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Rosai–Dorfman–Destombes disease (RDD) is a rare histiocytosis characterized by accumulation of S100 + , CD68 + , and CD1a- histiocytes, with emperipolesis. It occurs predominantly in black adolescents and young adults, but rarely in Japanese children. Recently, oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes were reported in 30–50% of patients with RDD, and several studies have described treatment of adult patients with MAPK inhibitors. Here, we present the case of a Japanese boy with refractory RDD without signs of cardiofaciocutaneous (CFC) syndrome who harbored MAP2K1 p.Lys59del and responded to trametinib. The patient had lymph node, nasal cavity, kidney, upper respiratory tract, and intracranial involvement. RDD progressed after multi-agent chemotherapy, but responded to trametinib (0.025 mg/kg). Trametinib did not eliminate the mass lesions, but trametinib plus minimal prednisolone (0.1 mg/kg) resulted in a good outcome for more than 15 months, without significant adverse effects. MAP2K1 p.Lys59del has been described as a germline mutation in a patient with CFC syndrome, but not as a somatic mutation in patients with malignancies. Trametinib may be a promising drug for children with RDD that is refractory to multi-agent chemotherapy. Its long-term efficacy and safety alone and in combination with chemotherapy should be investigated. [ABSTRACT FROM AUTHOR]

Background: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10–20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. Methods: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. Results: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. Conclusions: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings. [ABSTRACT FROM AUTHOR]

Abstract Background Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, influenced by aberrant circRNA expression. Investigating circRNA-miRNA-mRNA interactions can unveil underlying mechanisms of HCC and identify potential therapeutic targets. Methods In this study, we conducted differential analyses of mRNAs, miRNAs, and circRNAs, and established their relationships using various databases such as miRanda, miRDB, and miTarBase. Additionally, functional enrichment and immune infiltration analyses were performed to evaluate the roles of key genes. We also conducted qPCR assays and western blotting (WB) to examine the expression levels of circRNA, CCL25, and MAP2K1 in both HCC cells and clinical samples. Furthermore, we utilized overexpression and knockdown techniques for circ_0000069 and conducted wound healing, transwell invasion assays, and a tumorigenesis experiment to assess the migratory and invasive abilities of HCC cells. Results Our findings revealed significant differential expression of 612 upregulated genes and 1173 downregulated genes in HCC samples compared to normal liver tissue. Additionally, 429 upregulated circRNAs and 453 downregulated circRNAs were identified. Significantly, circ_0000069 exhibited upregulation in HCC tissues and cell lines. The overexpression of circ_0000069 notably increased the invasion and migration capacity of Huh7 cells, whereas the downregulation of circ_0000069 reduced this capability in HepG2 cells. Furthermore, this effect was counteracted by CCL25 silencing or overexpression, separately. Animal studies further confirmed that the overexpression of hsa_circ_0000069 facilitated tumor growth in xenografted nude mice, while the inhibition of CCL25 attenuated this effect. Conclusion Circ_0000069 appears to promote HCC progression by regulating CCL25, suggesting that both circ_0000069 and CCL25 can serve as potential therapeutic targets.

Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1, c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, influenced by aberrant circRNA expression. Investigating circRNA-miRNA-mRNA interactions can unveil underlying mechanisms of HCC and identify potential therapeutic targets. Methods: In this study, we conducted differential analyses of mRNAs, miRNAs, and circRNAs, and established their relationships using various databases such as miRanda, miRDB, and miTarBase. Additionally, functional enrichment and immune infiltration analyses were performed to evaluate the roles of key genes. We also conducted qPCR assays and western blotting (WB) to examine the expression levels of circRNA, CCL25, and MAP2K1 in both HCC cells and clinical samples. Furthermore, we utilized overexpression and knockdown techniques for circ_0000069 and conducted wound healing, transwell invasion assays, and a tumorigenesis experiment to assess the migratory and invasive abilities of HCC cells. Results: Our findings revealed significant differential expression of 612 upregulated genes and 1173 downregulated genes in HCC samples compared to normal liver tissue. Additionally, 429 upregulated circRNAs and 453 downregulated circRNAs were identified. Significantly, circ_0000069 exhibited upregulation in HCC tissues and cell lines. The overexpression of circ_0000069 notably increased the invasion and migration capacity of Huh7 cells, whereas the downregulation of circ_0000069 reduced this capability in HepG2 cells. Furthermore, this effect was counteracted by CCL25 silencing or overexpression, separately. Animal studies further confirmed that the overexpression of hsa_circ_0000069 facilitated tumor growth in xenografted nude mice, while the inhibition of CCL25 attenuated this effect. Conclusion: Circ_0000069 appears to promote HCC progression by regulating CCL25, suggesting that both circ_0000069 and CCL25 can serve as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Emerging evidence has indicated that circRNAs, a novel class of endogenous noncoding RNAs formed by a covalently closed loop, play an important role in oral cancer. However, the role of circ-0008798 and circ-0035967 in oral cancer remains unclear. Oral cancer has been considered as one of the major leading causes of cancer-related mortality. It involves different mechanisms and signaling pathways such as a MAPK pathway that comprises several key signalling components and phosphorylation events in tumorigenesis. The purpose of this study is to investigate the expression profile of circRNA in oral cancer tissue and explore the regulatory mechanism in oral cancer tumorigenesis. the present study, qRT-PCR was used to detect the expression of circ-0008798, circ-0035967 and map2k1 in 30 pairs of samples of oral cancer tissue and adjacent normal tissue.Significant upregulation of MAP2K1 gene was noted in the OLP (p value = 0.034), and OSCC (p value = 0.00), specimens compared with healthy controls. The expression level of circ-008798 and circ-0035967 expression was down-regulated in OSCC tissues (p value = 0.23), (p value = 0.00) and OLP tissues (p value = 0.088), (p value = 0.054).Moreover, the area under ROC curves (AUC) ofmap2k1 was 0.92, has_circ_0008798 was 1.00 (p < 0.001) and has_circ_0035967 was 0.99 (p < 0.001). Our data may help researchers to predict the molecular mechanisms of novel circ-0008798 and circ-0035967 in the development and progression of oral cancer comprehensively. Moreover, the present data indicate that novel circ-0008798 and circ-0035967 targets may be a series of promising candidates as biomarkers for oral cancer.

This study aimed to explore the role of lncRNA MALAT1 (Long non-coding RNAs metastasis-associated lung adenocarcinoma transcript), and its underlying mechanisms in Hypopharyngeal Squamous Cell Carcinoma (HSCC). Quantitative real-time PCR (qRT-PCR) was employed to measure lncRNA MALAT1 expression in HSCC and adjacent non-cancerous tissues, along with the expression of the downstream target mitogen-activated protein kinase kinase 1 (MAP2K1). The independent prognostic significance of lncRNA MALAT1 was assessed using Cox regression analysis. Potential downstream targets of MALAT1 were identified through PRM analysis and validated using the TCGA-HNSC database, Western blotting, and immunohistochemistry. CCK-8, flow cytometry, and Transwell assays were conducted to assess the effects of the lncRNA MALAT1/MAP2K1 axis on FaDu cells. Additionally, a nude mouse xenograft model was used to confirm the role of lncRNA MALAT1/MAP2K1 in tumor growth. LncRNA MALAT1 was significantly upregulated in HSCC tissues and closely associated with poor prognosis. Bioinformatics analysis, including parallel reaction monitoring (PRM) screening and TCGA-HNSC data, identified FERMT2, CSNK2A2, and MAP2K1 as potential downstream targets of MALAT1. Validation through qPCR, Western blotting, and immunohistochemistry confirmed MAP2K1 as a downstream target. In vitro and in vivo experiments demonstrated that inhibiting lncRNA MALAT1 suppressed cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT) by downregulating MAP2K1 expression. Additionally, it induced apoptosis, affected the cell cycle, and inhibited tumor growth. Our study uniquely demonstrates that targeting MALAT1 significantly impedes HSCC progression by downregulating its novel downstream target, MAP2K1, offering new insights into potential therapeutic strategies.

Rosai–Dorfman disease is the most frequent variant of non-Langerhans cell histiocytosis. Local forms can be resected or irradiated. If the process involves multiple organs, systemic chemotherapy can cure some patients. This article includes literature review and a case report of a 34-year-old patient with multifocal, multisystemic form of Rosai–Dorfman disease with bone and pleural involvement. The diagnosis was based on histological, immunohistochemical, and molecular studies of tumor tissue. Since November 2021, 6 courses of chemotherapy with cladribine and 8 infusions of zolendronic acid were carried out with achievement of durable remission. The tolerance was acceptable.

Previous case reports have demonstrated the effectiveness of combination therapy involving EGFR TKI, BRAF inhibitor dabrafenib, and MEK inhibitor trametinib in metastatic non-small-cell lung cancer (NSCLC) patients with acquired BRAF V600E and EGFR mutations. However, the current literature does not provide any reports on the presence of resistant mutations in response to the administration of three-drug combination therapy. Exploring the resistance mechanism of targeted therapy is helpful to optimize the subsequent treatment strategy of patients. Herein, we report a case of a patient with advanced EGFR positive lung adenocarcinoma harboring an acquired BRAF V600E mutation who responded to the combination of furmonertinib, dabrafenib, and trametinib therapy. Unexpectedly, a MAP2K1 K57N acquired mutation was identified by NGS (Next-generation sequencing) analysis of re-biopsy tumor tissue after the patient was resistant to three-drug therapy. As far as we know, this is the first report demonstrating that the efficacy of using combination of furmonertinib and BRAF/MEK inhibitors and the MAP2K1 K57N mutation serves as a resistant mechanism to the three-drug therapy. This novel finding not only revealed a new resistant mutation but also had important implications for the identification of effective patients to EGFR/BRAF/MEK combination therapy. [ABSTRACT FROM AUTHOR]

Treatment‐resistant epilepsy is among the most serious complications of cardiofaciocutaneous syndrome (CFCS), a rare disorder caused by germline variants in the RAS‐MAPK signaling pathway. This study analyzed the clinical characteristics of epilepsy and response to anti‐seizure medications (ASMs) in a multinational CFCS cohort. A caregiver survey provided data regarding seizure history, use of ASMs and other treatment approaches, adverse effects, caregiver perception of treatment response, and neurological disease burden impact among individuals with CFCS. Results from 138 survey responses were quantitatively analyzed in conjunction with molecular genetic results and neurological records. The disease burden impact of CFCS was higher among individuals with epilepsy (n = 74/138), especially those with more severe seizure presentation. Oxcarbazepine, a sodium‐channel blocker, had the best seizure control profile with relatively infrequent adverse effects. The most commonly prescribed ASM, levetiracetam, demonstrated comparatively poor seizure control. ASM efficacy was generally similar for individuals with BRAF and MAP2K1 gene variants. The high proportion of patients with CFCS who experienced poor seizure control despite use of multiple ASMs highlights a substantial unmet treatment need. Prospective study of ASM efficacy and clinical trials of therapies to attenuate RAS‐MAPK signaling may improve avenues for clinical management. [ABSTRACT FROM AUTHOR]

Background: Melanocytic tumors driven by MAP2K1 in‐frame deletions are among the most recently described class of melanocytic neoplasms. The reported range of diagnoses and associated genomic aberrations in these neoplasms is wide and includes melanomas, deep penetrating melanocytomas, and pigmented epithelioid melanocytoma. However, little is known about the characteristics of these tumors, especially in the absence of well‐known second molecular "hits." Moreover, despite their frequent spitzoid cytomorphology, their potential categorization among the Spitz tumors is debatable. Materials and Methods: We conducted a retrospective search through our molecular archives to identify sequenced melanocytic tumors with MAP2K1 in‐frame deletions. We reviewed the clinical and histomorphological features of these tumors and compared them to similar neoplasms reported to date. In addition, we performed single‐nucleotide polymorphism (SNP) array testing to identify structural chromosomal aberrations. Results: Of 27 sequenced tumors, 6 (22%) showed a pathogenic MAP2K1 in‐frame deletion (with or without insertion) and were included in this series. Five (83%) were females with lesions involving the upper limb. Histopathologically, all neoplasms were compounded with plaque‐like or wedge‐shaped silhouettes, spitzoid cytomorphology, and impaired cytologic maturation. All cases showed background actinic damage with sclerotic stroma replacing solar elastosis, variable pagetoid scatter, and occasional dermal mitotic figures (range 1–2/mm2). Five cases (83%) had a small component of nevic‐looking melanocytes. Biologically, these tumors likely fall within the spectrum of unusual nevi. Five cases (83%) had a relatively high mutational burden and four (67%) showed an ultraviolet radiation signature. Four cases (67%) showed in‐frame deletion involving the p.I103_K104del locus while two cases (33%) showed in‐frame deletion involving the p.Q58_E62del locus. SNP array testing showed structural abnormalities ranging from 1 to 5 per case. Five of these cases showed a gain of chromosome 15 spanning the MAP2K1 gene locus. Discussion and Conclusion: Melanocytic tumors with MAP2K1 in‐frame deletion could represent another spectrum of melanocytic tumors with close genotypic–phenotypic correlation. They are largely characterized by a spectrum that encompasses desmoplastic Spitz nevus as shown in our series and Spitz and Clark nevus as shown by others. Evolutionary, they share many similarities with tumors with BRAF V600E mutations, suggesting they are better classified along the conventional pathway rather than the Spitz pathway despite the frequent spitzoid morphology. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis (LCH) is a rare and clinically heterogeneous hematological disease characterized by the accumulation of mononuclear phagocytes in various tissues and organs. LCH is often characterized by activating mutations of the mitogen-activated protein kinase (MAPK) pathway with BRAFV600E being the most recurrent mutation. Although this discovery has greatly helped in understanding the disease and in developing better investigational tools, the process of malignant transformation and the cell of origin are still not fully understood. In this review, we focus on the newest updates regarding the molecular pathogenesis of LCH and novel suggested pathways with treatment potential. [ABSTRACT FROM AUTHOR]

Abstract Background Blueberry muffin is a descriptive term for a neonate with multiple purpuric skin lesions. Many causes are known, amongst them life-threatening diseases like congenital infections or leukemia. Indeterminate cell histiocytosis (ICH) is an exceptionally rare cause of blueberry muffin rash. ICH is a histiocytic disorder which can be limited to the skin or can present with systemic involvement. A mutation that has been described in histiocytic disorders is a MAP2K1 mutation. In ICH, this mutation has previously been described in merely one case. Case presentation A term male neonate was admitted to the neonatology ward directly after birth because of a blueberry muffin rash. ICH was diagnosed on skin biopsy. The lesions resolved spontaneously. The patient is currently 3 years old and has had no cutaneous lesions or systemic involvement so far. This disease course is similar to that of the Hashimoto-Pritzker variant of LCH. Conclusions ICH can manifest in neonates as resolving skin lesions. It is limited to the skin in most cases, but systemic development is possible. Therefore, it is essential to confirm the diagnosis with a biopsy before the lesions resolve and to monitor these patients closely with routine follow-up.

Langerhans cell histiocytosis (LCH) is a rare and clinically heterogeneous hematological disease characterized by the accumulation of mononuclear phagocytes in various tissues and organs. LCH is often characterized by activating mutations of the mitogen-activated protein kinase (MAPK) pathway with BRAFV600E being the most recurrent mutation. Although this discovery has greatly helped in understanding the disease and in developing better investigational tools, the process of malignant transformation and the cell of origin are still not fully understood. In this review, we focus on the newest updates regarding the molecular pathogenesis of LCH and novel suggested pathways with treatment potential.

Background: Blueberry muffin is a descriptive term for a neonate with multiple purpuric skin lesions. Many causes are known, amongst them life-threatening diseases like congenital infections or leukemia. Indeterminate cell histiocytosis (ICH) is an exceptionally rare cause of blueberry muffin rash. ICH is a histiocytic disorder which can be limited to the skin or can present with systemic involvement. A mutation that has been described in histiocytic disorders is a MAP2K1 mutation. In ICH, this mutation has previously been described in merely one case. Case presentation: A term male neonate was admitted to the neonatology ward directly after birth because of a blueberry muffin rash. ICH was diagnosed on skin biopsy. The lesions resolved spontaneously. The patient is currently 3 years old and has had no cutaneous lesions or systemic involvement so far. This disease course is similar to that of the Hashimoto-Pritzker variant of LCH. Conclusions: ICH can manifest in neonates as resolving skin lesions. It is limited to the skin in most cases, but systemic development is possible. Therefore, it is essential to confirm the diagnosis with a biopsy before the lesions resolve and to monitor these patients closely with routine follow-up. [ABSTRACT FROM AUTHOR]

The development of targeted therapies for non-BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF, NRAS, or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF-mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide MAP2K1 mutation without any BRAF mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a CDKN2A deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy. [ABSTRACT FROM AUTHOR]

Extracranial arteriovenous malformation (AVM) is a congenital vascular anomaly causing disfigurement, bleeding, ulceration, and pain. Most lesions are associated with somatic MAP2K1 activating mutations in endothelial cells (ECs). The purpose of this study was to determine if EC expression of mutant activated MAP2K1 is sufficient to produce vascular malformations in mice. We generated mice with a ROSA26 allele containing a lox-stop-lox gene trap (GT), Map2k1 cDNA with an activating p.K57N missense mutation, an internal ribosomal entry site, and green fluorescent protein cDNA (R26GT−Map2k1−GFP). We expressed mutant MAP2K1 and GFP in ECs of fetal and newborn mice using Tg-Cdh5Cre or Tg-Cdh5CreER alleles. Tg-Cdh5Cre+/−;R26GT−Map2k1−GFP/+ animals that express mutant MAP2K1 in ECs in utero developed diffuse vascular abnormalities and died by embryonic (E) day 16.5. Tg-Cdh5CreER+/−;R26GT−Map2k1−GFP/+ animals in which mutant MAP2K1 expression was induced in ECs by tamoxifen at postnatal (P) day 1 developed vascular malformations in the brain, ear, and intestines by P23. The lesions consisted of abnormal networks of blood vessels containing recombined and non-recombined ECs. In conclusion, expression of MAP2K1 p.K57N is sufficient to cause vascular malformations in mice. This model can be used to study the malformation process and for pre-clinical pharmacologic studies. [ABSTRACT FROM AUTHOR]

RASopathies are disorders caused by germline mutations in genes that encode components of the RAS/mitogen‐activated protein kinase (MAPK) pathway. These syndromes share features of developmental delay, facial dysmorphisms, and defects in various organs, as well as cancer predisposition. Somatic mutations of the same pathway are one of the primary causes of cancer. It is thought that germline cancer‐causing mutations would be embryonic lethal, as a more severe phenotype was shown in Drosophila and zebrafish embryos with cancer MAP2K1 mutations than in those with RASopathy mutations. Here we report the case of a patient with RASopathy caused by a cancer‐associated MAP2K1 p.Phe53Leu mutation. The postzygotic mosaic nature of this mutation could explain the patient's survival. [ABSTRACT FROM AUTHOR]

Cardio‐facio‐cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4‐year‐old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3‐year‐old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left‐hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2‐elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co‐occurrence of mitochondrial HMG‐CoA synthase deficiency and HMG‐CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia. [ABSTRACT FROM AUTHOR]

BackgroundWe aim to identify the prevalence and the role of the MAP2K1 K57N mutation in predicting resistance to anti-EGFR agents in metastatic colorectal cancer (mCRC) patients.MethodsWe retrospectively reviewed tumor-based next generation sequencing (NGS) results from mCRC patients screened for enrollment in the GO40872/STARTRK-2 clinical trial between July 2019 and March 2021. Then, in patients harboring microsatellite stable (MSS) RAS and BRAF wild-type MAP2K1 mutant mCRC, we reviewed outcome to treatment with anti-EGFR monoclonal antibodies.ResultsA total of 246 mCRC patients were screened. Most of them, 215/220 (97.7%), were diagnosed with MSS mCRC and 112/215 (52.1%) with MSS, RAS and BRAF wild-type mCRC. Among the latter, 2/112 (1.8%) had MAP2K1 K57N mutant mCRC and both received anti-EGFR monotherapy as third line treatment. In both patients, MAP2K1 K57N mutant tumors proved primary resistant to anti-EGFR agent panitumumab monotherapy. Of interest, one of these patients was treated with anti-EGFR agents three times throughout his course of treatment, achieving some clinical benefit only when associated with other cytotoxic agents (FOLFOX or irinotecan).ConclusionWe verified in a clinical real-world setting that MAP2K1 K57N mutation is a resistance mechanism to anti-EGFR agents in mCRC. Thus, we suggest avoiding the administration of these drugs to MSS RAS and BRAF wild-type MAP2K1 N57K mutant mCRC.

Background: Melorheostosis (MEL) is an exceptionally rare sclerosing bone dysplasia with asymmetrically exuberant bone formation and soft tissue lesions in a segmental distribution. We aimed to summarize the clinical characteristics of Chinese MEL patients and identify their pathogenic cause. Methods: In total, 10 Chinese MEL patients were recruited, and clinical manifestations and radiological characteristics were recorded. Sanger sequencing of the LEMD3 gene was performed on peripheral blood samples of all patients, while the exome sequencing of matched peripheral blood, melorheostotic bone, and skin lesion samples was conducted on one patient who provided affected bone and skin tissues. Micro‐computed tomography (micro‐CT) was also used to scan the melorheostotic bone tissue. Results: We found the average age of the 10 MEL patients was 29.5 years (range 11–40 years), and the major symptoms were bone pain, restricted movement, and bone deformity. The lesions sites were mainly located in femur (8/10), tibia (8/10), fibula (6/10), and foot (7/10), the next was pelvis (4/10), and the last were patella (1/10), hand (1/10) and spine (1/10). Radiological examinations showed a mixture of hyperostosis consisting of classic "dripping candle wax," "osteoma‐like," or "myositis ossificans‐like" patterns in most patients. No germline pathogenic variants in the LEMD3 gene were found in all patients, but a disease‐causing somatic variant of MAP2K1 (c.167A > C, p.Gln56Pro) was detected in melorheostotic bone from one patient. Moreover, the micro‐CT analysis showed increased porosity in the melorheostotic bone with somatic MAP2K1 variant. Conclusion: This is a summary of the clinical characteristics of Chinese MEL patients and we first identify the somatic MAP2K1 variant in Chinese patients. Our findings validate the molecular genetic mechanism of MEL and broaden its phenotype spectrum in the Chinese population. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the genetic and clinical features of children with MAP2K1-mutated Langerhans cell histiocytosis (LCH). Methods: We compared the clinical features of 37 children with MAP2K1-mutated LCH with those of the BRAFV600E mutation group (n = 133) and no known mutation group (n = 59) in the same period. Results: We found 13 mutations of the MAP2K1 gene, which were mainly concentrated at p.53–62 and p.98–103. The most common mutation site was c.172_186del (12/37). Compared with the BRAFV600E mutation group, the patients with MAP2K1 mutations were mainly characterized by single-system multiple bone involvement (P = 0.022), with later disease onset (P = 0.029) as well as less involvement of risk organs, especially liver (P = 0.024). There was no significant difference in clinical features compared with the no known mutation group. The 2-year progression-free survival rate of first-line treatment (ChiCTR1900025783, 07/09/2019) in MAP2K1-mutated patients was 65.6% ± 9.5%. The prognosis of patients with lung involvement was poor [HR (95% CI) = 6.312 (1.769–22.526), P = 0.005]. More progression or relapses could be found in patients with bony thorax involvement (8/17 vs. 2/20, P = 0.023), yet involvements in other sites of bones, such as craniofacial bone involvement (8/26 vs. 2/11, P = 0.688) and limb bone involvement (5/12 vs. 5/25, P = 0.240), were not correlated to disease progression or relapse. Conclusion: The children with MAP2K1-mutated LCH have specific clinical features requiring clinical stratification and precise treatment. MAP2K1-mutated patients with lung involvement (especially with bony thorax involvement) had poor prognosis. [ABSTRACT FROM AUTHOR]

We report three unrelated individuals with atypical clinical findings for cardio-facio-cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing. MAP2K1 encodes MEK1, dual specificity mitogen-activated protein kinase kinase 1, and is one of four genes in the canonical RAS/MAPK signal transduction pathway associated with CFC syndrome. The p.H119Y variant is a non-conservative amino acid substitution that is predicted to impact the tertiary protein structure, and it occurs at a position in the protein kinase domain of MAP2K1 that is highly conserved across species. The clinical findings in these three individuals include facial features that are nonclassical for CFC syndrome, extremely poor weight gain, absence of congenital cardiac defects or cardiomyopathy, normal cognition or only mild intellectual disabilities, normal hair, mild skin abnormalities, and consistent behavioral features of anxiety, photophobia, and sensory hypersensitivities. These individuals expand the phenotypic spectrum of MAP2K1-related RASopathy., (© 2024 Wiley Periodicals LLC.)

Bożena Kosztyła-Hojna,1 Jan Borys,2 Maciej Zdrojkowski,1 Emilia Duchnowska,1 Anna Kraszewska,1 Daria Wasilewska,3 Christiane Zweier,4,5 Alina Teresa Midro3 1Department of Clinical Phonoaudiology and Speech Therapy, Medical University of Białystok, Białystok, Poland; 2Department of Maxillofacial and Plastic Surgery, Medical University of Białystok, Białystok, Poland; 3Department of Clinical Genetics, Medical University of Białystok, Białystok, Poland; 4Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; 5Department of Human Genetics, Inselspital, University Hospital Bern, University of Bern, Bern, SwitzerlandCorrespondence: Emilia DuchnowskaDepartment of Clinical Phonoaudiology and Speech Therapy, Medical University of Białystok, ul. Szpitalna 37, Białystok, 15-295, PolandTel +48 603330294Email emilia.duchnowska@umb.edu.plAbstract: Cardio-facio-cutaneous syndrome 3 (CFC3) due to variants in MAP2K1 is a rare genetic disorder manifested mainly by short stature, facial dysmorphism, abnormalities of the cardiovascular system, skin changes, and intellectual disability. The aim of the study is the evaluation of the occurrence of pathological changes in the upper respiratory tract, orthodontic disorders, as well as voice, speech and hearing abnormalities in an 11-year-old boy with CFC3 syndrome. The lack of detailed diagnostics of speech, voice and hearing disorders, as well as the degree of their severity was an inspiration to undertake research in this field. Pathological changes in face, oral cavity, upper respiratory tract (nose, nasopharynx, larynx), and hearing organ, as well as voice and speech quality, were assessed in an 11-year-old boy with CFC3 syndrome. Pathologies of the upper respiratory tract (adenoid hypertrophy, narrowing of the nasal passages) and laryngeal asymmetry were found without significant changes in voice quality in the acoustic examination, except for the voice timbre change confirmed in narrowband spectrography. Complex audiological assessment confirmed the existence of bilateral sensorineural hearing loss. Speech pathology assessment revealed abnormalities in the structure of articulation organ, its decreased motor efficiency, imprecision, reduced coordination, as well as the presence of autistic features. Exome sequencing showed the heterozygous variant c.371C>T (p.Pro124Leu) in the MAP2K1 gene, previously described as pathogenic, thus supporting a causative relevance. Phoniatric, audiological, orodental and speech problems should be considered as features of cardio-facio-cutaneous syndrome type 3 (CFC 3) phenotype due to a pathogenic variant in MAP2K1.Keywords: cardio-facio-cutaneous syndrome, hearing loss, voice disorders, articulation, MAP2K1

Abstract Background Melorheostosis (MEL) is an exceptionally rare sclerosing bone dysplasia with asymmetrically exuberant bone formation and soft tissue lesions in a segmental distribution. We aimed to summarize the clinical characteristics of Chinese MEL patients and identify their pathogenic cause. Methods In total, 10 Chinese MEL patients were recruited, and clinical manifestations and radiological characteristics were recorded. Sanger sequencing of the LEMD3 gene was performed on peripheral blood samples of all patients, while the exome sequencing of matched peripheral blood, melorheostotic bone, and skin lesion samples was conducted on one patient who provided affected bone and skin tissues. Micro‐computed tomography (micro‐CT) was also used to scan the melorheostotic bone tissue. Results We found the average age of the 10 MEL patients was 29.5 years (range 11–40 years), and the major symptoms were bone pain, restricted movement, and bone deformity. The lesions sites were mainly located in femur (8/10), tibia (8/10), fibula (6/10), and foot (7/10), the next was pelvis (4/10), and the last were patella (1/10), hand (1/10) and spine (1/10). Radiological examinations showed a mixture of hyperostosis consisting of classic “dripping candle wax,” “osteoma‐like,” or “myositis ossificans‐like” patterns in most patients. No germline pathogenic variants in the LEMD3 gene were found in all patients, but a disease‐causing somatic variant of MAP2K1 (c.167A > C, p.Gln56Pro) was detected in melorheostotic bone from one patient. Moreover, the micro‐CT analysis showed increased porosity in the melorheostotic bone with somatic MAP2K1 variant. Conclusion This is a summary of the clinical characteristics of Chinese MEL patients and we first identify the somatic MAP2K1 variant in Chinese patients. Our findings validate the molecular genetic mechanism of MEL and broaden its phenotype spectrum in the Chinese population.

Cardio-facio-cutaneous syndrome (CFCS) belongs to the group of RASopathies, clinical disorders defined by disruptions in the RAS/MAPK signaling pathway. It is caused by heterozygous gain-of-function germline mutations in genes encoding protein kinases: BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), and in the GTPase-encoding gene KRAS. CFCS is characterized by craniofacial dysmorphic features, congenital heart defects, severe malnutrition, proportionate short stature, anomalies within the structure of skin and hair, and psychomotor disability. The pathophysiology of growth impairment is multifactorial with feeding difficulties, growth hormone deficiency, and insensitivity. Immunodeficiency has not been hitherto reported as an integral part of CFCS yet an increased activation of the RAS/MAPK signaling pathway may contribute to explaining the causal relationship between RASopathy and the dysfunctions within the B and T lymph cell compartments resulting in a deficiency in T cell costimulation and B cell maturation with impaired class switch recombination, somatic hypermutation, and high-affinity antibody production. We report on a boy born prematurely at 32 WGA, with the perinatal period complicated by pneumonia, respiratory distress syndrome, and valvular pulmonary stenosis. The boy suffered from recurrent pneumonia, obstructive bronchitis, sepsis, urinary tract infection, and recurrent fevers. He presented with severe hypotrophy, psychomotor disability, short stature, craniofacial dysmorphism, dental hypoplasia, sparse hair, and cryptorchidism. Whole genome sequencing showed a novel heterozygous pathogenic germline missense variant: c.364A > G; p.Asn122Asp in the MAP2K1 gene, supporting the diagnosis of CFCS. The immunological workup revealed hypogammaglobulinemia, IgG subclass, and specific antibody deficiency accompanied by decreased numbers of T helper cells and naive and memory B cells. Replacement immunoglobulin therapy with timely antibiotic prophylaxis were instituted. At the age of six years, growth hormone deficiency was diagnosed and the rGH therapy was started. The ever-increasing progress in genetic studies contributes to establishing the definitive CFCS diagnosis and sheds the light on the interrelated genotype-phenotype heterogeneity of RASopathies. Herein, we add new phenotypic features of predominating humoral immunodeficiency to the symptomatology of CFCS with a novel mutation in MAP2K1. While CFCS is a multifaceted disease, increased pediatricians’ awareness is needed to prevent the delay in diagnostics and therapeutic interventions.

Congenital Langerhans cell histiocytosis (LCH) (formerly called Letterer–Siwe disease) is characterized by a clonal proliferation of Langerhans cells occurring in children at birth and manifests typically with multifocal cutaneous lesions, hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and destructive osteolytic bone lesions. We present a case of LCH involving multiple systems high-risk organs (LCH MS-RO+), in a 32-week stillborn from a 20-year-old G2A1. The fetus was mildly hydropic and pale. Apart from maceration, the skin showed multiple targetoid lesions over the face, trunk, and limbs. There was hepatosplenomegaly and a pale brain. The placenta was large and bulky. Despite severe autolysis, histological examination showed disseminated histiocytes with multinucleated giant cells in the skin, lungs, thymus, mesenteric lymph nodes, spleen, and brain. By immunohistochemistry, the histiocytes were positive for S100, CD1a, and Langerin (CD207), confirming the diagnosis of LCH. There was extramedullary hematopoiesis in the spleen, brain, and placenta. Targeted next-generation sequencing performed on thymic DNA did not show the BRAF p.V600E variant but did show the MAP2K1 p.F53_Q58delinsL. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. Our case is unusual in that the newborn presented with severe multiorgan involvement including brain and intrauterine death. LCH is still poorly understood requiring further genetic and molecular studies. [ABSTRACT FROM AUTHOR]

The development of targeted therapies for non-BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF, NRAS, or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF-mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide MAP2K1 mutation without any BRAF mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a CDKN2A deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy.

Simple Summary: The diagnosis of hairy cell leukemia (cHCL) and HCL-like disorders, including the variant form of HCL (vHCL) and splenic diffuse red pulp lymphoma (SDRPL) can be challenging, particularly in complex situations. The integration of all data, including molecular data, is essential for distinguishing the different entities. The BRAFV600E mutation is identified in most cHCL cases, whereas it is absent in vHCL and SDRPL. MAP2K1 mutations are observed in half of vHCL cases and in cHCL BRAFWT and they are associated with a worse prognosis. The interest in deep sequencing for the diagnosis and prognosis of hairy cell leukemia and HCL-like disorders is essential. Some KLF2 genetic alterations have been localized on the AID consensus motif, suggesting an AID-induced mutation mechanism. KLF2 is the second most altered gene in HCL, and mutations must be investigated to confirm whether AID could be responsible for the genetic alterations in this gene. Clonal evolution can be observed in half of the cases. Hairy cell leukemia (cHCL) patients have, in most cases, a specific clinical and biological presentation with splenomegaly, anemia, leukopenia, neutropenia, monocytopenia and/or thrombocytopenia, identification of hairy cells that express CD103, CD123, CD25, CD11c and identification of the V600E mutation in the B-Raf proto-oncogene (BRAF) in 90% of cases. Monocytopenia is absent in vHCL and SDRPL patients and the abnormal cells do not express CD25 or CD123 and do not present the BRAFV600E mutation. Ten percent of cHCL patients are BRAFWT and the distinction between cHCL and HCL-like disorders including the variant form of HCL (vHCL) and splenic diffuse red pulp lymphoma (SDRPL) can be challenging. We performed deep sequencing in a large cohort of 84 cHCL and 16 HCL-like disorders to improve insights into the pathogenesis of the diseases. BRAF mutations were detected in 76/82 patients of cHCL (93%) and additional mutations were identified in Krüppel-like Factor 2 (KLF2) in 19 patients (23%) or CDKN1B in 6 patients (7.5%). Some KLF2 genetic alterations were localized on the cytidine deaminase (AID) consensus motif, suggesting AID-induced mutations. When analyzing sequential samples, a clonal evolution was identified in half of the cHCL patients (6/12 pts). Among the 16 patients with HCL-like disorders, we observed an enrichment of MAP2K1 mutations in vHCL/SDRPL (3/5 pts) and genes involved in the epigenetic regulation (KDM6A, EZH2, CREBBP, ARID1A) (3/5 pts). Furthermore, MAP2K1 mutations were associated with a bad prognosis and a shorter time to next treatment (TTNT) and progression-free survival (PFS), independently of the HCL classification. [ABSTRACT FROM AUTHOR]

Spitz neoplasms are a heterogeneous group of melanocytic proliferations with a great variability in the histological characteristics and in the biological behavior. Thanks to recent discoveries, the morpho-molecular landscape of Spitz lineage is becoming clearer, with the identification of subtypes with recurrent features thus providing the basis for a more solid and precise tumor classification. Indeed, specific mutually exclusive driver molecular events, namely HRAS or MAP2K1 mutations, copy number gains of 11p, and fusions involving ALK, ROS, NTRK1, NTRK2, NTRK3, MET, RET, MAP3K8, and BRAF genes, correlate with distinctive histological features. The accumulation of further molecular aberrations, instead, promotes the increasing malignant transformation of Spitz neoplasms. Thus, the detection of a driver genetic alteration can be achieved using the appropriate diagnostic tests chosen according to the histological characteristics of the lesion. This allows the recognition of subtypes with aggressive behavior requiring further molecular investigations. This review provides an update on the morpho-molecular correlations in Spitz neoplasms. [ABSTRACT FROM AUTHOR]

background was more complex. About 21.1% (4/19) had mutations, including 3 mutations in NRAS 2 exon and 1 mutation in KRAS 2 exon. Two of the three NRAS mutations were located in the skin, accounting for 20% (2/10) of skin RDD. Conclusion: Extranodal RDD was more common in males than in females, and might occur in all ages, with a greater incidence in skin, head, and neck. Besides the obvious microscopic characteristics in those with skin RDD, the background of other parts was complex and easily missed or misdiagnosed. Some RDD with gene mutations, mainly in NRAS 2 exon, especially in skin RDD, support partial RDD is a clonal disease. [ABSTRACT FROM AUTHOR]

Background: In children, Langerhans cell histiocytosis (LCH), which is the most prevalent histiocytic disorder, exhibits a wide variety of manifestations and outcomes. There is no standard prognosis evaluation system for LCH. We investigated the combined predictive significance of complete blood counts (CBCs), BRAF V600E and MAP2K1 in childhood LCH. Methods: A cohort of 71 childhood LCH patients was retrospectively studied. The prognosis predictive significance of platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), systemic inflammation response index (SIRI), systemic immune inflammation index (SII), BRAF V600E , and MAP2K1 were analyzed. Results: Histiocyte Society (HS) classification of LCH patients was correlated with NLR, SIRI, and progression free survival (PFS), bone involvement was correlated with SIRI, liver involvement was correlated with NLR, SII, SIRI, and PFS, spleen involvement was correlated with SIRI, lung involvement was correlated with NLR and PFS, CNS involvement was correlated with PFS, while BRAF V600E was correlated with PLR, NLR, SIRI, SII, PFS, and OS (p <0.05). MAP2K1 was correlated with NLR, SIRI, PFS, and OS (p <0.05). Elevated NLR, PLR SIRI, and SII predicted inferior PFS and OS (p < 0.05). PLR, NLE, SIRI, SII, BRAF V600E , and MAP2K1 were used to establish a risk model for stratifying the LCH patients into 3 different risk groups. Respective median PFS for low-, mediate-, and high-risk groups were not reached, 26, and 14 months (p <0.001), and all median OS were not reached (p <0.001). Conclusion: The risk model combined with CBCs, BRAF V600E , and MAP2K1 might be a promising prognostic system for LCH in children. [ABSTRACT FROM AUTHOR]

BackgroundIn children, Langerhans cell histiocytosis (LCH), which is the most prevalent histiocytic disorder, exhibits a wide variety of manifestations and outcomes. There is no standard prognosis evaluation system for LCH. We investigated the combined predictive significance of complete blood counts (CBCs), BRAF V600E and MAP2K1 in childhood LCH.MethodsA cohort of 71 childhood LCH patients was retrospectively studied. The prognosis predictive significance of platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), systemic inflammation response index (SIRI), systemic immune inflammation index (SII), BRAF V600E, and MAP2K1 were analyzed.ResultsHistiocyte Society (HS) classification of LCH patients was correlated with NLR, SIRI, and progression free survival (PFS), bone involvement was correlated with SIRI, liver involvement was correlated with NLR, SII, SIRI, and PFS, spleen involvement was correlated with SIRI, lung involvement was correlated with NLR and PFS, CNS involvement was correlated with PFS, while BRAF V600E was correlated with PLR, NLR, SIRI, SII, PFS, and OS (p

Chao Zhou,1,* Pu Wang,1,* Mengtian Tu,1 Yi Huang,2 Fei Xiong,1 Yue Wu3 1Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, People’s Republic of China; 2Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Sichuan 610072, People’s Republic of China; 3Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Sichuan 610072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yue WuDepartment of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, No. 32 West Second Section First Ring Road, Chengdu, Sichuan, People’s Republic of ChinaTel +86-028-87393405Email zegyex@163.comBackground: Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy worldwide. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as effective markers for the detection of multiple cancers. This study aimed to illuminate the mechanism of prostate androgen regulated transcript 1 (PART1) in HCC.Materials and Methods: The levels of PART1, miR-149-5p and mitogen-activated protein kinase 1 (MAP2K1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) assay, and cell migration and invasion were evaluated by transwell assay. Dual-luciferase reporter assay was carried out to examine the relationship among PART1, miR-149-5p and MAP2K1. Western blot assay was conducted to measure the protein expression of MAP2K1.Results: PART1 and MAP2K1 expression were greatly increased and miR-149-5p level was decreased in HCC tissues. Functional analysis revealed that the si-PART1 inhibited proliferation, migration and invasion of HCC cells. PART1 directly bound to miR-149-5p and miR-149-5p level was down-regulated by PART1. Moreover, restoration experiment demonstrated that the effect of PART1 knockdown on HCC cell progression could be partially rescued by miR-149-5p depletion. MiR-149-5p was predicted to target MAP2K1 and MAP2K1 expression was negatively modulated by miR-149-5p. Also, MAP2K1 rescued the inhibitory effects of miR-149-5p overexpression on proliferation, migration and invasion in HCC cells. Besides, the inhibition of miR-149-5p weakened the impact on MAP2K1 expression mediated by PART1 repression.Conclusion: PART1 promoted proliferation, migration and invasion of HCC cells by regulating miR-149-5p/MAP2K1 axis.Keywords: hepatocellular carcinoma, PART1, miR-149-5p, MAP2K1

Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1 , c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC., Competing Interests: MK received contracts and honoraria from Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd., Daiichi Sankyo Co., Ltd., and UCB Japan Co., Ltd. MK is an associate editor for BMC Neurology. The remaining authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Tsuburaya-Suzuki, Ohori, Hamanaka, Fujita, Matsumoto and Kinoshita.)

Pneumonia is an inflammatory disease induced by infection with different pathogens. Currently, multiple preclinical studies have revealed that shikonin, a natural naphthoquinone, can mitigate lipopolysaccharide (LPS)‐induced inflammation, but its underlying mechanism in pneumonia remains unknown. This research was designed to explore the function and regulatory mechanism of shikonin in LPS‐induced cell injury and inflammation in WI‐38 cells. In‐vitro model of pneumonia was constructed by treating WI‐38 cells with LPS. Expression of miR‐489‐3p and MAP2K1 was tested by RT‐qPCR and (or) Western blot analysis. Cell viability was examined by 3‐(4,5)‐dimethylthiahiazo (−z‐y1)‐3,5‐di‐phenytetrazoliumromide assay. The productions of pro‐inflammatory cytokines were determined by enzyme‐linked immunosorbent assays. Cell apoptosis was detected by Western blot and flow cytometry analysis. In the current study, LPS induced WI‐38 cell damage by inhibiting cell viability and promoting cell apoptosis and inflammation. Shikonin ameliorated LPS‐induced cell injury and elevated miR‐489‐3p expression. LPS‐induced inflammatory injury was further mitigated by upregulation of miR‐489‐3p. In addition, MAP2K1, the target of miR‐489‐3p, was upregulated by LPS. Furthermore, upregulation of MAP2K1 reversed the influence of shikonin and miR‐489‐3p mimics on LPS‐induced cell injury and inflammation. This study revealed that shikonin protected WI‐38 cells against LPS‐induced cell injury and inflammatory response by regulating the miR‐489‐3p/MAP2K1 axis, thus affecting the progression of pneumonia. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase kinase 1 (MAP2K1) is a dual specificity protein kinase that phosphorylates both threonine and tyrosine residues in ERK. MAP2K1 mutations have been identified in several cancers. However, their role in Middle Eastern papillary thyroid cancer (PTC) and colorectal cancer (CRC) is lacking. In this study, we evaluated the prevalence of MAP2K1 mutations in a large cohort of Middle Eastern PTC and CRC using whole-exome and Sanger sequencing technology. In the discovery cohort of 100 PTC and 100 CRC cases (comprising 50 MAPK mutant and 50 MAPK wildtype cases each), we found one MAP2K1 mutation each in PTC and CRC, both of which were MAPK wildtype. We further analyzed 286 PTC and 289 CRC MAPK wildtype cases and found three MAP2K1 mutant PTC cases and two MAP2K1 mutant CRC cases. Thus, the overall prevalence of MAP2K1 mutation in MAPK wildtype cases was 1.1% (4/336) in PTC and 0.9% (3/339) in CRC. Histopathologically, three of the four MAP2K1 mutant PTC cases were follicular variant and all four tumors were unifocal with absence of extra-thyroidal extension. All the three CRC cases harboring MAP2K1 mutation were of older age (> 50 years) and had moderately differentiated stage II/III tumors located in the left colon. In conclusion, this is the first comprehensive report of MAP2K1 somatic mutations prevalence in PTC and CRC from this ethnicity. The mutually exclusive nature of MAP2K1 and MAPK mutations suggests that each of these mutation may function as an initiating mutation driving tumorigenesis through MAPK signaling pathway.

The molecular background of a significant proportion of spitzoid neoplasms is still unknown. Recently, activating mutations in MAP2K1 have been described in a few spitzoid lesions, but not in benign Spitz nevi. We report four cases of melanocytic tumors with spitzoid features in which a MAP2K1 mutation was detected. The lesions did not show a single distinct phenotype and ranged from benign to malignant. Two cases resembled desmoplastic Spitz nevi. Based on the combination of morphological, immunohistochemical, and molecular findings, one case was classified as benign, one as probably benign, possibly intermediate low-grade (MELTUMP—melanocytic tumor of unknown malignant potential), one case was classified as intermediate (MELTUMP), and one case was considered a superficial spreading melanoma with spitzoid features. Based on this, we conclude that MAP2K1 mutations can indicate a spitzoid genetic signature and can be found in both benign and malignant spitzoid neoplasms. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase kinase 1 (MAP2K1) is a dual specificity protein kinase that phosphorylates both threonine and tyrosine residues in ERK. MAP2K1 mutations have been identified in several cancers. However, their role in Middle Eastern papillary thyroid cancer (PTC) and colorectal cancer (CRC) is lacking. In this study, we evaluated the prevalence of MAP2K1 mutations in a large cohort of Middle Eastern PTC and CRC using whole-exome and Sanger sequencing technology. In the discovery cohort of 100 PTC and 100 CRC cases (comprising 50 MAPK mutant and 50 MAPK wildtype cases each), we found one MAP2K1 mutation each in PTC and CRC, both of which were MAPK wildtype. We further analyzed 286 PTC and 289 CRC MAPK wildtype cases and found three MAP2K1 mutant PTC cases and two MAP2K1 mutant CRC cases. Thus, the overall prevalence of MAP2K1 mutation in MAPK wildtype cases was 1.1% (4/336) in PTC and 0.9% (3/339) in CRC. Histopathologically, three of the four MAP2K1 mutant PTC cases were follicular variant and all four tumors were unifocal with absence of extra-thyroidal extension. All the three CRC cases harboring MAP2K1 mutation were of older age (> 50 years) and had moderately differentiated stage II/III tumors located in the left colon. In conclusion, this is the first comprehensive report of MAP2K1 somatic mutations prevalence in PTC and CRC from this ethnicity. The mutually exclusive nature of MAP2K1 and MAPK mutations suggests that each of these mutation may function as an initiating mutation driving tumorigenesis through MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

ABSTRACT Melorheostosis is a rare disease of bone overgrowth that is primarily diagnosed based on imaging studies. Recently, the association of different radiological patterns of the disease with distinct genetic cause was reported. Several case reports have described the radiological findings in patients with melorheostosis. However, the added value of cross‐sectional imaging with CT and MRI beyond X‐rays has not been investigated. The aim of the current study was to investigate this existing gap in knowledge. Forty patients with melorheostosis seen at the National Institute of Health Clinical Center were included in the study, and all their imaging studies were analyzed. The sequence of interpretation was X‐ray followed by CT and then MRI. CT images were extracted from whole‐body 18F‐sodium fluoride positron emission tomography/CT studies. The information from CT reclassified the initial X‐rays based radiological pattern in 13 patients. Additionally, CT comprehensively identified joint involvement and disease extent. In 76% of patients (n = 29) who underwent MRI, additional findings were noted, ranging from soft tissue edema to identification of soft tissue masses and incidental findings. MRI did not provide additional information on skeletal lesions beyond CT scans. However, it revealed the extension of soft tissue ossification into ischiofemoral space in four patients who complained of deep gluteal pain consistent with ischiofemoral impingement syndrome. In addition, MRI revealed soft tissue edema in 20 patients, 9 of whom had bone marrow edema and periosteal edema in the tibias consistent with shin splints. These findings suggest that select patients with melorheostosis should be evaluated with both CT and MRI, particularly patients in whom the distribution of pain does not correlate with the anatomic location of the disease in plain radiographs. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Melorheostosis is a rare disease of bone overgrowth that is primarily diagnosed based on imaging studies. Recently, the association of different radiological patterns of the disease with distinct genetic cause was reported. Several case reports have described the radiological findings in patients with melorheostosis. However, the added value of cross‐sectional imaging with CT and MRI beyond X‐rays has not been investigated. The aim of the current study was to investigate this existing gap in knowledge. Forty patients with melorheostosis seen at the National Institute of Health Clinical Center were included in the study, and all their imaging studies were analyzed. The sequence of interpretation was X‐ray followed by CT and then MRI. CT images were extracted from whole‐body 18F‐sodium fluoride positron emission tomography/CT studies. The information from CT reclassified the initial X‐rays based radiological pattern in 13 patients. Additionally, CT comprehensively identified joint involvement and disease extent. In 76% of patients (n = 29) who underwent MRI, additional findings were noted, ranging from soft tissue edema to identification of soft tissue masses and incidental findings. MRI did not provide additional information on skeletal lesions beyond CT scans. However, it revealed the extension of soft tissue ossification into ischiofemoral space in four patients who complained of deep gluteal pain consistent with ischiofemoral impingement syndrome. In addition, MRI revealed soft tissue edema in 20 patients, 9 of whom had bone marrow edema and periosteal edema in the tibias consistent with shin splints. These findings suggest that select patients with melorheostosis should be evaluated with both CT and MRI, particularly patients in whom the distribution of pain does not correlate with the anatomic location of the disease in plain radiographs. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Spitz neoplasms are a heterogeneous group of melanocytic proliferations with a great variability in the histological characteristics and in the biological behavior. Thanks to recent discoveries, the morpho-molecular landscape of Spitz lineage is becoming clearer, with the identification of subtypes with recurrent features thus providing the basis for a more solid and precise tumor classification. Indeed, specific mutually exclusive driver molecular events, namely HRAS or MAP2K1 mutations, copy number gains of 11p, and fusions involving ALK, ROS, NTRK1, NTRK2, NTRK3, MET, RET, MAP3K8, and BRAF genes, correlate with distinctive histological features. The accumulation of further molecular aberrations, instead, promotes the increasing malignant transformation of Spitz neoplasms. Thus, the detection of a driver genetic alteration can be achieved using the appropriate diagnostic tests chosen according to the histological characteristics of the lesion. This allows the recognition of subtypes with aggressive behavior requiring further molecular investigations. This review provides an update on the morpho-molecular correlations in Spitz neoplasms.

Alcoholic liver disease (ALD) serves as the leading cause of chronic liver diseases-related morbidity and mortality, which threatens the life of millions of patients in the world. However, the molecular mechanisms underlying ALD progression remain unclear. Here, we applied microarray analysis and experimental approaches to identify miRNAs and related regulatory signaling that associated with ALD. Microarray analysis identified that the expression of miR-99b was elevated in the ALD mouse model. The AML-12 cells were treated with EtOH and the expression of miR-99b was enhanced in the cells. The expression of miR-99b was positively correlated with ALT levels in the ALD mice. The microarray analysis identified the abnormally expressed mRNAs in ALD mice and the overlap analysis was performed with based on the differently expressed mRNAs and the transcriptional factors of miR-99b, in which STAT1 was identified. The elevated expression of STAT1 was validated in ALD mice. Meanwhile, the treatment of EtOH induced the expression of STAT1 in the AML-12 cells. The expression of STAT1 was positively correlated with ALT levels in the ALD mice. The positive correlation of STAT1 and miR-99b expression was identified in bioinformatics analysis and ALD mice. The expression of miR-99b and pri-miR-99b was promoted by the overexpression of STAT1 in AML-12 cells. ChIP analysis confirmed the enrichment of STAT1 on miR-99b promoter in AML-12 cells. Next, we found that the expression of mitogen-activated protein kinase kinase 1 (MAP2K1) was negatively associated with miR-99b. The expression of MAP2K1 was downregulated in ALD mice. Consistently, the expression of MAP2K1 was reduced by the treatment of EtOH in AML-12 cells. The expression of MAP2K1 was negative correlated with ALT levels in the ALD mice. We identified the binding site of MAP2K1 and miR-99b. Meanwhile, the treatment of miR-99b mimic repressed the luciferase activity of MAP2K1 in AML-12 cells. The expression of MAP2K1 was suppressed by miR-99b in the cells. We observed that the expression of MAP2K1 was inhibited by the overexpression of STAT1 in AML-12 cells. Meanwhile, the apoptosis of AML-12 cells was induced by the treatment of EtOH, while miR-99b mimic promoted but the overexpression of MAP2K1 attenuated the effect of EtOH in the cells. In conclusion, we identified the correlation and effect of STAT1, miR-99b, and MAP2K1 in ALD mouse model and hepatocyte. STAT1, miR-99b, and MAP2K1 may serve as potential therapeutic target of ALD.

Langerhans cell histiocytosis (LCH) is characterized by mutations of the RAS-RAF-MAPK signaling pathway. We analyzed MAP2K1, NRAS and KIT mutation incidence in skin lesions of BRAF wild-type (wt) LCH patients. We evaluated the occurrence of MAP2K1, NRAS and KIT mutations in seven LCH and one indeterminate cell histiocytosis (ICH) patients. MAP2K1 mutation frequency was found to be 3/7 (42.9%) in LCH and also found in ICH. Similarly, the KIT mutation frequency was found to be equally prevalent (4/7, 57.1%) in LCH and also occurred in ICH. Involvement of KIT exons in LCH-ICH indicated that exon 9/11/18 were equally prevalent followed by exon 13. This exploratory analysis on BRAF-wt LCH revealed a KIT mutation rate comparable to MAP2K1. Although the detected KIT mutations are different from activating mutations found in other KIT-dependent neoplasms, our data suggest that KIT-inhibitors might have a role in treating BRAF-wt LCH patients. [ABSTRACT FROM AUTHOR]

Abstract Background β3‐αC loop is a highly conserved structural domain across oncogene families, which is a switch for kinase activity. There have been numerous researches on mutations within β3‐αC loop in EGFR, but relatively less in ERBB2, BRAF, and MAP2K1. In addition, previous studies mainly focus on β3‐αC deletion in EGFR, which is the most common type affecting kinase activity and driving lung cancer. Other mutation types are not well studied. Methods Here we analyzed the profile of β3‐αC loop mutations in a total of 10,000 tumor biopsy and/or ctDNA patient samples using hybridization capture‐based next‐generation sequencing. Results We identified 1616 mutations within β3‐αC loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAF, and MAP2K1. EGFR β3‐αC deletions occurred at a high percentage of 96.7% and were all drug‐relevant. We also detected rare EGFR β3‐αC insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 β3‐αC deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAF and MAP2K1 mutations within β3‐αC loop also demonstrated drugs relevance. Conclusion Our study showed that oncogenic mutations within the β3‐αC loop of ERBB2, MAP2K1, and BRAF are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the β3‐αC loop is critical for targeted therapies.

Background: β3‐αC loop is a highly conserved structural domain across oncogene families, which is a switch for kinase activity. There have been numerous researches on mutations within β3‐αC loop in EGFR, but relatively less in ERBB2, BRAF, and MAP2K1. In addition, previous studies mainly focus on β3‐αC deletion in EGFR, which is the most common type affecting kinase activity and driving lung cancer. Other mutation types are not well studied. Methods: Here we analyzed the profile of β3‐αC loop mutations in a total of 10,000 tumor biopsy and/or ctDNA patient samples using hybridization capture‐based next‐generation sequencing. Results: We identified 1616 mutations within β3‐αC loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAF, and MAP2K1. EGFR β3‐αC deletions occurred at a high percentage of 96.7% and were all drug‐relevant. We also detected rare EGFR β3‐αC insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 β3‐αC deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAF and MAP2K1 mutations within β3‐αC loop also demonstrated drugs relevance. Conclusion: Our study showed that oncogenic mutations within the β3‐αC loop of ERBB2, MAP2K1, and BRAF are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the β3‐αC loop is critical for targeted therapies. [ABSTRACT FROM AUTHOR]