NTRK1

In-frame fusions in NTRK genes, with intact kinase domain, have been reported to occur at higher frequencies in rare tumors like infantile fibrosarcoma, congenital mesoblastic nephroma, and secretory carcinoma, whereas they occur at very low frequencies in common malignancies like NSCLC and colon cancers (0.1%-1%). Despite the rare occurrence, these alterations have gained importance owing to approval of drugs like entrectinib and larotrectinib targeting the kinase domain of the gene. More than 50 fusion partners have been described, and only in-frame fusions result in constitutive ligand-independent kinase activity leading to oncogenesis...

The molecular characterization of male breast cancer (MaBC) has received limited attention in research, mostly due to its low incidence rate, accounting for only 0.5-1% of all reported cases of breast cancer each year. Managing MaBC presents significant challenges, with most treatment protocols being adapted from those developed for female breast cancer. Utilizing whole-genome sequencing (WGS) and state-of-the-art analyses, the genomic features of ten (n=10) MaBC cases were delineated and correlated with clinical and histopathological characteristics...

The 2021 World Health Organization (WHO) classification system for thoracic tumors (including lung cancer) contains several updates to the 2015 edition. Revisions for lung cancer include a new grading system for invasive nonmucinous adenocarcinoma that better reflects prognosis, reorganization of squamous cell carcinomas and neuroendocrine neoplasms, and description of some new entities. Moreover, remarkable advancements in our knowledge of genetic mutations and targeted therapies have led to a much greater emphasis on genetic testing than that in 2015...

Introduction: The discovery of neurotrophic tyrosine receptor kinase ( NTRK ) gene fusions has facilitated the development of precision oncology. Two first-generation NTRK inhibitors (larotrectinib and entrectinib) are currently approved for the treatment of patients with solid tumors harboring NTRK gene fusions. Nevertheless, comprehensive NTRK profiling at the pan-cancer genomic level and real-world studies pertaining to the adverse events of NTRK inhibitors are lacking. Methods: We characterize the genome of NTRK at the pan-cancer level through multi-omics databases such as The Cancer Genome Atlas (TCGA)...

NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) are rare soft tissue tumor molecularly characterized by NTRK gene rearrangement, which occurs mostly in children and young adults, and rarely in adults. The abnormal tumor located in superficial or deep soft tissues of human extremities and trunk mostly, and rarely also involves abdominal organs. In this case, we report a malignant NTRK-RSCN that occurred in the pelvic region of an adult. The patient was found to have a large tumor in the pelvic region with a pathological diagnosis of infiltrative growth of short spindle-shaped tumor cells with marked heterogeneity...

BACKGROUND: Lung cancer is a major cause of cancer-related mortality worldwide, with a 5-year survival rate of approximately 22%. Cisplatin is one of the standard first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC), but its efficacy is often limited by the development of resistance. Despite extensive research on the molecular mechanisms of chemoresistance, the underlying causes remain elusive and complex. AIMS: We analyzed three microarray datasets to find the gene signature and key pathways related to cisplatin resistance in NSCLC...

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions...

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months)...

Glioblastoma is the most frequent and malignant primary neoplasm of the central nervous system. In a recent breakthrough study on a prospective Discovery cohort, I proposed the first all-inclusive molecular classification of glioblastoma into seven subgroups, G1-G7, based on MAPK pathway activation. New data from a WHO-grade-4 diffuse glioma prospective Validation cohort offers, in this study, an integrated demographic-molecular analysis of a 213-patient Combined cohort. Despite cohort differences in the median age and molecular subgroup distribution, all the prospectively-acquired cases from the Validation cohort mapped into one of the G1-G7 subgroups defined in the Discovery cohort...

RATIONALE: Hereditary sensory and autonomic neuropathy type IV (HSAN IV) may be misdiagnosed because of low awareness among clinical professionals and overlap with other subtypes of congenital insensitivity to pain (CIP). PATIENT: The patient was a 1-year-and-5-months-old boy whose main symptoms were delayed psychomotor development and recurrent fever. Whole-exome sequencing (WES) revealed a compound heterozygous mutation (c. 1927C > T, c. 851-33T > A) in the NTRK1 gene of the child...

OBJECTIVES: Actionable, solid tumor activating neurotrophic receptor tyrosine kinase (NTRK) fusions are best detected via nucleic acid-based assays, while Pan-TRK immunohistochemistry (IHC) serves as a reasonable screening modality. We describe a practical and cost-effective approach to validate pan-TRK and discuss challenges that may be encountered. METHODS: Pan-TRK Clone EPR17341 was validated in accordance with the 2014 consensus statements set forth by the College of American Pathologists...

Lung cancer is the most common cause of cancer-related deaths globally, with the highest mortality rates among both men and women. Most lung cancers are diagnosed at late stages, necessitating systemic therapy. Modern clinical management of lung cancer relies heavily upon application of biomarkers, which guide the selection of systemic treatment. Here, we provide an overview of currently approved and emerging biomarkers of non-small cell lung cancer (NSCLC), including EGFR, ALK, ROS1, RET, NTRK1-3, KRAS, BRAF, MET, ERBB2/HER2, NRG1, PD-L1, TROP2, and CEACAM5...

Parkinson's disease is the second most prevalent age-related neurodegenerative disease and disrupts the lives of people aged > 60 years. Meanwhile, single-target drugs becoming inapplicable as PD pathogenesis diversifies. Mitochondrial dysfunction and neurotoxicity have been shown to be relevant to the pathogenesis of PD. The novel synthetic compound J24335 (11-Hydroxy-1-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-one oxime), which has been researched similarly to J2326, has the potential to be a multi-targeted drug and alleviate these lesions...

Background. Pigmented microcystic chromophobe renal cell carcinoma (RCC) is a subtype of chromophobe RCC. Its distinct histopathologic features are microcystic and microtubular pattern, pigmentation, and microcalcifications. Pigmented microcystic chromophobe RCC has ultrastructure, immunophenotypic structure, and molecular results similar to chromophobe RCC. Methods. We report five tumors of pigmented microcystic chromophobe RCC. Morphological observation and immunohistochemical examination were performed, and clinical and molecular features were analyzed...

NTRK-rearranged uterine sarcoma is a recently described entity that represents a subset of uterine sarcomas with distinct clinicopathological features. From a molecular point of view, this tumour is defined by NTRK gene rearrangement, resulting in overexpression or constitutive activation of Trk receptors. The presence of NTRK fusion is indicative of treatment response with a selective small-molecule inhibitor of the Trk kinases. Here, we report a case of an NTRK-rearranged sarcoma of the uterine cervix in a 43-year-old patient, measuring 80 mm in its largest dimension, with a novel NUMA1-NTRK1 fusion, not previously reported in NTRK-rearranged uterine sarcomas or other NTRK-rearranged tumours...

The family of the neurotrophic tyrosine kinase receptor ( NTRK ) gene encodes for members of the tropomyosin receptor kinase (TRK) family. Rearrangements involving NTRK1/2/3 are rare oncogenic factors reported with variable frequencies in an extensive range of cancers in pediatrics and adult populations, although they are more common in the former than in the latter. The alterations in these genes are causative of the constitutive activation of TRKs that drive carcinogenesis. In 2017, first-generation TRK inhibitor (TRKi) larotrectinib was granted accelerated approval from the FDA, having demonstrated histologic-agnostic activity against NTRK s fusions tumors...

After 25 years, "Ackerman's conundrum", namely, the distinction of benign from malignant Spitz neoplasms, remains challenging. Genomic studies have shown that most Spitz tumors harbor tyrosine and serine/threonine kinase fusions, including ALK , ROS1 , NTRK1 , NTRK2 , NTRK3 , BRAF and MAP3K8 , or some mutations, such as HRAS and MAP3K8 . These chromosomal abnormalities act as drivers, initiating the oncogenetic process and conferring basic bio-morphological features. Most Spitz tumors show no additional genomic alterations or few ones; others harbor a variable number of mutations, capable of conferring characteristics related to clinical behavior, including CDKN2A deletion and TERT -p mutation...

Hereditary sensory and autonomic neuropathy type 4 (HSAN4), also known as congenital insensitivity to pain with anhidrosis (CIPA), is a rare genetic disorder caused by NTRK1 gene mutations, affecting nerve growth factor signaling. This study investigates the central nervous system's (CNS) involvement and its relation to pain insensitivity in HSAN4. We present a 15-year-old girl with HSAN4, displaying clinical signs suggestive of CNS impact, including spasticity and a positive Babinski's sign. Using Technetium-99m ethyl cysteinate dimer single-photon emission computed tomography (Tc-99m ECD SPECT) imaging, we discovered perfusion deficits in key brain regions, notably the cerebellum, thalamus, and postcentral gyrus...

INTRODUCTION: Chromosomal rearrangements involving the neurotrophin kinase (NTRK) genes NTRK1, NTRK2 and NTRK3 with different fusion partners occur in non-small cell lung cancers (NSCLCs) and other solid tumors. Novel NTRK rearrangement-related tumors are still being discovered. METHODS: Herin, we describe a male patient with a mass in the left upper lobe that was biopsied by bronchoscopy. This case was diagnosed with stage Ⅳ lung atypical carcinoid (AC) harboring the ETV6::NTRK3 gene fusion...

OBJECTIVES: Aberrant serotonin (5-hydroxytryptamine, 5-HT) metabolism and neurite outgrowth were associated with abdominal pain in irritable bowel syndrome (IBS). We previously demonstrated that 5-HT receptor subtype 7 (5-HT₇) was involved in visceral hypersensitivity of IBS-like mouse models. The aim was to compare the analgesic effects of a novel 5-HT₇ antagonist to reference standards in mouse models and investigate the mechanisms of 5-HT₇-dependent neuroplasticity...