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Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications. 胆囊癌的基因组和分子景观阐明致病机制、新治疗靶点和临床意义。

Mutation research Pub Date : 2024-12-26 DOI: 10.1016/j.mrfmmm.2024.111896

Manishankar Kumar, Arun Kumar, Abhinav Srivastav, Ashok Ghosh, Dhruv Kumar

{"title":"Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications.","authors":"Manishankar Kumar, Arun Kumar, Abhinav Srivastav, Ashok Ghosh, Dhruv Kumar","doi":"10.1016/j.mrfmmm.2024.111896","DOIUrl":"https://doi.org/10.1016/j.mrfmmm.2024.111896","url":null,"abstract":"Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages due to subtle early symptoms. Recent studies have provided a comprehensive view of GBC's genetic and mutational landscape, uncovering crucial pathways involved in its pathogenesis. Environmental exposures, particularly to heavy metals, have been linked to elevated GBC risk. Established signaling pathways, including hormonal, apoptotic, metabolic, inflammatory, and DNA damage repair pathways, are integral to GBC progression, and evidence points to the involvement of specific germline and somatic mutations in its development. Key mutations in genes such as KRAS, TP53, IDH1/2, ERBB, PIK3CA, MET, MYC, BRAF, MGMT, CDKN2A and p16 have been identified as contributors to tumorigenesis, with additional alterations including chromosomal aberrations and epigenetic modifications. These molecular insights reveal several potential therapeutic targets that could address the limited treatment options for GBC. Promising therapeutic avenues under investigation include immune checkpoint inhibitors, tyrosine kinase inhibitors, tumor necrosis factor-related apoptosis-inducing ligands (TRAIL), and phytochemicals. Numerous clinical trials are assessing the efficacy of these targeted therapies. This review provides a detailed examination of GBC's genetic and mutational underpinnings, highlighting critical pathways and emerging therapeutic strategies. We discuss the implications of germline and somatic mutations for early detection and individualized treatment, aiming to bridge current knowledge gaps. By advancing our understanding of GBC's molecular profile, we hope to enhance diagnostic accuracy and improve treatment outcomes, ultimately paving the way for precision medicine approaches in managing GBC.","PeriodicalId":94147,"journal":{"name":"Mutation research","volume":"830 ","pages":"111896"},"PeriodicalIF":0.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of the simultaneous effects of KRAS G12V and LCS6 alterations on the behavior of head and neck squamous cell carcinoma. 评估 KRAS G12V 和 LCS6 改变同时对头颈部鳞状细胞癌行为的影响。

Mutation research Pub Date : 2024-12-11 DOI: 10.1016/j.mrfmmm.2024.111895

Vildan Betul Yenigun, Vasfiye Betul Ucar, Zeynep Betul Sari, Ali Ahmed Azzawri, Yasemin Sena Acar, Muhammed Burak Kaplan, Suleyman Nergiz, Hasan Acar

{"title":"Evaluation of the simultaneous effects of KRAS G12V and LCS6 alterations on the behavior of head and neck squamous cell carcinoma.","authors":"Vildan Betul Yenigun, Vasfiye Betul Ucar, Zeynep Betul Sari, Ali Ahmed Azzawri, Yasemin Sena Acar, Muhammed Burak Kaplan, Suleyman Nergiz, Hasan Acar","doi":"10.1016/j.mrfmmm.2024.111895","DOIUrl":"https://doi.org/10.1016/j.mrfmmm.2024.111895","url":null,"abstract":"Background: Head and neck squamous cell carcinomas are the seventh most common cancer accounting for 90 % of malignant neoplasia of the upper respiratory system. KRAS is a very important oncogene, leading to the suppression of apoptosis, and promoting the pathogenesis and development of tumors. MicroRNAs (miRNAs) are highly conserved, small noncoding RNA molecules aberrantly expressed in various pathologies including regulation of tumor and metastasis-associated genes. Variant (rs61764370) of the let-7 miRNA complementary site of KRAS 3'-untranslated region (KRAS-LCS6) has been shown to disrupt the ability of miRNAs to target genes resulting in differential target mRNA and protein expression.Methods: In this study, the effects of variant complementary site LCS6 of the let-7 miRNA in head and neck cancer were investigated in vitro using laryngeal carcinoma HEp-2 carrying G12V and LCS6 alterations in the KRAS gene. Non-cancer HEK-293 cells were also used as control cells.Results: G12V mutation in the KRAS gene increases invasion capacity and is specifically active on the ERK pathway associated with metastasis. Alteration in the LCS6 region of the KRAS gene did not show additional effects compared to cells only carrying G12V mutation. Our results also showed that the coexistence of G12V and LCS6 alterations is lethal to specific cell types, UM-SCC-17A laryngeal cancer cells in our case.Conclusions: The LCS6 region alteration of the KRAS may play a key role in further cancer progression, and more research is needed to fully understand the mechanisms by which the LCS6 alterations promote cancer progression.","PeriodicalId":94147,"journal":{"name":"Mutation research","volume":"830 ","pages":"111895"},"PeriodicalIF":0.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0