy Selection in Breast Cancer Patients with Hereditary Genetic Background.

Using multigene panel testing for the diagnostic evaluation of patients with hereditary breast and ovarian cancer (HBOC) syndrome often identifies clinically actionable variants in genes with varying levels of penetrance. High-penetrance genes (, , , , , , ) inform specific clinical surveillance and therapeutic decisions, while recommendations for moderate-penetrance genes (, , , , , , , , , , , ) are more limited. A detailed disease history, including pedigree data, helps formulate the most appropriate and personalised management strategies.

TULIPs decorate the three-dimensional genome of PFA ependymoma.

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues.

Cost-effectiveness of Genetic Testing of Endocrine Tumor Patients Using a Comprehensive Hereditary Cancer Gene Panel.

Introduction: Heterogenous clinical manifestations, overlapping phenotypes, and complex genetic backgrounds are common in patients with endocrine tumors. There are no comprehensive recommendations for genetic testing and counseling of these patients compared to other hereditary cancer syndromes. The application of multigene panel testing is common in clinical genetic laboratories, but their performance for patients with endocrine tumors has not been assessed.

Variants Extend the Mutational Profile of Hungarian Patients with Breast and Ovarian Cancer.

Background: The pathogenic/likely pathogenic (P/LP) variant detection rate and profile of , the third most important breast cancer gene, may vary between different populations.

Methods: was analyzed in peripheral blood samples of three independent cohorts: prospectively between September 2021 and March 2023 (i) in 1280 consecutive patients with breast and/or ovarian cancer (HBOC), (ii) in 568 patients with other cancers (controls), and retrospectively, (iii) in 191 young breast cancer (<33 years, yBC) patients. These data were compared with data of 134,187 non-cancer individuals retrieved from the Genome Aggregation Database.

A common genetic variation in may associate with cancer risk in patients with Lynch syndrome.

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is a common genetic predisposition to cancer due to germline mutations in genes affecting DNA mismatch repair. Due to mismatch repair deficiency, developing tumors are characterized by microsatellite instability (MSI-H), high frequency of expressed neoantigens and good clinical response to immune checkpoint inhibitors. Granzyme B (GrB) is the most abundant serine protease in the granules of cytotoxic T-cells and natural killer cells, mediating anti-tumor immunity.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation.

Germline Structural Variations in Cancer Predisposition Genes.

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes.

Application of Multilayer Evidence for Annotation of C-Terminal Variants.

The clinical relevance of the C-terminal stop codon variants is controversial. The pathogenic role of the germline c.9976A>T and c.

Complex Characterization of Germline Large Genomic Rearrangements of the and Genes in High-Risk Breast Cancer Patients-Novel Variants from a Large National Center.

Large genomic rearrangements (LGRs) affecting one or more exons of and constitute a significant part of the mutation spectrum of these genes. Since 2004, the National Institute of Oncology, Hungary, has been involved in screening for LGRs of breast or ovarian cancer families enrolled for genetic testing. LGRs were detected by multiplex ligation probe amplification method, or next-generation sequencing.

The Spectrum of Protein Truncating Variants in European Breast Cancer Cases.

Germline protein truncating variants (PTVs) in the gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with PTVs ascertained in 20 centers from 13 European countries.

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

Background: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.

mTOR pathway as a potential target in a subset of human medulloblastoma.

As mammalian Target of Rapamycin (mTOR) plays role in protein synthesis and metabolism, mTOR pathway activation is involved in the pathogenesis of several types of tumors. Our aim was to elucidate its role in medulloblastoma in terms of prognosis and as a therapeutic target. Members of activated mTOR complex 1 (mTORC1) pathway, phospho-mTOR (p-mTOR) and phospho-S6 (p-S6) were examined by immunohistochemistry in formalin fixed paraffin embedded samples of 40 patients with medulloblastoma, and results were compared to clinical features and survival of patients.

[Antiangiogenic treatment of pediatric CNS tumors in Hungary with the Kieran schedule].

In Hungary a new oral antiangiogenic treatment was introduced in cases of primary chemoresistant or recurrent pediatric CNS tumors, called Kieran schedule. The early results of this treatment were analyzed. From 2010 at Semmelweis University on individual decisions a daily combined per oral treatment was introduced in pediatric patients with recurrent or progressive CNS tumor (Kieran schedule: thalidomid, celecoxib, etoposid and cyclophosphamid).

Adenosine A2A receptor activation protects CD4+ T lymphocytes against activation-induced cell death.

Activation-induced cell death (AICD) is initiated by T-cell receptor (TCR) restimulation of already activated and expanded peripheral T cells and is mediated through Fas/Fas ligand (FasL) interactions. Adenosine is a purine nucleoside signaling molecule, and its immunomodulatory effects are mediated by 4 G-protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In this study, we investigated the role of A(2A) receptors in regulating CD4(+) T lymphocyte AICD.