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Keywords = NOTCH3 gene mutation

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20 pages, 2234 KiB  
Review
Intracranial Large Artery Involvement in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Tale of Two Genes?
by Marialuisa Zedde and Rosario Pascarella
Genes 2025, 16(8), 882; https://doi.org/10.3390/genes16080882 - 26 Jul 2025
Viewed by 347
Abstract
Background/Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a prevalent Mendelian disorder caused by mutations in the NOTCH3 gene, primarily impacting cerebral small blood vessels. This review aims to explore the involvement of large intracranial arteries in CADASIL, [...] Read more.
Background/Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a prevalent Mendelian disorder caused by mutations in the NOTCH3 gene, primarily impacting cerebral small blood vessels. This review aims to explore the involvement of large intracranial arteries in CADASIL, particularly focusing on the association with RNF213 polymorphisms, especially in Asian populations. Methods: A comprehensive literature review was conducted to gather data on the morphological features of both small and large intracranial arteries in CADASIL, examining clinical manifestations, imaging findings, and genetic associations. Results: The findings indicate that while CADASIL is predominantly characterized by small vessel disease, a significant number of patients also exhibit large artery involvement, particularly Asian populations where RNF213 polymorphisms may play a critical role. The review highlights the evidence of intracranial stenosis and the potential implications of traditional vascular risk factors, such as hypertension and diabetes mellitus, which are prevalent in these populations. Conclusions: The involvement of larger intracranial arteries in CADASIL underscores the complexity of the disease, suggesting that both genetic predispositions and environmental factors contribute to vascular abnormalities. Further research is needed to clarify these relationships and improve diagnostic and therapeutic strategies for CADASIL patients. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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13 pages, 1527 KiB  
Article
Ethnic-Specific and UV-Independent Mutational Signatures of Basal Cell Carcinoma in Koreans
by Ye-Ah Kim, Seokho Myung, Yueun Choi, Junghyun Kim, Yoonsung Lee, Kiwon Lee, Bark-Lynn Lew, Man S. Kim and Soon-Hyo Kwon
Int. J. Mol. Sci. 2025, 26(14), 6941; https://doi.org/10.3390/ijms26146941 - 19 Jul 2025
Viewed by 310
Abstract
Basal cell carcinoma (BCC), the most common skin cancer, is primarily driven by Hedgehog (Hh) and TP53 pathway alterations. Although additional pathways were implicated, the mutational landscape in Asian populations, particularly Koreans, remains underexplored. We performed whole-exome sequencing of BCC tumor tissues from [...] Read more.
Basal cell carcinoma (BCC), the most common skin cancer, is primarily driven by Hedgehog (Hh) and TP53 pathway alterations. Although additional pathways were implicated, the mutational landscape in Asian populations, particularly Koreans, remains underexplored. We performed whole-exome sequencing of BCC tumor tissues from Korean patients and analyzed mutations in 11 established BCC driver genes (PTCH1, SMO, GLI1, TP53, CSMD1/2, NOTCH1/2, ITIH2, DPP10, and STEAP4). Mutational profiles were compared with Caucasian cohort profiles to identify ethnicity-specific variants. Ultraviolet (UV)-exposed and non-UV-exposed tumor sites were compared; genes unique to non-UV-exposed tumors were further analyzed with protein–protein interaction analysis. BCCs in Koreans exhibited distinct features, including fewer truncating and more intronic variants compared to Caucasians. Korean-specific mutations in SMO, PTCH1, TP53, and NOTCH2 overlapped with oncogenic gain-of-function/loss-of-function (GOF/LOF) variants annotated in OncoKB, with some occurring at hotspot sites. BCCs in non-exposed areas showed recurrent mutations in CSMD1, PTCH1, and NOTCH1, suggesting a UV-independent mechanism. Novel mutations in TAS1R2 and ADCY10 were exclusive to non-exposed BCCs, with protein–protein interaction analysis linking them to TP53 and NOTCH2. We found unique ethnic-specific and UV-independent mutational profiles of BCCs in Koreans. TAS1R2 and ADCY10 may contribute to tumorigenesis of BCC in non-exposed areas, supporting the need for population-specific precision oncology. Full article
(This article belongs to the Special Issue Skin Cancer: From Molecular Pathophysiology to Novel Treatment)
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11 pages, 557 KiB  
Review
Molecular Characterization of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma
by Jason C. Klein, Breelyn A. Wilky and Heide L. Ford
Cancers 2025, 17(11), 1785; https://doi.org/10.3390/cancers17111785 - 27 May 2025
Viewed by 874
Abstract
Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are dermal-based sarcomas that fall along a spectrum with different rates of local recurrence and metastasis. While AFX is less aggressive and confined to the dermis, PDS invades the subcutis. These tumors are most likely [...] Read more.
Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are dermal-based sarcomas that fall along a spectrum with different rates of local recurrence and metastasis. While AFX is less aggressive and confined to the dermis, PDS invades the subcutis. These tumors are most likely of mesenchymal origin, although they share common mutations with undifferentiated squamous cell carcinoma. Due to the rarity of these tumors, few studies have examined their molecular composition and gene expression. Initial studies, including exome and bulk RNA sequencing, targeted DNA sequencing of gene panels, DNA methylation, and copy number analyses, have identified recurrent UV-induced mutations in TP53, NOTCH, CDKN2A, and the TERT promoter. Recently, the first scRNA-seq dataset in AFX and PDS identified COL6A3 as a novel biomarker. In this review, we synthesize the above datasets and discuss our current understanding of the molecular drivers and prognostic biomarkers in these tumors. Full article
(This article belongs to the Special Issue Precision Oncology for Rare Skin Cancers)
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23 pages, 7972 KiB  
Article
Short Tandem Repeat (STR) Somatic Mutation in Non-Melanoma Skin Cancer (NMSC): Association with Transcriptomic Profile and Potential Implications for Therapy
by Muhammad G. Kibriya, Armando Almazan, Maria Argos, Tariqul Islam, Christopher R. Shea, Habibul Ahsan and Farzana Jasmine
Cancers 2025, 17(10), 1669; https://doi.org/10.3390/cancers17101669 - 15 May 2025
Viewed by 671
Abstract
Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times [...] Read more.
Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times (e.g., AAAAA or TTTTT). Only recently have mutations in such STR regions been seen in colorectal cancer, where microsatellite instability (MSI) is common. In non-melanoma skin cancer (NMSC), MSI is rare. In this study, we focus on somatic mutations in such homopolymeric regions in NMSC and their functional implications. Methods: We performed targeted DNA sequencing (paired tissue and blood from the same individual), using more than 400 cancer-related genes from 32 NMSC patients as cases and non-lesional skin tissue from 16 independent individuals as controls. Results: We identified NMSC-associated STR somatic mutations. These are associated with the dysregulation of DNA damage and repair mechanisms. In artificial intelligence (AI) predictive modeling, these markers could successfully differentiate basal cell carcinoma (BCC) and non-lesional skin tissue. To our knowledge, we present the first study focusing on STR somatic mutations in multiple cancer-related genes in NMSC found only in tumor tissue and not in non-lesional skin tissue. Some of them (APC, BRAF) are associated with more pronounced dysregulation of relevant gene pathways (hedgehog, Notch signaling, and Wnt signaling). Conclusions: Our findings suggest that this STR somatic mutation status might potentially be used to select BCC patients who could benefit from certain precision therapy including hedgehog inhibitors, gamma-secretase inhibitors, anti-Vasuclar endothelial growth factor (VEGF), proteasome inhibitors, and immune check-point inhibitors. Full article
(This article belongs to the Special Issue Advances in Genetic and Molecular Approaches to Skin Cancer)
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41 pages, 614 KiB  
Review
Glial Cells in Spinal Muscular Atrophy: Speculations on Non-Cell-Autonomous Mechanisms and Therapeutic Implications
by Andrej Belančić, Tamara Janković, Elvira Meni Maria Gkrinia, Iva Kristić, Jelena Rajič Bumber, Valentino Rački, Kristina Pilipović, Dinko Vitezić and Jasenka Mršić-Pelčić
Neurol. Int. 2025, 17(3), 41; https://doi.org/10.3390/neurolint17030041 - 13 Mar 2025
Cited by 1 | Viewed by 1627
Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous deletions or mutations in the SMN1 gene, leading to progressive motor neuron degeneration. While SMA has been classically viewed as a motor neuron-autonomous disease, increasing evidence indicates a significant role of glial [...] Read more.
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous deletions or mutations in the SMN1 gene, leading to progressive motor neuron degeneration. While SMA has been classically viewed as a motor neuron-autonomous disease, increasing evidence indicates a significant role of glial cells—astrocytes, microglia, oligodendrocytes, and Schwann cells—in the disease pathophysiology. Astrocytic dysfunction contributes to motor neuron vulnerability through impaired calcium homeostasis, disrupted synaptic integrity, and neurotrophic factor deficits. Microglia, through reactive gliosis and complement-mediated synaptic stripping, exacerbate neurodegeneration and neuroinflammation. Oligodendrocytes exhibit impaired differentiation and metabolic support, while Schwann cells display abnormalities in myelination, extracellular matrix composition, and neuromuscular junction maintenance, further compromising motor function. Dysregulation of pathways such as NF-κB, Notch, and JAK/STAT, alongside the upregulation of complement proteins and microRNAs, reinforces the non-cell-autonomous nature of SMA. Despite the advances in SMN-restorative therapies, they do not fully mitigate glial dysfunction. Targeting glial pathology, including modulation of reactive astrogliosis, microglial polarization, and myelination deficits, represents a critical avenue for therapeutic intervention. This review comprehensively examines the multifaceted roles of glial cells in SMA and highlights emerging glia-targeted strategies to enhance treatment efficacy and improve patient outcomes. Full article
(This article belongs to the Special Issue Molecular Research of CNS Diseases and Neurological Disorders)
15 pages, 5075 KiB  
Article
Novel De Novo BRCA2 Variant in an Early-Onset Ovarian Cancer Reveals a Unique Tumor Evolution Pathway
by Gianmaria Miolo, Giovanni Canil, Maurizio Polano, Michele Dal Bo, Alessia Mondello, Antonio Palumbo, Fabio Puglisi and Giuseppe Corona
Int. J. Mol. Sci. 2025, 26(5), 2295; https://doi.org/10.3390/ijms26052295 - 5 Mar 2025
Viewed by 1168
Abstract
Ovarian cancer (OC) is a highly heterogeneous malignancy, often characterized by complex genomic alterations that drive tumor progression and therapy resistance. In this paper, we report a novel de novo BRCA2 germline variant NM_000059.3:c.(8693_8695delinsGT) associated with early-onset OC that featured two regions with [...] Read more.
Ovarian cancer (OC) is a highly heterogeneous malignancy, often characterized by complex genomic alterations that drive tumor progression and therapy resistance. In this paper, we report a novel de novo BRCA2 germline variant NM_000059.3:c.(8693_8695delinsGT) associated with early-onset OC that featured two regions with differential MMR (Mismatch Repair) gene expression. To date, only six cases of de novo BRCA2 variants have been reported, none of which were associated with early-onset high-grade serous OC. The immunohistochemical analysis of MMR genes revealed two distinct tumor areas, separated by a clear topographic boundary, with the heterogeneous expression of MLH1 and PMS2 proteins. Seventy-five percent of the tumor tissue showed positivity, while the remaining 25% exhibited a complete absence of expression, underscoring the spatial variability in MMR gene expression within the tumor. Integrated comparative spatial genomic profiling identified several tumor features associated with the genetic variant as regions of loss of heterozygosity (LOH) that involved BRCA2 and MLH1 genes, along with a significantly higher mutational tumor burden in the tumor area that lacked MLH1 and PMS2 expression, indicating its further molecular evolution. The following variants were acquired: c.6572C>T in NOTCH2, c.1852C>T in BCL6, c.191A>T in INHBA, c.749C>T in CUX1, c.898C>A in FANCG, and c.1712G>C in KDM6A. Integrated comparative spatial proteomic profiles revealed defects in the DNA repair pathways, as well as significant alterations in the extracellular matrix (ECM). The differential expression of proteins involved in DNA repair, particularly those associated with MMR and Base Excision Repair (BER), highlights the critical role of defective repair mechanisms in driving genomic instability. Furthermore, ECM components, such as collagen isoforms, Fibrillin-1, EMILIN-1, Prolargin, and Lumican, were found to be highly expressed in the MLH1/PMS2-deficient tumor area, suggesting a connection between DNA repair deficiencies, ECM remodeling, and tumor progression. Thus, the identification of the BRCA2 variant sheds light on the poorly understood interplay between DNA repair deficiencies and ECM remodeling in OC, providing new insights into their dual role in shaping tumor evolution and suggesting potential targets for novel therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)
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16 pages, 1466 KiB  
Review
Reviewing the Genetic and Molecular Foundations of Congenital Spinal Deformities: Implications for Classification and Diagnosis
by Diana Samarkhanova, Maxat Zhabagin and Nurbek Nadirov
J. Clin. Med. 2025, 14(4), 1113; https://doi.org/10.3390/jcm14041113 - 9 Feb 2025
Cited by 1 | Viewed by 1746
Abstract
Congenital spinal deformities (CSDs) are rare but severe conditions caused by abnormalities in vertebral development during embryogenesis. These deformities, including scoliosis, kyphosis, and lordosis, significantly impair patients’ quality of life and present challenges in diagnosis and treatment. This review integrates genetic, molecular, and [...] Read more.
Congenital spinal deformities (CSDs) are rare but severe conditions caused by abnormalities in vertebral development during embryogenesis. These deformities, including scoliosis, kyphosis, and lordosis, significantly impair patients’ quality of life and present challenges in diagnosis and treatment. This review integrates genetic, molecular, and developmental insights to provide a comprehensive framework for classifying and understanding CSDs. Traditional classification systems based on morphological criteria, such as failures in vertebral formation, segmentation, or mixed defects, are evaluated alongside newer molecular-genetic approaches. Advances in genetic technologies, including whole-exome sequencing, have identified critical genes and pathways involved in somitogenesis and sclerotome differentiation, such as TBX6, DLL3, and PAX1, as well as key signaling pathways like Wnt, Notch, Hedgehog, BMP, and TGF-β. These pathways regulate vertebral development, and their disruption leads to skeletal abnormalities. The review highlights the potential of molecular classifications based on genetic mutations and developmental stage-specific defects to enhance diagnostic precision and therapeutic strategies. Early diagnosis using non-invasive prenatal testing (NIPT) and emerging tools like CRISPR-Cas9 gene editing offer promising but ethically complex avenues for intervention. Limitations in current classifications and the need for further research into epigenetic and environmental factors are discussed. This study underscores the importance of integrating molecular genetics into clinical practice to improve outcomes for patients with CSDs. Full article
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14 pages, 280 KiB  
Review
Recent Advances in Stroke Genetics—Unraveling the Complexity of Cerebral Infarction: A Brief Review
by Takeshi Yoshimoto, Hiroshi Yamagami and Yuji Matsumaru
Genes 2025, 16(1), 59; https://doi.org/10.3390/genes16010059 - 6 Jan 2025
Cited by 1 | Viewed by 2359
Abstract
Background/Objectives: Recent advances in stroke genetics have substantially enhanced our understanding of the complex genetic architecture underlying cerebral infarction and other stroke subtypes. As knowledge in this field expands, healthcare providers must remain informed about these latest developments. This review aims to provide [...] Read more.
Background/Objectives: Recent advances in stroke genetics have substantially enhanced our understanding of the complex genetic architecture underlying cerebral infarction and other stroke subtypes. As knowledge in this field expands, healthcare providers must remain informed about these latest developments. This review aims to provide a comprehensive overview of recent advances in stroke genetics, with a focus on cerebral infarction, and discuss their potential impact on patient care and future research directions. Methods: We reviewed recent literature about advances in stroke genetics, focusing on cerebral infarction, and discussed their potential impact on patient care and future research directions. Key developments include the identification of monogenic stroke syndromes, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy caused by mutations in the NOTCH3 and HTRA1 genes, respectively. In addition, the role of RNF213 in moyamoya disease and other cerebrovascular disorders, particularly in East Asian populations, has been elucidated. The development of polygenic risk scores for assessing genetic predisposition to stroke has demonstrated the potential to improve risk prediction beyond traditional factors. Genetic studies have also elucidated the distinct genetic architecture of stroke subtypes, including large artery atherosclerosis, small vessel disease, and cardioembolic stroke. Furthermore, the investigation of epigenetic modifications influencing stroke risk and its outcomes has revealed new research avenues, while advancements in pharmacogenomics highlight the potential for personalized stroke treatment based on individual genetic profiles. Conclusions: These genetic discoveries have important clinical implications, including improved risk stratification, targeted prevention strategies, and the development of novel therapeutic approaches. Full article
(This article belongs to the Special Issue Stroke Genomics and Exit Strategies)
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19 pages, 3494 KiB  
Article
Leveraging Tumor Mutation Profiles to Forecast Immune Checkpoint Blockade Resistance in Melanoma, Lung, Head and Neck, Bladder and Renal Cancers
by Guillaume Mestrallet
Onco 2024, 4(4), 439-457; https://doi.org/10.3390/onco4040031 - 10 Dec 2024
Cited by 1 | Viewed by 1263
Abstract
Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I [...] Read more.
Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I analyzed 350 lung cancer, 320 melanoma, 215 bladder cancer, 139 head and neck cancer and 151 renal carcinoma patients treated with ICB to identify tumor mutations associated with response and resistance to treatment. I identified several tumor mutations linked with a difference in survival outcomes following ICB. In lung cancer, missense mutations in ABL1, ASXL1, EPHA3, EPHA5, ERBB4, MET, MRE11A, MSH2, NOTCH1, PAK7, PAX5, PGR, ZFHX3, PIK3C3 and REL genes were indicative of favorable responses to ICB. Conversely, mutations in TGFBR2, ARID5B, CDKN2C, HIST1H3I, RICTOR, SMAD2, SMAD4 and TP53 genes were associated with shorter overall survival post-ICB treatment. In melanoma, mutations in FBXW7, CDK12, CREBBP, CTNNB1, NOTCH1 and RB1 genes predict resistance to ICB, whereas missense mutations in FAM46C and RHOA genes are associated with extended overall survival. In bladder cancer, mutations in HRAS genes predict resistance to ICB, whereas missense mutations in ERBB2, GNAS, ATM, CDKN2A and LATS1 genes, as well as nonsense mutations in NCOR1 and TP53 genes, are associated with extended overall survival. In head and neck cancer, mutations in genes like PIK3CA and KRAS correlated with longer survival, while mutations in genes like TERT and TP53 were linked to shorter survival. In renal carcinoma, mutations such as EPHA5, MGA, PIK3R1, PMS1, TSC1 and VHL were linked to prolonged overall survival, while others, including total splice mutations and mutations in B2M, BCOR, JUN, FH, IGF1R and MYCN genes were associated with shorter overall survival following ICB. Then, I developed predictive survival models by machine learning that correctly forecasted cancer patient survival following ICB within an error between 5 and 8 months based on their distinct tumor mutational attributes. In conclusion, this study advocates for personalized immunotherapy approaches in cancer patients. Full article
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11 pages, 1791 KiB  
Article
Association of Genomic Alterations with the Presence of Serum Monoclonal Proteins in Chronic Lymphocytic Leukemia
by Juan A. Piñeyroa, Irene López-Oreja, Ferran Nadeu, Ares Martínez-Farran, Juan Ignacio Aróstegui, Mónica López-Guerra, Juan Gonzalo Correa, Aleix Fabregat, Neus Villamor, Ines Monge-Escatín, Nil Albiol, Dolors Costa, Marta Aymerich, Sílvia Beà, Elías Campo, Julio Delgado, Dolors Colomer and Pablo Mozas
Cells 2024, 13(22), 1839; https://doi.org/10.3390/cells13221839 - 7 Nov 2024
Cited by 1 | Viewed by 1283
Abstract
The presence of a monoclonal protein detected by serum immunofixation electrophoresis (sIFE) has been reported as an adverse prognostic factor in chronic lymphocytic leukemia (CLL). However, the genetic underpinning of this finding has not been studied. We retrospectively studied 97 CLL patients with [...] Read more.
The presence of a monoclonal protein detected by serum immunofixation electrophoresis (sIFE) has been reported as an adverse prognostic factor in chronic lymphocytic leukemia (CLL). However, the genetic underpinning of this finding has not been studied. We retrospectively studied 97 CLL patients with simultaneous information on sIFE and genetic alterations detected by next-generation sequencing. sIFE was positive in 49 patients. The most common isotypes were IgG κ (27%) and bi/triclonal (25%). A +sIFE was associated with a higher number of mutated genes [median 2 (range 0–3) vs. 0 (range 0–2), p = 0.006], and a higher frequency of unmutated IGHV status (60 vs. 29%, p = 0.004). An IgM monoclonal protein was associated with TP53 mutations (36% in IgM +sIFE vs. 12% in non-IgM +sIFE or –sIFE, p = 0.04), and bi/triclonal proteins with NOTCH1 mutations (33% in bi/triclonal vs. 9% in monoclonal +sIFE or –sIFE, p = 0.04). These data suggest an association between a +sIFE and a higher mutational burden, and some monoclonal isotypes with specific mutations. Full article
(This article belongs to the Special Issue Molecular and Genetic Pathogenesis of Hematological Disorders)
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16 pages, 30847 KiB  
Article
Notch3 and Its Clinical Importance in Ovarian Cancer
by Bimal Prasad Jit, Alisha Behera, Sahar Qazi, Khushi Mittal, Subhadip Kundu, Babul Bansal, MD Ray and Ashok Sharma
Drugs Drug Candidates 2024, 3(4), 707-722; https://doi.org/10.3390/ddc3040040 - 16 Oct 2024
Viewed by 1690
Abstract
Background: Ovarian cancer (OC) is the most prevalent gynecological malignancy in women, often diagnosed at an advanced stage due to the absence of specific clinical biomarkers. Notch signaling, particularly Notch3, is frequently activated in OC and contributes to its oncogenic role. Despite its [...] Read more.
Background: Ovarian cancer (OC) is the most prevalent gynecological malignancy in women, often diagnosed at an advanced stage due to the absence of specific clinical biomarkers. Notch signaling, particularly Notch3, is frequently activated in OC and contributes to its oncogenic role. Despite its known association with poor clinical outcomes, the biomarker potential of Notch3 remains inadequately explored. Methods: We investigated the biomarker potential of Notch3 in OC using multiple databases, including ONCOMINE, GEPIA, Human Protein Atlas, UALCAN, Kaplan–Meier Plotter, and LinkedOmics. We analyzed Notch3 expression levels, survival correlations, and clinicopathological parameters. Results: Notch3 expression was significantly upregulated in OC, as well as other cancers. Correlation analysis demonstrated that high Notch3 mRNA levels were associated with poor overall survival (OS) (p < 0.05) and relapse-free survival (p < 0.05) in OC patients. Human Protein Atlas data showed elevated Notch3 protein levels in OC tissues compared to healthy controls. Clinicopathological analysis indicated significant associations between Notch3 expression and patient age (p < 0.5), TP53 mutation status (p < 0.5), and cancer stage (p < 0.1). Additionally, genes such as WIZ, TET1, and CHD4 were found to be co-expressed with Notch3 in OC. Notch3 expression also correlated with immune cell infiltration in OC. Conclusions: Our bioinformatics analysis highlights Notch3 as a potential biomarker for poor prognosis in OC. However, further in vitro and in vivo studies, along with validation using larger tissue samples, are necessary to confirm its biomarker utility. Full article
(This article belongs to the Section Preclinical Research)
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24 pages, 5399 KiB  
Article
Whole Exome Sequencing of Intracranial Epidermoid Cysts Reveals Immune-Associated Mechanistic and Potential Targets
by Shruthi Kondaboina, Oscar Parrish, Carolina Angelica Parada and Manuel Ferreira
Cancers 2024, 16(20), 3487; https://doi.org/10.3390/cancers16203487 - 15 Oct 2024
Cited by 2 | Viewed by 1792
Abstract
Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor [...] Read more.
Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor genetic profiling has revealed potential targets for drug development, including FDA-approved options and reshaping treatment. The genetic landscape of IECs has not been explored. We applied Whole Exome Sequencing (WES) to IECs to gain insights into the mechanisms of oncogenesis and identify potential therapeutic targets. Methods: We performed WES on tumor tissue and matched blood samples, when available. Following GATK best practices, we conducted read processing, quality control, somatic variant calling, and copy-number inference. Data analyses and visualization were conducted in R. Results: Top altered genes are associated with the immune system and tumor microenvironment, suggesting a mechanism of immune evasion. Gene and pathway enrichment revealed a high mutation burden in genes associated with Extracellular Matrix (ECM) and PI3K-AKT-mTOR cascades. Recurrent and deleterious alterations in NOTCH2 and USP8 were identified in 50% and 30% of the cohort, respectively. Frequent amplifications in deubiquitinases and beta-defensins strengthened the involvement of immune mechanisms for oncogenic transformation. Conclusions: Top altered genes and recurrent mutations may play a role in shaping the microenvironment and modulating immune evasion in IECs. USP8 and NOTCH2 may serve as clinically relevant target for IECs. Finally, we present evidence that the crosstalk between the PI3K-Akt-mTOR and ECM signaling pathways may play a role in modulating the immune escape mechanism in IECs. Full article
(This article belongs to the Section Cancer Immunology and Immunotherapy)
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22 pages, 1136 KiB  
Review
Personalized Treatment Strategies via Integration of Gene Expression Biomarkers in Molecular Profiling of Laryngeal Cancer
by Antonino Maniaci, Giovanni Giurdanella, Carlos Chiesa Estomba, Simone Mauramati, Andy Bertolin, Marco Lionello, Miguel Mayo-Yanez, Paolo Boscolo Rizzo, Jerome R. Lechien and Mario Lentini
J. Pers. Med. 2024, 14(10), 1048; https://doi.org/10.3390/jpm14101048 - 10 Oct 2024
Cited by 3 | Viewed by 3121
Abstract
Laryngeal cancer poses a substantial challenge in head and neck oncology, and there is a growing focus on customized medicine techniques. The present state of gene expression indicators in laryngeal cancer and their potential to inform tailored therapy choices are thoroughly examined in [...] Read more.
Laryngeal cancer poses a substantial challenge in head and neck oncology, and there is a growing focus on customized medicine techniques. The present state of gene expression indicators in laryngeal cancer and their potential to inform tailored therapy choices are thoroughly examined in this review. We examine significant molecular changes, such as TP53, CDKN2A, PIK3CA, and NOTCH1 mutations, which have been identified as important participants in the development of laryngeal cancer. The study investigates the predictive and prognostic significance of these genetic markers in addition to the function of epigenetic changes such as the methylation of the MGMT promoter. We also go over the importance of cancer stem cell-related gene expression patterns, specifically CD44 and ALDH1A1 expression, in therapy resistance and disease progression. The review focuses on indicators, including PD-L1, CTLA-4, and tumor mutational burden (TMB) in predicting immunotherapy responses, highlighting recent developments in our understanding of the intricate interactions between tumor genetics and the immune milieu. We also investigate the potential for improving prognosis accuracy and treatment selection by the integration of multi-gene expression panels with clinicopathological variables. The necessity for uniform testing and interpretation techniques is one of the difficulties, in implementing these molecular insights into clinical practice, that are discussed. This review seeks to provide a comprehensive framework for promoting personalized cancer therapy by combining the most recent data on gene expression profiling in laryngeal cancer. Molecularly guided treatment options may enhance patient outcomes. Full article
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17 pages, 841 KiB  
Article
Comprehensive Catalog of Variants Potentially Associated with Hidradenitis Suppurativa, Including Newly Identified Variants from a Cohort of 100 Patients
by Kévin Muret, Vincent Le Goff, Claire Dandine-Roulland, Claire Hotz, Francette Jean-Louis, Bertrand Boisson, Lilia Mesrob, Florian Sandron, Delphine Daian, Robert Olaso, Edith Le Floch, Vincent Meyer, Pierre Wolkenstein, Jean-Laurent Casanova, Yves Lévy, Eric Bonnet, Jean-François Deleuze and Sophie Hüe
Int. J. Mol. Sci. 2024, 25(19), 10374; https://doi.org/10.3390/ijms251910374 - 26 Sep 2024
Viewed by 2156
Abstract
Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases such as metabolic syndrome [...] Read more.
Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases such as metabolic syndrome and inflammatory bowel disease. Genetic studies have identified mutations in the γ-secretase complex that affect Notch signaling pathways critical for skin cell regulation. Despite its high heritability, most reported HS cases do not follow a simple genetic pattern. In this article, we performed whole-exome sequencing (WES) on a cohort of 100 individuals with HS, and we provide a comprehensive review of the variants known to be described or associated with HS. 91 variants were associated with the γ-secretase complex, and 78 variants were associated with other genes involved in the Notch pathway, keratinization, or immune response. Through this new genetic analysis, we have added ten new variants to the existing catalogs. All variants are available in a .vcf file and are provided as a resource for future studies. Full article
(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)
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35 pages, 4731 KiB  
Article
Whole-Exome Sequencing Reveals Novel Candidate Driver Mutations and Potential Druggable Mutations in Patients with High-Risk Neuroblastoma
by Natakorn Nokchan, Praewa Suthapot, Pongsakorn Choochuen, Natthapon Khongcharoen, Suradej Hongeng, Usanarat Anurathapan, Komwit Surachat, Surasak Sangkhathat and Thai Pediatric Cancer Atlas (TPCA) Consortium
J. Pers. Med. 2024, 14(9), 950; https://doi.org/10.3390/jpm14090950 - 8 Sep 2024
Cited by 1 | Viewed by 3003
Abstract
Neuroblastoma is the most prevalent solid tumor in early childhood, with a 5-year overall survival rate of 40–60% in high-risk cases. Therefore, the identification of novel biomarkers for the diagnosis, prognosis, and therapy of neuroblastoma is crucial for improving the clinical outcomes of [...] Read more.
Neuroblastoma is the most prevalent solid tumor in early childhood, with a 5-year overall survival rate of 40–60% in high-risk cases. Therefore, the identification of novel biomarkers for the diagnosis, prognosis, and therapy of neuroblastoma is crucial for improving the clinical outcomes of these patients. In this study, we conducted the whole-exome sequencing of 48 freshly frozen tumor samples obtained from the Biobank. Somatic variants were identified and selected using a bioinformatics analysis pipeline. The mutational signatures were determined using the Mutalisk online tool. Cancer driver genes and druggable mutations were predicted using the Cancer Genome Interpreter. The most common mutational signature was single base substitution 5. MUC4, MUC16, and FLG were identified as the most frequently mutated genes. Using the Cancer Genome Interpreter, we identified five recurrent cancer driver mutations spanning MUC16, MUC4, ALK, and CTNND1, with the latter being novel and containing a missense mutation, R439C. We also identified 11 putative actionable mutations including NF1 Q1798*, Q2616*, and S636X, ALK F1174L and R1275Q, SETD2 P10L and Q1829E, BRCA1 R612S, NOTCH1 D1670V, ATR S1372L, and FGFR1 N577K. Our findings provide a comprehensive overview of the novel information relevant to the underlying molecular pathogenesis and therapeutic targets of neuroblastoma. Full article
(This article belongs to the Section Omics/Informatics)
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