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1.
Pigment Cell Melanoma Res ; 37(3): 363-371, 2024 May.
Article in English | MEDLINE | ID: mdl-38158377

ABSTRACT

Primary malignant melanoma of the esophagus (PMME) is an extremely rare but highly aggressive malignancy with a poor prognosis. Due to the scarcity of driver gene alterations, there is a need for more clinical data to comprehensively depict its molecular alterations. This study reviewed 26 PMME cases from three medical centers. Hybrid capture-based targeted sequencing of 295 and 1021 genes was performed in 14 and 12 cases, respectively. We found that PMME patients had a relatively low tumor mutation burden (median, 2.88 mutations per Mb) and were simultaneously accompanied by mutations in genes such as KIT (6/26, 23%), TP53 (6/26, 23%), SF3B1 (4/26, 15%), and NRAS (3/26, 12%). KIT, NRAS, and BRAF were mutually exclusive, and SF3B1 co-occurred with KIT mutation and amplification. The most common pathways affected were the mitogen-activated protein kinases and DNA damage response (DDR) pathways. Stage IV was a risk factor for both progression-free survival (hazard ratio [HR] = 5.14, 95% confidence interval [CI] = 1.32-19.91) and overall survival (OS), HR = 4.33, 95% CI = 1.22-15.30). Treatment with immune-checkpoint inhibitors (ICIs) was an independent factor for favorable OS (HR = 0.10, 95% CI = 0.01-0.91). Overall, PMME is a complex malignancy with diverse gene alterations, especially with harboring DDR alterations for potentially response from ICIs.


Subject(s)
Esophageal Neoplasms , Melanoma , Mutation , Humans , Melanoma/genetics , Melanoma/pathology , Male , Female , Aged , Middle Aged , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Mutation/genetics , Aged, 80 and over , Adult , Biomarkers, Tumor/genetics , Prognosis
2.
Cancer Cell Int ; 23(1): 187, 2023 Aug 30.
Article in English | MEDLINE | ID: mdl-37649078

ABSTRACT

BACKGROUND: To date, data on the efficacy of targeted therapies for mucosal melanoma (MM) are limited. In this study, we analyzed genetic alterations according to the primary site of origin, which could provide clues for targeted therapy for MM. METHODS: We conducted a retrospective cohort study of 112 patients with MM. Targeted sequencing was performed to analyze genetic aberrations. Kaplan-Meier analysis was conducted with the log-rank test to compare the significance among subgroups. RESULTS: In total, 112 patients with MM were included according to the anatomic sites: 38 (33.9%) in the head and neck, 22 (19.6%) in the genitourinary tract, 21 (18.8%) in the anorectum, 19 (17.0%) in the esophagus, 10 (8.9%) in the uvea, and 2 (1.8%) in the small bowel. The most significantly mutated genes included BRAF (17%), KIT (15%), RAS (15%), TP53 (13%), NF1 (12%), SF3B1 (11%), GNA11 (7%), GNAQ (5%), and FBXW7 (4%). A large number of chromosomal structural variants was found. The anatomic sites of esophagus and small bowel were independent risk factors for progression-free survival (PFS, hazard ratio [HR] 4.78, 95% confidence interval [CI] 2.42-9.45, P < 0.0001) and overall survival (OS, HR 5.26, 95% CI 2.51-11.03, P < 0.0001). Casitas B-lineage lymphoma (CBL) mutants showed significantly poorer PFS and OS. In contrast, MM patients who received immune checkpoint inhibitors (ICIs) had a significantly more favorable OS (HR 0.39, 95% CI 0.20-0.75, P = 0.008). CONCLUSIONS: Our findings reveal the genetic features of patients with MM, mainly across six anatomic sites, offering a potential avenue for targeted therapies.

3.
Signal Transduct Target Ther ; 6(1): 59, 2021 02 11.
Article in English | MEDLINE | ID: mdl-33568623

ABSTRACT

It remains unknown for decades how some of the therapeutic fusion proteins positive in a small percentage of cancer cells account for patient outcome. Here, we report that osteosarcoma Rab22a-NeoF1 fusion protein, together with its binding partner PYK2, is sorted into exosomes by HSP90 via its KFERQ-like motif (RVLFLN142). The exosomal Rab22a-NeoF1 fusion protein facilitates the pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages. The exosomal PYK2 activates RhoA in its negative recipient osteosarcoma cells and induces signal transducer and activator of transcription 3 activation in its recipient macrophages to increase M2 phenotype. Consequently, lung metastases of its recipient osteosarcoma cells are promoted by this exosomal Rab22a-NeoF1 fusion protein, and this event can be targeted by disrupting its interaction with PYK2 using a designed internalizing RGD peptide.


Subject(s)
Focal Adhesion Kinase 2/genetics , Lung Neoplasms/genetics , Osteosarcoma/genetics , rab GTP-Binding Proteins/genetics , Animals , Cell Line, Tumor , Exosomes/genetics , Gene Expression Regulation, Neoplastic/genetics , HSP90 Heat-Shock Proteins/genetics , Humans , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Mice , Oligopeptides/genetics , Oncogene Proteins, Fusion/genetics , Osteosarcoma/pathology , Protein Binding/genetics , RAW 264.7 Cells , rhoA GTP-Binding Protein/genetics
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