The genetic basis of nonsyndromic familial nonmedullary thyroid carcinoma (FNMTC) is still poorly understood, as the susceptibility genes identified so far only account for a small percentage of the genetic burden. Recently, germline mutations in DNA repair-related genes have been reported in cases with thyroid cancer. In order to clarify the genetic basis of FNMTC, 94 genes involved in hereditary cancer predisposition, including DNA repair genes, were analyzed in 48 probands from FNMTC families, through targeted next-generation sequencing (NGS). Genetic variants were selected upon bioinformatics analysis and in silico studies. Structural modeling and network analysis were also performed. In silico results of NGS data unveiled likely pathogenic germline variants in 15 families with FNMTC, in genes encoding proteins involved in DNA repair (ATM, CHEK2, ERCC2, BRCA2, ERCC4, FANCA, FANCD2, FANCF, and PALB2) and in the DICER1, FLCN, PTCH1, BUB1B, and RHBDF2 genes. Structural modeling predicted that most missense variants resulted in the disruption of networks of interactions between residues, with implications for local secondary and tertiary structure elements. Functional annotation and network analyses showed that the involved DNA repair proteins functionally interact with each other, within the same DNA repair pathway and across different pathways. MAPK activation was a common event in tumor progression. This study supports that rare germline variants in DNA repair genes may be accountable for FNMTC susceptibility, with potential future utility in patients\' clinical management, and reinforces the relevance of DICER1 in disease etiology.

Kaspar Hauser\'s parentage has been the subject of research and debate for nearly 200 years. As for his possible aristocratic descent through the House of Baden, there is suspicion that he was swapped as a baby, kidnapped, and kept in isolation to bring a collateral lineage to the throne. In the last 28 years, various genetic analyses have been carried out to investigate this possible aristocratic origin. Previous results using less sensitive Sanger and electrophoresis-based methods were contradictory, and moreover, the authenticity of some samples was disputed, thus leaving the question open. Our analyses using modern capture- and whole genome-based massively parallel sequencing techniques reveal that the mitochondrial DNA haplotypes in different samples attributed to Kaspar Hauser were identical, demonstrating authenticity for the first time, and clearly different from the mitochondrial lineage of the House of Baden, which rules out a maternal relationship and thus the widely believed \"Prince theory\".

This article explores the emergence of molecular approaches in German genetic research during the 1958-1968 decade as a period of contingency and alternative possibilities. We introduce \"Narratives of Contingency\" as an analytical framework to examine how scientists construct a specific narrative - linking past experiences with expectations of future conditions - in order to outline and navigate pathway-decisions in the present. We apply this framework to Hans-Jörg Rheinberger\'s developmental model of molecular genetics and illustrate how the stages he identifies - the direction of the field, institutional developments, and epistemological demarcations - were already central themes in the comparative practices underlying narratives of contingency in this early period. Narratives of contingency can thus serve as a systematic framework for analyzing the processes through which new scientific fields, institutions, and epistemic horizons emerge, and possibly also for identifying historically plausible fork moments or alternative pathways not taken.

Pediatric arteriovenous malformations (AVMs) are rare but carry a risk of devastating neurological morbidity and mortality. Rupture of a cerebral AVM is the most common cause of spontaneous intracranial hemorrhage in children, with an unruptured AVM having an approximate hemorrhage risk of 2%-4% per year. The complex etiology of pediatric AVMs persists as an impediment to a comprehensive understanding of pathogenesis and subsequent targeted gene therapies. While AVMs secondary to vascular malformation syndromes have a clearer pathogenesis, a variety of gene mutations have been identified within sporadic AVM cases. The Ephrin B2/EphB4 (RASA-1, KRAS, and MEK) signaling axis, hemorrhagic telangiectasia, NOTCH, and TIE2 receptor complexes (PIK3CA and mTOR), in addition to other isolated gene variants, have been implicated in AVM pathogenesis. Furthering the understanding of the molecular mechanisms of AVM pathogenesis will lead to future novel therapies and treatment paradigms. Given the expected lifespan of a child, pediatric patients have an unacceptably high cumulative lifetime risk of hemorrhage. AVM treatment strategies are dependent on AVM grade, provider preference, and institutional resources. While open microsurgery is the mainstay of treatment for some AVMs, radiosurgery for definitive treatment and adjunctive endovascular embolization are also used extensively. There is increasing evidence indicating that all three modalities play important and potentially synergistic roles in the armamentarium for pediatric AVM treatment. This review serves to report current understanding in the genetic and molecular mechanisms of pediatric AVMs, review clinical diagnostic and classification criteria, and detail treatment options and subsequent outcomes of pediatric AVM patients.

Glioneuronal and neuronal tumors (GNTs) are slow-growing, lower-grade neuroepithelial tumors characterized by mature neuronal differentiation and, less consistently, glial differentiation. Their identification has traditionally relied on histological proof of neuronal differentiation, reflecting the well-differentiated nature of GNTs. However, after discovering genetic alterations in GNTs, particularly those in the MAP-kinase pathway, it became evident that histological diagnoses do not always correlate with genetic alterations and vice versa. Therefore, molecular-based classification is now warranted since several inhibitors targeting the MAP-kinase pathway are available. The World Health Organization classification published in 2021 applied DNA methylation profiling to segregate low-grade neuroepithelial tumors. As GNTs are essentially indolent, radical resection and unnecessary chemoradiotherapy may be more harmful than beneficial for patients. Preserving tumor tissue for potential future treatments is more important for patients with GNTs.

Chromosomal instability (CIN) is a pivotal factor in gliomas, contributing to their complexity, progression, and therapeutic challenges. CIN, characterized by frequent genomic alterations during mitosis, leads to genetic abnormalities and impacts cellular functions. This instability results from various factors, including replication errors and toxic compounds. While CIN\'s role is well documented in cancers like ovarian cancer, its implications for gliomas are increasingly recognized. CIN influences glioma progression by affecting key oncological pathways, such as tumor suppressor genes (e.g., TP53), oncogenes (e.g., EGFR), and DNA repair mechanisms. It drives tumor evolution, promotes inflammatory signaling, and affects immune interactions, potentially leading to poor clinical outcomes and treatment resistance. This review examines CIN\'s impact on gliomas through a narrative approach, analyzing data from PubMed/Medline, EMBASE, the Cochrane Library, and Scopus. It highlights CIN\'s role across glioma subtypes, from adult glioblastomas and astrocytomas to pediatric oligodendrogliomas and astrocytomas. Key findings include CIN\'s effect on tumor heterogeneity and its potential as a biomarker for early detection and monitoring. Emerging therapies targeting CIN, such as those modulating tumor mutation burden and DNA damage response pathways, show promise but face challenges. The review underscores the need for integrated therapeutic strategies and improved bioinformatics tools like CINdex to advance understanding and treatment of gliomas. Future research should focus on combining CIN-targeted therapies with immune modulation and personalized medicine to enhance patient outcomes.

BACKGROUND: Prostate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADT) are a cornerstone of treatment. ADT responsiveness may be associated with germline alterations in genes that regulate androgen production, uptake, and conversion (APUC).
METHODS: We analyzed whole-exome sequencing (WES) and whole transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris POA DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates.
RESULTS: Six APUC genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) exhibited coalescent gene behavior in a cohort of metastatic tumors (n = 208). In the Caris POA dataset, the 6 APUC genes (APUC-6) exhibited robust clustering in primary prostate (n = 4,490) and metastatic (n = 2,593) biopsies. Surprisingly, tumors with elevated APUC-6 expression had statically lower expression of AR, AR-V7, and AR signaling scores suggesting ligand-driven disease biology. APUC-6 genes instead associated with the expression of alternative steroid hormone receptors, ESR1/2 and PGR. We used RNA expression of AR or APUC-6 genes to define two subgroups of tumors with differential association with hallmark pathways and cell surface targets.
CONCLUSIONS: The APUC-6 high/AR-low tumors represented a subgroup of patients with good clinical outcomes in contrast to the AR-high or neuroendocrine prostate cancers. Altogether, measuring the aggregate expression of APUC-6 genes in current genomic tests identifies PCs that are ligand- (rather than AR-) driven and require distinct therapeutic strategies.
BACKGROUND: NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.

BackgroundCystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases.MethodsUsing whole genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies.ResultsIn 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with novel statistically significant gene-based signals in COL4A3 and (monoallelic) PKHD1. Quantification of disease risk for each gene (with replication in the separate UK BioBank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations but suggested this category of variation contributes 3-9% to the heritability of CyKD across European ancestries.ConclusionBy providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counselling in the clinic.Keywords: genomics, cystic kidney disease, renal, ADPKD, WGS.

Tumors resembling tenosynovial giant cell tumor (TGCT) but additionally forming chondroid matrix (C-TGCT) are rare and most often involve the temporomandibular joint (TMJ). We studied 21 tumors consisting of synoviocytes (large, eosinophilic mononuclear cells containing hemosiderin) and chondroid matrix to better understand these unusual neoplasms. The tumors occurred in 10 males and 11 females, ranging from 31-80 years (median, 50 years) and involved the temporomandibular joint region (16), extremities (4), and spine (1). As in conventional TGCT, all were composed of synoviocytes, small histiocytes, foamy macrophages, siderophages and osteoclast-like giant cells in variably hyalinized background. Expansile nodules of large, moderately atypical synoviocytes were present, in addition to \"chondroblastoma-like\", \"chondroma-like\", or \"phosphaturic mesenchymal tumor-like\" calcified matrix. The synoviocytes expressed clusterin (17/19) and less often desmin (3/15). The tumors were frequently CSF1-positive by CISH (8/13) but at best weakly positive for CSF1 by IHC (0/3). Background small histiocytes were CD163-positive (12/12). All were FGF23-negative (0/10). Cells within lacunae showed a synoviocytic phenotype (clusterin-positive; S100 protein and ERG-negative). RNA-seq was successful in 13 cases; fusions were present in 7 tumors, including FN1::TEK (5 cases), FN1::PRG4 (2 cases), MALAT1::FN1, PDGFRA::USP35 and TIMP3::ZCCHC7 (1 case each). Three tumors contained more than one fusion (FN1::PRG4 with TIMP3::ZCCHC7, FN1::TEK with FN1::PRG4, and FN1::TEK with MALAT1::FN1). Clinical follow up (17 patients; median follow up duration 38 months; range 4-173 months) showed 13 (76%) to be alive without evidence of disease and 4 (24%) to be alive with persistent/recurrent local disease. No metastases or deaths from disease were observed. We conclude that these unusual tumors represent a distinct category of synoviocytic neoplasia, which we term \"chondroid synoviocytic neoplasm\", rather than simply ordinary TGCT with cartilage. Despite potentially worrisome morphologic features, they appear to behave in at most a locally aggressive fashion.

BACKGROUND: The International Federation of Gynecology and Obstetrics (FIGO) revised the staging system of endometrial cancer in 2023. In this study, we aimed to determine stage transitions and prognosis of endometrial cancer using FIGO2008, FIGO2023 without molecular classification (FIGO2023), and FIGO2023 with molecular classification (FIGO2023m).
METHODS: Eighty-three patients diagnosed with endometrial cancer who underwent surgery and next-generation sequencing (NGS) molecular profiling as part of the Project HOPE cohort study were enrolled. Each case was staged according to the FIGO2008 and FIGO2023 criteria, and we evaluated changes in stage and disease-specific survival (DSS). Molecular classification based on NGS was performed to evaluate FIGO2023m, and the concordance rate with immunohistochemical marker analysis was assessed.
RESULTS: Transitioning from FIGO2008 to FIGO2023 resulted in the restaging of 18 cases. Conversely, transitioning from FIGO2008 to FIGO2023m led to the restaging of 15 cases. The concordance rate between FIGO2023 and FIGO2023m staging was 96.4%. With FIGO2023m, the 5-year DSS was 97.6% for stage I (95% confidence interval [CI] 83.9-99.7), 83.3% for stage II (95% CI 56.8-94.3), 100% for stage III (95% CI NA), and 25.0% for stage IV (95% CI 0.9-66.5). Discrepancies in disease staging due to discordance between simplified surrogate marker analysis and NGS evaluation occurred in two cases.
CONCLUSIONS: The revision of the staging system from FIGO2008 to FIGO2023 and FIGO2023m resulted in the restaging of several cases, with significant changes between stages I and II.