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1
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Payva F, K S S, James R, E AP, Sivaramakrishnan V. Systems biology approach delineates critical pathways associated with papillary thyroid cancer: a multi-omics data analysis. Thyroid Res 2025; 18:15. [PMID: 40211357 PMCID: PMC11987294 DOI: 10.1186/s13044-025-00230-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/10/2025] [Indexed: 04/13/2025] Open
Abstract
BACKGROUND Papillary thyroid cancer (PTC) is the most prevalent follicular cell-derived subtype of thyroid cancer. A systems biology approach to PTC can elucidate the mechanism by which molecular components work and interact with one another to decipher a panoramic view of the pathophysiology. METHODOLOGY PTC associated genes and transcriptomic data were retrieved from DisGeNET and Gene Expression Omnibus database respectively. Published proteomic and metabolomic datasets in PTC from EMBL-EBI were used. Gene Ontology and pathway analyses were performed with SNPs, differentially expressed genes (DEGs), proteins, and metabolites linked to PTC. The effect of a nucleotide substitution on a protein's function was investigated. Additionally, significant transcription factors (TFs) and kinases were identified. An integrated strategy was used to analyse the multi-omics data to determine the key deregulated pathways in PTC carcinogenesis. RESULTS Pathways linked to carbohydrate, protein, and lipid metabolism, along with the immune response, signaling, apoptosis, gene expression, epithelial-mesenchymal transition (EMT), and disease onset, were identified as significant for the clinical and functional aspects of PTC. Glyoxylate and dicarboxylate metabolism and citrate cycle were the most common pathways among the PTC omics datasets. Commonality analysis deciphered five TFs and fifty-seven kinases crucial for PTC genesis and progression. Core deregulated pathways, TFs, and kinases modulate critical biological processes like proliferation, angiogenesis, immune infiltration, invasion, autophagy, EMT, and metastasis in PTC. CONCLUSION Identified dysregulated pathways, TFs and kinases are critical in PTC and may help in systems level understanding and device specific experiments, biomarkers, and drug targets for better management of PTC.
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Affiliation(s)
- Febby Payva
- Department of Zoology, St. Joseph's College for Women, Alappuzha, Kerala, 688001, India.
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu, 641043, India.
| | - Santhy K S
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu, 641043, India.
| | - Remya James
- Department of Zoology, St. Joseph's College for Women, Alappuzha, Kerala, 688001, India
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu, 641043, India
| | - Amrisa Pavithra E
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu, 641043, India
| | - Venketesh Sivaramakrishnan
- Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthinilayam, Puttaparthi, Andhra Pradesh, 515134, India.
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Danishevich A, Fedorova D, Bodunova N, Makarova M, Byakhova M, Semenova A, Galkin V, Litvinova M, Nikolaev S, Efimova I, Osinin P, Lisitsa T, Khakhina A, Shipulin G, Nasedkina T, Shumilova S, Gusev O, Bilyalov A, Shagimardanova E, Shigapova L, Nemtsova M, Sagaydak O, Woroncow M, Gadzhieva S, Khatkov I. Assessing germline TP53 mutations in cancer patients: insights into Li-Fraumeni syndrome and genetic testing guidelines. Hered Cancer Clin Pract 2025; 23:5. [PMID: 39962599 PMCID: PMC11834258 DOI: 10.1186/s13053-025-00307-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 02/07/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Germline TP53 gene variants are intricately linked to Li-Fraumeni syndrome, a rare and aggressive hereditary cancer syndrome. This study investigated the frequency and spectrum of TP53 pathogenic variants associated with Li-Fraumeni syndrome in a large cohort of mainly breast cancer patients from Russia. METHODS The study analyzed 3,455 genomic DNA samples from cancer patients using next-generation sequencing panels and whole-genome sequencing. Clinically significant TP53 variants were identified and validated using Sanger sequencing. The clinical and family history characteristics of patients with TP53 variants were analyzed. RESULTS The analysis identified 13 (0.4%) individuals with clinically significant germline TP53 variants, all of whom were females with either unilateral breast cancer or breast cancer as part of multiple primary malignant neoplasms. The average age of breast cancer manifestation was 39.9 years, with a median of 36 years. Only 38.5% of the TP53 mutation carriers met the modified Chompret criteria for TP53 testing. CONCLUSIONS The findings underscore the necessity of thorough phenotype and family history analysis in genetic counseling to effectively diagnose LFS, and emphasize the importance of identifying TP53 variant carriers for developing treatment strategies, prognosis, and monitoring, as well as for identifying high-risk family members. The study also highlights that the current guidelines fail to identify over half of the TP53 mutation carriers, suggesting the need for a more comprehensive approach to genetic testing in suspected hereditary cancer cases.
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Affiliation(s)
- Anastasiia Danishevich
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia.
| | - Daria Fedorova
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia
| | - Natalia Bodunova
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia
| | - Maria Makarova
- Evogen LLC, Moscow, 115191, Russia
- Russian Scientific Center of Roentgenoradiology of the Ministry of Health of the Russian Federation, Moscow, 117997, Russia
| | - Maria Byakhova
- City Clinical Oncological Hospital No. 1 of Moscow Healthcare Department, Moscow, 117152, Russia
| | - Anna Semenova
- City Clinical Oncological Hospital No. 1 of Moscow Healthcare Department, Moscow, 117152, Russia
| | - Vsevolod Galkin
- City Clinical Oncological Hospital No. 1 of Moscow Healthcare Department, Moscow, 117152, Russia
| | - Maria Litvinova
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Sergey Nikolaev
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia
| | - Irina Efimova
- Medical Genetic Research Center Named After Academician N.P. Bochkov, Moscow, 115522, Russia
| | - Pavel Osinin
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia
| | - Tatyana Lisitsa
- FSBI "Centre for Strategic Planning and Management of Biomedical Health Risks" of the Federal Medical and Biological Agency, Moscow, 119435, Russia
- FSBI "National Medical Research Center of Oncology Named After N.N. Blokhin" of the Ministry of Health of the Russian Federation, Moscow, 115522, Russia
| | - Anastasiya Khakhina
- FSBI "Centre for Strategic Planning and Management of Biomedical Health Risks" of the Federal Medical and Biological Agency, Moscow, 119435, Russia
| | - German Shipulin
- FSBI "Centre for Strategic Planning and Management of Biomedical Health Risks" of the Federal Medical and Biological Agency, Moscow, 119435, Russia
| | - Tatiana Nasedkina
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, 119991, Russia
| | - Syuykum Shumilova
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, 119991, Russia
| | - Oleg Gusev
- Life Improvement By Future Technologies (LIFT) Center, Skolkovo, Moscow, 143025, Russia
| | - Airat Bilyalov
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia
- Kazan Federal University, Kazan, 420008, Russia
| | - Elena Shagimardanova
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia
- Life Improvement By Future Technologies (LIFT) Center, Skolkovo, Moscow, 143025, Russia
| | | | - Marina Nemtsova
- Evogen LLC, Moscow, 115191, Russia
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russian Federation (Sechenov University), Moscow, 119991, Russia
- Medical Genetic Research Center Named After Academician N.P. Bochkov, Moscow, 115522, Russia
| | | | - Mary Woroncow
- National Medical Research Center of Endocrinology, Moscow, 117292, Russia
- Lomonosov Moscow State University, Moscow, 119991, Russia
| | | | - Igor Khatkov
- SBHI Moscow Clinical Scientific Center Named After Loginov of Moscow Healthcare Department, Moscow, 111123, Russia.
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Drejeriene I, Gruode J, Cicenas S, Loizides C, Eliades A, Achilleos A, Kypri E, Tsangaras K, Ioannides M, Koumbaris G, Stanciute D, Krasauskas A, Patsalis PC. Comparison of targeted next generation sequencing assays in non-small cell lung cancer patients. Discov Oncol 2024; 15:757. [PMID: 39692940 DOI: 10.1007/s12672-024-01640-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 09/18/2024] [Indexed: 12/19/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer the mutational spectrum of which has been extensively characterized. Treatment of patients with NSCLC based on their molecular profile is now part of the standard clinical care. The aim of this study was firstly to investigate two different NGS-based tumor profile genetic tests and secondly to assess the clinical actionability of the mutations and their association with survival and clinicopathological characteristics. Overall, 52 mutations were identified in 31 patients by either one or both assays. The most frequently mutated genes were TP53 (40.4%), KRAS (13.46%) and EGFR (9.62%). TP53 and KRAS mutations were associated with worst overall survival while KRAS was positively correlated with adenocarcinoma. The two methods showed a high concordance for the commonly covered genomic regions (97.14%). Ten mutations were identified in a genomic region exclusively covered by the MEDICOVER Genetics custom tumor profile assay. Likewise, one MET mutation was identified by the Ion Amliseq assay in a genomic region exclusively covered by Ion Amliseq. In conclusion both assays showed highly similar results in the commonly covered genomic areas, however, the MEDICOVER Genetics assay identified additional clinically actionable mutations that can be applied in clinical practice for personalized treatment decision making for patients with NSCLC.
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Affiliation(s)
- Ieva Drejeriene
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
- Klaipeda University Hospital, Klaipeda, Lithuania.
| | - Jurate Gruode
- Klaipeda University Hospital, Klaipeda, Lithuania
- Faculty of Medicine, Klaipeda University, Klaipeda, Lithuania
| | | | | | | | | | | | - Kyriakos Tsangaras
- MEDICOVER Genetics, Nicosia, Cyprus
- Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus
| | | | | | | | - Arnoldas Krasauskas
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
- National Cancer Institute, Vilnius, Lithuania
| | - Philippos C Patsalis
- MEDICOVER Genetics, Nicosia, Cyprus.
- Department of Human Genetics, School of Medicine, University of Nicosia Medical School, Nicosia, Cyprus.
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Pervushin NV, Nilov DK, Pushkarev SV, Shipunova VO, Badlaeva AS, Yapryntseva MA, Kopytova DV, Zhivotovsky B, Kopeina GS. BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition. Apoptosis 2024; 29:2197-2213. [PMID: 39222276 PMCID: PMC11550243 DOI: 10.1007/s10495-024-02014-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2024] [Indexed: 09/04/2024]
Abstract
The development of drug resistance reduces the efficacy of cancer therapy. Tumor cells can acquire resistance to MDM2 inhibitors, which are currently under clinical evaluation. We generated RG7388-resistant neuroblastoma cells, which became more proliferative and metabolically active and were less sensitive to DNA-damaging agents in vitro and in vivo, compared with wild-type cells. The resistance was associated with a mutation of the p53 protein (His193Arg). This mutation abated its transcriptional activity via destabilization of the tetrameric p53-DNA complex and was observed in many cancer types. Finally, we found that Cisplatin and various BH3-mimetics could enhance RG7388-mediated apoptosis in RG7388-resistant neuroblastoma cells, thereby partially overcoming resistance to MDM2 inhibition.
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Affiliation(s)
- N V Pervushin
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, 119991, Russia
| | - D K Nilov
- Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - S V Pushkarev
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119234, Russia
| | - V O Shipunova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- Moscow Center for Advanced Studies, Moscow, 123592, Russia
| | - A S Badlaeva
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Russian Ministry of Health, Moscow, 117513, Russia
| | - M A Yapryntseva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, 119991, Russia
| | - D V Kopytova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
| | - B Zhivotovsky
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, 119991, Russia.
- Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177, Stockholm, Sweden.
| | - G S Kopeina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, 119991, Russia.
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Chang YW, Kuo HL, Chen TC, Chen J, Lim L, Wang KL, Chen JR. Abnormal p53 expression is associated with poor outcomes in grade I or II, stage I, endometrioid carcinoma: a retrospective single-institute study. J Gynecol Oncol 2024; 35:e78. [PMID: 38576345 PMCID: PMC11543261 DOI: 10.3802/jgo.2024.35.e78] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/04/2024] [Accepted: 02/25/2024] [Indexed: 04/06/2024] Open
Abstract
OBJECTIVE The Cancer Genome Atlas study revealed an association between copy-number high (p53 abnormal) genetic mutation and poor prognosis in endometrial cancer in 2013. This retrospective study investigated outcomes in patients with abnormal p53 expression and stage I, low-grade endometrial endometrioid carcinoma (EEC). METHODS We enrolled women with stage I, grade 1 or 2 EEC who received comprehensive staging and adjuvant therapy between January 2019 and December 2022 at MacKay Memorial Hospital, Taipei, Taiwan. Pathologists interpreted immunohistochemistry stains of cancerous tissues to detect p53 mutation. We compared recurrence, survival, progression-free survival, and overall survival between p53 abnormal and p53 normal groups. RESULTS Of the 115 patients included, 26 had pathologically confirmed abnormal p53 expression. Of these 26 patients, five (19.2%) experienced recurrence, and two died due to disease progression. By contrast, no patients in the normal p53 group experienced disease recurrence or died due to disease progression. Significant intergroup differences were discovered in recurrent disease status (19.4% vs. 0%, p<0.001), mortality (7.7% vs. 0%, p<0.001), and progression-free survival (p<0.001). The overall survival (p=0.055) also showed powerful worse trend. CONCLUSION For patients with stage I, low-grade EEC, abnormal p53 expression may be used as an indicator of poor prognosis. Therefore, we suggest considering aggressive adjuvant therapies for these patients.
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Affiliation(s)
- Yu-Wei Chang
- Department of Obstetrics & Gynecology, MacKay Memorial Hospital, Taipei, Taiwan
| | - Hsiao-Li Kuo
- Department of Nursing, MacKay Memorial Hospital, Taipei, Taiwan
| | - Tzu-Chien Chen
- Department of Obstetrics & Gynecology, MacKay Memorial Hospital, Hsinchu Branch, Hsinchu, Taiwan
| | - Jessica Chen
- Department of Obstetrics & Gynecology, MacKay Memorial Hospital, Tamsui Branch, New Taipei City, Taiwan
| | - Ling Lim
- Department of Obstetrics & Gynecology, MacKay Memorial Hospital, Tamsui Branch, New Taipei City, Taiwan
| | - Kung-Liahng Wang
- Department of Obstetrics & Gynecology, MacKay Memorial Hospital, Taipei, Taiwan
- Department of General Education, MacKay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan
| | - Jen-Ruei Chen
- Department of Obstetrics & Gynecology, MacKay Memorial Hospital, Taipei, Taiwan
- Department of General Education, MacKay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
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Naito K, Sangai T, Yamashita K. CAF-Associated Genes in Breast Cancer for Novel Therapeutic Strategies. Biomedicines 2024; 12:1964. [PMID: 39335478 PMCID: PMC11428270 DOI: 10.3390/biomedicines12091964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/30/2024] Open
Abstract
Breast cancer (BC) is the most common cancer in women, and therapeutic strategies for it are based on the molecular subtypes of luminal BC, HER2 BC, and triple-negative BC (TNBC) because each subtype harbors different unique genetic aberrations. Recently, features of the tumor microenvironment (TME), especially cancer-associated fibroblasts (CAFs), have been demonstrated to play a critical role in BC progression, and we would like to understand the molecular features of BC CAFs for novel therapeutic strategies. In a recent study, 115 CAF-associated genes (CAFGs) were identified in a public database of microdissection and microarray data (GSE35602) from 13 colorectal cancer (CRC) tumors. Using a public database (GSE10797) of 28 BC tumors, a similar analysis was performed. In BC, 59 genes from the 115 CAFGs identified in CRC (CRC CAFGs) were also closely associated with a CAFs marker, SPARC (R = 0.6 or beyond), and POSTN was of particular interest as one of the BC CAFGs with the highest expression levels and a close association with SPARC expression (R = 0.94) in the cancer stroma of BC tumors. In BC stroma, POSTN was followed in expression levels by DKK3, MMP2, PDPN, and ACTA2. Unexpectedly, FAP and VIM were not as highly associated with SPARC expression in the cancer stroma of BC tumors and exhibited low expression. These findings suggested that ACTA2 might be the most relevant conventional CAFs marker in BC, and ACTA2 was actually correlated in expression with many CRC CAFGs, such as SPARC. Surprisingly, the SE ratio values of the BC CAFGs were much lower (average SE = 3.8) than those of the CRC CAFGs (SE = 10 or beyond). We summarized the current understanding of BC CAFs from the literature. Finally, in triple-negative BC (TNBC) (n = 5), SPARC expression uniquely showed a close association with COL11A1 and TAGLN expression, representing a myofibroblast (myCAFs) marker in the cancer stroma of the BC tumors, suggesting that myCAFs may be molecularly characterized by TNBC in contrast to other BC phenotypes. In summary, CAFs could have unique molecular characteristics in BC, and such TME uniqueness could be therapeutically targeted in BC.
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Affiliation(s)
- Kanako Naito
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara 252-0374, Japan
| | - Takafumi Sangai
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara 252-0374, Japan
| | - Keishi Yamashita
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara 252-0374, Japan
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7
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Reshkin SJ, Cardone RA, Koltai T. Genetic Signature of Human Pancreatic Cancer and Personalized Targeting. Cells 2024; 13:602. [PMID: 38607041 PMCID: PMC11011857 DOI: 10.3390/cells13070602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.
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Affiliation(s)
- Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Tomas Koltai
- Oncomed, Via Pier Capponi 6, 50132 Florence, Italy
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8
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Stan A, Bosart K, Kaur M, Vo M, Escorcia W, Yoder RJ, Bouley RA, Petreaca RC. Detection of driver mutations and genomic signatures in endometrial cancers using artificial intelligence algorithms. PLoS One 2024; 19:e0299114. [PMID: 38408048 PMCID: PMC10896512 DOI: 10.1371/journal.pone.0299114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/05/2024] [Indexed: 02/28/2024] Open
Abstract
Analyzed endometrial cancer (EC) genomes have allowed for the identification of molecular signatures, which enable the classification, and sometimes prognostication, of these cancers. Artificial intelligence algorithms have facilitated the partitioning of mutations into driver and passenger based on a variety of parameters, including gene function and frequency of mutation. Here, we undertook an evaluation of EC cancer genomes deposited on the Catalogue of Somatic Mutations in Cancers (COSMIC), with the goal to classify all mutations as either driver or passenger. Our analysis showed that approximately 2.5% of all mutations are driver and cause cellular transformation and immortalization. We also characterized nucleotide level mutation signatures, gross chromosomal re-arrangements, and gene expression profiles. We observed that endometrial cancers show distinct nucleotide substitution and chromosomal re-arrangement signatures compared to other cancers. We also identified high expression levels of the CLDN18 claudin gene, which is involved in growth, survival, metastasis and proliferation. We then used in silico protein structure analysis to examine the effect of certain previously uncharacterized driver mutations on protein structure. We found that certain mutations in CTNNB1 and TP53 increase protein stability, which may contribute to cellular transformation. While our analysis retrieved previously classified mutations and genomic alterations, which is to be expected, this study also identified new signatures. Additionally, we show that artificial intelligence algorithms can be effectively leveraged to accurately predict key drivers of cancer. This analysis will expand our understanding of ECs and improve the molecular toolbox for classification, diagnosis, or potential treatment of these cancers.
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Affiliation(s)
- Anda Stan
- Biology Program, The Ohio State University, Marion, Ohio, United States of America
| | - Korey Bosart
- Biology Program, The Ohio State University, Marion, Ohio, United States of America
| | - Mehak Kaur
- Biology Program, The Ohio State University, Marion, Ohio, United States of America
| | - Martin Vo
- Biology Department, Xavier University, Cincinnati, Ohio, United States of America
| | - Wilber Escorcia
- Biology Department, Xavier University, Cincinnati, Ohio, United States of America
| | - Ryan J Yoder
- Department of Chemistry and Biochemistry, The Ohio State University, Marion, Ohio, United States of America
| | - Renee A Bouley
- Department of Chemistry and Biochemistry, The Ohio State University, Marion, Ohio, United States of America
| | - Ruben C Petreaca
- Department of Molecular Genetics, The Ohio State University, Marion, Ohio, United States of America
- James Comprehensive Cancer Center, The Ohio State University Columbus, Columbus, Ohio, United States of America
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9
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Li X, Hou Y, Han G, Yang Y, Wang S, Lv X, Gao M. S100A4/NF-κB axis mediates the anticancer effect of epigallocatechin-3-gallate in platinum-resistant ovarian cancer. iScience 2024; 27:108885. [PMID: 38313051 PMCID: PMC10835441 DOI: 10.1016/j.isci.2024.108885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/06/2023] [Accepted: 01/08/2024] [Indexed: 02/06/2024] Open
Abstract
Resistance to cisplatin (cis-dichlorodiamineplatinum, DDP) in ovarian cancer is a significant clinical challenge. Epigallocatechin-3-gallate (EGCG) has shown promise in cancer therapy. However, its effects on DDP-resistant ovarian cancer remain understudied. This study aims to assess the impact of EGCG on DDP-resistant cells and elucidate the associated molecular mechanisms. DDP-resistant cell lines were utilized for biological characterization. EGCG effectively inhibited proliferation, mobility, and induced apoptosis in OC/DDP cells. It downregulated the expression of S100A4 and NF-κB while upregulating p53 expression. These effects were reversed upon overexpression of S100A4 or NF-κB. In vivo experiments confirmed tumor inhibition and KI67 inhibition by EGCG. Moreover, EGCG downregulated the expression of S100A4 and NF-κB while upregulating p53 in xenograft mice compared to those without EGCG treatment. This study suggests that EGCG suppresses cancer progression through the S100A4/NF-κB signaling pathway, involving interaction with p53. EGCG holds potential as an anticancer candidate for OC/DDP.
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Affiliation(s)
- Xiaoli Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
| | - Yidan Hou
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
| | - Gaoyang Han
- Department of Thoracic Surgery, Zhengzhou Central Hospital, Henan 450052, China
| | - Yudan Yang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
| | - Shaofang Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
| | - Xiufang Lv
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
| | - Ming Gao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
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Perriera R, Vitale E, Pibiri I, Carollo PS, Ricci D, Corrao F, Fiduccia I, Melfi R, Zizzo MG, Tutone M, Pace A, Lentini L. Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target Effects on Natural Termination Codons (NTCs) on TP53 and Housekeeping Gene Expression. Int J Mol Sci 2023; 24:15084. [PMID: 37894764 PMCID: PMC10606485 DOI: 10.3390/ijms242015084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/11/2023] [Accepted: 10/08/2023] [Indexed: 10/29/2023] Open
Abstract
Nonsense mutations cause several genetic diseases such as cystic fibrosis, Duchenne muscular dystrophy, β-thalassemia, and Shwachman-Diamond syndrome. These mutations induce the formation of a premature termination codon (PTC) inside the mRNA sequence, resulting in the synthesis of truncated polypeptides. Nonsense suppression therapy mediated by translational readthrough-inducing drugs (TRIDs) is a promising approach to correct these genetic defects. TRIDs generate a ribosome miscoding of the PTC named "translational readthrough" and restore the synthesis of full-length and potentially functional proteins. The new oxadiazole-core TRIDs NV848, NV914, and NV930 (NV) showed translational readthrough activity in nonsense-related in vitro systems. In this work, the possible off-target effect of NV molecules on natural termination codons (NTCs) was investigated. Two different in vitro approaches were used to assess if the NV molecule treatment induces NTC readthrough: (1) a study of the translational-induced p53 molecular weight and functionality; (2) the evaluation of two housekeeping proteins' (Cys-C and β2M) molecular weights. Our results showed that the treatment with NV848, NV914, or NV930 did not induce any translation alterations in both experimental systems. The data suggested that NV molecules have a specific action for the PTCs and an undetectable effect on the NTCs.
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Affiliation(s)
| | | | - Ivana Pibiri
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy; (R.P.); (E.V.); (P.S.C.); (D.R.); (F.C.); (I.F.); (R.M.); (M.G.Z.); (M.T.); (A.P.)
| | | | | | | | | | | | | | | | | | - Laura Lentini
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy; (R.P.); (E.V.); (P.S.C.); (D.R.); (F.C.); (I.F.); (R.M.); (M.G.Z.); (M.T.); (A.P.)
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11
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Maslenkina K, Mikhaleva L, Naumenko M, Vandysheva R, Gushchin M, Atiakshin D, Buchwalow I, Tiemann M. Signaling Pathways in the Pathogenesis of Barrett's Esophagus and Esophageal Adenocarcinoma. Int J Mol Sci 2023; 24:ijms24119304. [PMID: 37298253 DOI: 10.3390/ijms24119304] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Barrett's esophagus (BE) is a premalignant lesion that can develop into esophageal adenocarcinoma (EAC). The development of Barrett's esophagus is caused by biliary reflux, which causes extensive mutagenesis in the stem cells of the epithelium in the distal esophagus and gastro-esophageal junction. Other possible cellular origins of BE include the stem cells of the mucosal esophageal glands and their ducts, the stem cells of the stomach, residual embryonic cells and circulating bone marrow stem cells. The classical concept of healing a caustic lesion has been replaced by the concept of a cytokine storm, which forms an inflammatory microenvironment eliciting a phenotypic shift toward intestinal metaplasia of the distal esophagus. This review describes the roles of the NOTCH, hedgehog, NF-κB and IL6/STAT3 molecular pathways in the pathogenesis of BE and EAC.
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Affiliation(s)
- Ksenia Maslenkina
- A.P. Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119991 Moscow, Russia
| | - Liudmila Mikhaleva
- A.P. Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119991 Moscow, Russia
| | - Maxim Naumenko
- A.P. Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119991 Moscow, Russia
| | - Rositsa Vandysheva
- A.P. Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119991 Moscow, Russia
| | - Michail Gushchin
- A.P. Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119991 Moscow, Russia
| | - Dmitri Atiakshin
- Research and Educational Resource Centre for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia Named after Patrice Lumumba, 117198 Moscow, Russia
| | - Igor Buchwalow
- Research and Educational Resource Centre for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia Named after Patrice Lumumba, 117198 Moscow, Russia
- Institute for Hematopathology, Fangdieckstr. 75a, 22547 Hamburg, Germany
| | - Markus Tiemann
- Institute for Hematopathology, Fangdieckstr. 75a, 22547 Hamburg, Germany
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12
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Ryckx S, De Schepper J, Giron P, Maes K, Vaeyens F, Wilgenhof K, Lefesvre P, Ernst C, Vanderlinden K, Klink D, Hes F, Vanbesien J, Gies I, Staels W. Peripheral precocious puberty in Li-Fraumeni syndrome: a case report and literature review of pure androgen-secreting adrenocortical tumors. J Med Case Rep 2023; 17:195. [PMID: 37179382 PMCID: PMC10183130 DOI: 10.1186/s13256-023-03889-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 03/14/2023] [Indexed: 05/15/2023] Open
Abstract
INTRODUCTION Pure androgen-secreting adrenocortical tumors are a rare but important cause of peripheral precocious puberty. CASE PRESENTATION Here, we report a pure androgen-secreting adrenocortical tumor in a 2.5-year-old boy presenting with penile enlargement, pubic hair, frequent erections, and rapid linear growth. We confirmed the diagnosis through laboratory tests, medical imaging, and histology. Furthermore, genetic testing detected a pathogenic germline variant in the TP53 gene, molecularly confirming underlying Li-Fraumeni syndrome. DISCUSSION Only 15 well-documented cases of pure androgen-secreting adrenocortical tumors have been reported so far. No clinical or imaging signs were identified to differentiate adenomas from carcinomas, and no other cases of Li-Fraumeni syndrome were diagnosed in the four patients that underwent genetic testing. However, diagnosing Li-Fraumeni syndrome is important as it implies a need for intensive tumor surveillance and avoidance of ionizing radiation. CONCLUSION In this article, we emphasize the need to screen for TP53 gene variants in children with androgen-producing adrenal adenomas and report an association with arterial hypertension.
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Affiliation(s)
- Sofie Ryckx
- Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, ZNA Queen Paola Child Hospital, Lindendreef 1, 2020, Antwerp, Belgium.
- Division of Pediatric Endocrinology, Department of Pediatrics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium.
| | - Jean De Schepper
- Division of Pediatric Endocrinology, Department of Pediatrics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Philippe Giron
- Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Ken Maes
- Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Freya Vaeyens
- Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Kaat Wilgenhof
- Department of Pathology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Pierre Lefesvre
- Department of Pathology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Caroline Ernst
- Department of Radiology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Kim Vanderlinden
- Division of Pediatric Surgery, Department of Surgery, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Daniel Klink
- Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, ZNA Queen Paola Child Hospital, Lindendreef 1, 2020, Antwerp, Belgium
| | - Frederik Hes
- Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Jesse Vanbesien
- Division of Pediatric Endocrinology, Department of Pediatrics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Inge Gies
- Division of Pediatric Endocrinology, Department of Pediatrics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Willem Staels
- Division of Pediatric Endocrinology, Department of Pediatrics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
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13
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Kaida T, Fujiyama Y, Soeno T, Yokota M, Nakamoto S, Goto T, Watanabe A, Okuno K, Nie Y, Fujino S, Yokota K, Harada H, Tanaka Y, Tanaka T, Yokoi K, Kojo K, Miura H, Yamanashi T, Sato T, Sasaki J, Sangai T, Hiki N, Kumamoto Y, Naitoh T, Yamashita K. Less demand on stem cell marker-positive cancer cells may characterize metastasis of colon cancer. PLoS One 2023; 18:e0277395. [PMID: 37098074 PMCID: PMC10128954 DOI: 10.1371/journal.pone.0277395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 10/26/2022] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical significance of such markers remains elusive. METHODS Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors. RESULTS (1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (p<0.0001), while CD133 was expressed even in non-cancerous mucosa and rather decreased in the tumors (p = 0.048). (2) CD44V expression was significantly associated with CD44T expression (R = 0.62, p<0.0001), while they were not correlated to CD133 at all in the primary tumors. (3) CD44V/CD44T expressions were significantly higher in right colon cancer than in left colon cancer (p = 0.035/p = 0.012, respectively), while CD133 expression were not (p = 0.20). (4) In primary tumors, unexpectedly, CD44V/CD44T/CD133 mRNA expressions were not correlated with aggressive phenotypes, but CD44V/CD44T rather significantly with less aggressive lymph node metastasis/distant metastasis (p = 0.040/p = 0.039, respectively). Moreover, both CD44V and CD133 expressions were significantly decreased in liver metastasis as compared to primary tumors (p = 0.0005 and p = 0.0006, respectively). CONCLUSION Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.
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Affiliation(s)
- Takeshi Kaida
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshiki Fujiyama
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of General Pediatric and Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takafumi Soeno
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Mitsuo Yokota
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Shuji Nakamoto
- Department of General Pediatric and Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takuya Goto
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Akiko Watanabe
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kota Okuno
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yusuke Nie
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of General Pediatric and Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Shiori Fujino
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kazuko Yokota
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiroki Harada
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoko Tanaka
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Toshimichi Tanaka
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keigo Yokoi
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Ken Kojo
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hirohisa Miura
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takahiro Yamanashi
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeo Sato
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Jiichiro Sasaki
- Multidisciplinary Cancer Care and Treatment Center, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takafumi Sangai
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Naoki Hiki
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yusuke Kumamoto
- Department of General Pediatric and Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeshi Naitoh
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keishi Yamashita
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
- Division of Advanced Surgical Oncology, Research and Development Center for New Frontiers, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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14
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Aepala MR, Peiris MN, Jiang Z, Yang W, Meyer AN, Donoghue DJ. Nefarious NTRK oncogenic fusions in pediatric sarcomas: Too many to Trk. Cytokine Growth Factor Rev 2022; 68:93-106. [PMID: 36153202 DOI: 10.1016/j.cytogfr.2022.08.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 01/30/2023]
Abstract
Neurotrophic Tyrosine Receptor Kinase (NTRK) genes undergo chromosomal translocations to create novel open reading frames coding for oncogenic fusion proteins; the N-terminal portion, donated by various partner genes, becomes fused to the tyrosine kinase domain of either NTRK1, NTRK2, or NTRK3. NTRK fusion proteins have been identified as driver oncogenes in a wide variety of tumors over the past three decades, including Pediatric Gliomas, Papillary Thyroid Carcinoma, Spitzoid Neoplasms, Glioblastoma, and additional tumors. Importantly, NTRK fusions function as drivers of pediatric sarcomas, accounting for approximately 15% of childhood cancers including Infantile Fibrosarcoma (IFS), a subset of pediatric soft tissue sarcoma (STS). While tyrosine kinase inhibitors (TKIs), such as larotrectinib and entrectinib, have demonstrated profound results against NTRK fusion-positive cancers, acquired resistance to these TKIs has resulted in the formation of gatekeeper, solvent-front, and compound mutations. We present a comprehensive compilation of oncogenic fusions involving NTRKs focusing specifically on pediatric STS, examining their biological signaling pathways and mechanisms of activation. The importance of an obligatory dimerization or multimerization domain, invariably donated by the N-terminal fusion partner, is discussed using characteristic fusions that occur in pediatric sarcomas. In addition, examples are presented of oncogenic fusion proteins in which the N-terminal partners may contribute additional biological activities beyond an oligomerization domain. Lastly, therapeutic approaches to the treatment of pediatric sarcoma will be presented, using first generation and second-generation agents such as selitrectinib and repotrectinib.
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Affiliation(s)
- Megha R Aepala
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0367, USA
| | - Malalage N Peiris
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0367, USA
| | - Zian Jiang
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0367, USA
| | - Wei Yang
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0367, USA
| | - April N Meyer
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0367, USA
| | - Daniel J Donoghue
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0367, USA; UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0367, USA.
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15
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Munisamy M, Mukherjee N, Thomas L, Pham AT, Shakeri A, Zhao Y, Kolesar J, Rao PPN, Rangnekar VM, Rao M. Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions. Am J Cancer Res 2021; 11:5762-5781. [PMID: 35018225 PMCID: PMC8727821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/22/2021] [Indexed: 06/14/2023] Open
Abstract
Ubiquitination is a key enzymatic post-translational modification that influences p53 stability and function. p53 protein regulates the expression of MDM2 (mouse double-minute 2 protein) E3 ligase and MDMX (double-minute 4 protein), through proteasome-based degradation. Exploration of targeting the ubiquitination pathway offers a potentially promising strategy for precision therapy in a variety of cancers. The p53-MDM2-MDMX pathway provides multiple molecular targets for small molecule screening as potential therapies for wild-type p53. As a result of its effect on molecular carcinogenesis, a personalized therapeutic approach based on the wild-type and mutant p53 protein is desirable. We highlighted the implications of p53 mutations in cancer, p53 ubiquitination mechanistic details, targeting p53-MDM2/MDMX interactions, significant discoveries related to MDM2 inhibitor drug development, MDM2 and MDMX dual target inhibitors, and clinical trials with p53-MDM2/MDMX-targeted drugs. We also investigated potential therapeutic repurposing of selective estrogen receptor modulators (SERMs) in targeting p53-MDM2/MDMX interactions. Molecular docking studies of SERMs were performed utilizing the solved structures of the p53/MDM2/MDMX proteins. These studies identified ormeloxifene as a potential dual inhibitor of p53/MDM2/MDMX interaction, suggesting that repurposing SERMs for dual targeting of p53/MDM2 and p53/MDMX interactions is an attractive strategy for targeting wild-type p53 tumors and warrants further preclinical research.
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Affiliation(s)
- Murali Munisamy
- Department of Translational Medicine Centre, All India Institute of Medical SciencesBhopal, Madhya Pradesh 462020, India
- Department of Pharmacy Practice, Center for Translational Research, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationManipal, Karnataka 576104, India
| | - Nayonika Mukherjee
- Department of Pharmacy Practice, Center for Translational Research, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationManipal, Karnataka 576104, India
| | - Levin Thomas
- Department of Pharmacy Practice, Center for Translational Research, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationManipal, Karnataka 576104, India
| | - Amy Trinh Pham
- Medicinal and Bioorganic Chemistry Lab, School of Pharmacy, Health Sciences Campus, 200 University Avenue West, University of WaterlooWaterloo, ON N2L 3G1, Canada
| | - Arash Shakeri
- Medicinal and Bioorganic Chemistry Lab, School of Pharmacy, Health Sciences Campus, 200 University Avenue West, University of WaterlooWaterloo, ON N2L 3G1, Canada
| | - Yusheng Zhao
- Medicinal and Bioorganic Chemistry Lab, School of Pharmacy, Health Sciences Campus, 200 University Avenue West, University of WaterlooWaterloo, ON N2L 3G1, Canada
| | - Jill Kolesar
- Department of Pharmacy Practice & Science, University of Kentucky567 TODD Building, 789 South Limestone Street, Lexington, Kentucky 40539-0596, USA
| | - Praveen P N Rao
- Medicinal and Bioorganic Chemistry Lab, School of Pharmacy, Health Sciences Campus, 200 University Avenue West, University of WaterlooWaterloo, ON N2L 3G1, Canada
| | - Vivek M Rangnekar
- Markey Cancer Center, University of KentuckyLexington, Kentucky 40536, USA
| | - Mahadev Rao
- Department of Pharmacy Practice, Center for Translational Research, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationManipal, Karnataka 576104, India
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16
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Konishi M, Kameyama KI, Yamamoto T. Mutations in the tumor suppressor gene p53 in cattle are associated with enzootic bovine leukosis. Vet Microbiol 2021; 263:109269. [PMID: 34781193 DOI: 10.1016/j.vetmic.2021.109269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/25/2021] [Indexed: 12/21/2022]
Abstract
Enzootic bovine leukosis (EBL) is a B-cell lymphoma caused by the bovine leukemia virus (BLV). Although an association between EBL and mutations in the bovine tumor suppressor gene TP53 (bTP53) has been suggested, the substantive incidence rate of bTP53 mutations in EBL cattle is still unclear. In this study, we investigated the complete sequence (exons 2-11) of bTP53 in tissue and peripheral blood leukocyte (PBL) samples obtained from 154 EBL cattle and 117 cattle without EBL (non-EBL cattle) to elucidate the correlation between bTP53 mutations and EBL. The detection frequencies of non-synonymous (NS) and deletion mutations in bTP53 in EBL cattle were significantly higher than those in non-EBL cattle in both tissue and PBL samples (p < 0.05). Among these mutations in EBL cattle, 73.7 % (42/54) were homologous to those of human TP53 (hTP53), which were previously detected in various tumors. It has been reported that 95.2 % (40/42) of these hTP53 mutations induced complete or partial loss of the transactivating function of its encoding protein, P53. Moreover, the BLV proviral load in tissue samples was significantly higher in cattle harboring bTP53 NS and deletion mutations than in cattle without these mutations in both EBL and BLV-infected non-EBL cattle (p < 0.05). Although the activity of the mutant variants of bP53 must be further investigated, our findings revealed that bTP53 mutations are involved in tumorigenesis in BLV-infected cells and EBL-associated carcinogenesis.
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Affiliation(s)
- Misako Konishi
- Epidemiology Unit, National Institute of Animal Health, National Agriculture and Food Research Organization, 3-1-5 Kannondai, Tsukuba, Ibaraki, 305-0856, Japan.
| | - Ken-Ichiro Kameyama
- Exotic Disease Research Group, National Institute of Animal Health, National Agriculture and Food Research Organization, 6-20-1 Josuihoncho, Kodaira, Tokyo, 187-0022, Japan.
| | - Takehisa Yamamoto
- Epidemiology Unit, National Institute of Animal Health, National Agriculture and Food Research Organization, 3-1-5 Kannondai, Tsukuba, Ibaraki, 305-0856, Japan.
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17
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Yamashita K, Hosoda K, Niihara M, Hiki N. History and emerging trends in chemotherapy for gastric cancer. Ann Gastroenterol Surg 2021; 5:446-456. [PMID: 34337293 PMCID: PMC8316740 DOI: 10.1002/ags3.12439] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/29/2020] [Accepted: 01/15/2021] [Indexed: 12/24/2022] Open
Abstract
Chemotherapy is indispensable for gastric cancer. For unresectable and/or recurrent gastric cancer, first-line chemotherapy consists of multidrug regimens including oral 5-FU agents such as S1/Xeloda and platinum preparations, as well as Trastuzumab, which is effective in HER2-positive cases. Second- and third-line chemotherapy regimens include taxanes, Ramucirumab (R-mab), and Nivolumab (N-mab), which have different mechanisms of action from first-line chemotherapy. R-mab is molecularly targeted to vascular endothelial growth factor receptor 2 in the host cells, but its indication is not conditional. For resectable gastric cancer, in Eastern countries, postoperative adjuvant chemotherapy has been successful, including S1, Docetaxel/S1 (DS), and Xeloda/Oxaliplatin (Xelox) regimens, whereas, in Western countries, the 5-FU/Leucovorin/Oxaliplatin/Docetaxel (FLOT) regimen was recently shown to be effective in the perioperative chemotherapy setting. Most recently, however, in Eastern countries, perioperative SOX was demonstrated to be effective in specific advanced gastric cancer. For stage IV gastric cancer, new therapeutic strategies have been proposed such as neoadjuvant chemotherapy and conversion surgery, and cures can be conditionally obtained. Recent genomic understanding of gastric cancer proposed a diversity of molecular targets by molecular profiling. Such optimized chemotherapy regimens, according to the specific clinical situations, have been rigorously established for the best survival of advanced gastric cancer.
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Affiliation(s)
- Keishi Yamashita
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical FrontiersKitasato University School of MedicineSagamiharaJapan
- Department of Upper Gastrointestinal SurgeryKitasato University School of MedicineSagamiharaJapan
| | - Kei Hosoda
- Department of Upper Gastrointestinal SurgeryKitasato University School of MedicineSagamiharaJapan
| | - Masahiro Niihara
- Department of Upper Gastrointestinal SurgeryKitasato University School of MedicineSagamiharaJapan
| | - Naoki Hiki
- Department of Upper Gastrointestinal SurgeryKitasato University School of MedicineSagamiharaJapan
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18
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Xiao G, Annor GK, Fung K, Keinänen O, Zeglis BM, Bargonetti J. Targeting Triple Negative Breast Cancer with a Nucleus-Directed p53 Tetramerization Domain Peptide. Mol Pharm 2021; 18:338-346. [PMID: 33289569 PMCID: PMC8068092 DOI: 10.1021/acs.molpharmaceut.0c00978] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Triple negative breast cancer (TNBC) has no targeted detection or treatment method. Mutant p53 (mtp53) is overexpressed in >80% of TNBCs, and the stability of mtp53 compared to the instability of wild-type p53 (wtp53) in normal cells makes mtp53 a promising TNBC target for diagnostic and theranostic imaging. We generated Cy5p53Tet, a novel nucleus-penetrating mtp53-oligomerization-domain peptide (mtp53ODP) to the tetramerization domain (TD) of mtp53. This mtp53ODP contains the p53 TD sequence conjugated to a Cy5 fluorophore for near-infrared fluorescence imaging (NIRF). In vitro co-immunoprecipitation and glutaraldehyde cross-linking showed a direct interaction between mtp53 and Cy5p53Tet. Confocal microscopy and flow cytometry demonstrated higher uptake of Cy5p53Tet in the nuclei of TNBC MDA-MB-468 cells with mtp53 R273H than in ER-positive MCF7 cells with wtp53. Furthermore, depletion of mtp53 R273H caused a decrease in the uptake of Cy5p53Tet in nuclei. In vivo analysis of the peptide in mice bearing MDA-MB-468 xenografts showed that Cy5p53Tet could be detected in tumor tissue 12 min after injection. In these in vivo experiments, significantly higher uptake of Cy5p53Tet was observed in mtp53-expressing MDA-MB-468 xenografts compared with the wtp53-expressing MCF7 tumors. Cy5p53Tet has clinical potential as an intraoperative imaging agent for fluorescence-guided surgery, and the mtp53ODP scaffold shows promise for modification in the future to enable the delivery of a wide variety of payloads including radionuclides and toxins to mtp53-expressing TNBC tumors.
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Affiliation(s)
- Gu Xiao
- Department of Biological Sciences Hunter College, City University of New York, New York, New York 10021, United States
| | - George K Annor
- Department of Biological Sciences Hunter College, City University of New York, New York, New York 10021, United States
- The Graduate Center Biochemistry PhD Program of City University of New York, New York, New York 10016, United States
| | - Kimberly Fung
- Department of Chemistry Hunter College of the City University of New York, New York, New York 10021, United States
- Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York 10016, United States
| | - Outi Keinänen
- Department of Chemistry Hunter College of the City University of New York, New York, New York 10021, United States
| | - Brian M Zeglis
- Department of Chemistry Hunter College of the City University of New York, New York, New York 10021, United States
- Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York 10016, United States
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, United States
| | - Jill Bargonetti
- Department of Biological Sciences Hunter College, City University of New York, New York, New York 10021, United States
- The Graduate Center Biochemistry PhD Program of City University of New York, New York, New York 10016, United States
- Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10021, United States
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19
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Xu HY, Song HM, Zhou Q. Comprehensive analysis of the expression and prognosis for S100 in human ovarian cancer: A STROBE study. Medicine (Baltimore) 2020; 99:e22777. [PMID: 33217795 PMCID: PMC7676574 DOI: 10.1097/md.0000000000022777] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
S100 family members are frequently deregulated in human malignancies, including ovarian cancer. However, the prognostic roles of each individual S100 family member in ovarian cancer (OC) patients remain elusive. In the present study, we assessed the prognostic roles and molecular function of 20 individual members of the S100 family in OC patients using GEPIA, Kaplan-Meier plotter, SurvExpress, GeneMANIA and Funrich database. Our results indicated that the mRNA expression levels of S100A1, S100A2, S100A4, S100A5, S100A11, S100A14, and S100A16 were significantly upregulated in patients with OC, and high mRNA expression of S100A1, S100A3, S100A5, S100A6, and S100A13 were significantly correlated with better overall survival, while increased S100A2, S100A7A, S100A10, and S100A11 mRNA expressions were associated with worse prognosis in OC patients. In stratified analysis, the trends of high expression of individual S100 members were nearly the same in different pathological grade, clinical stage, TP53 mutation status, and treatment. More importantly, S100 family signatures may be useful potential prognostic markers for OC. These findings suggest that S100 family plays a vital role in prognostic value and could potentially be an S100-targeted inhibitors for OC patients.
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Affiliation(s)
- Hong-Yu Xu
- Department of Gynecology and Obstetrics, the Second People's Hospital of Yichang, China Three Gorges University
| | - Hua-Mei Song
- Department of Gynecology and Obstetrics, the People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, Hubei, China
| | - Quan Zhou
- Department of Gynecology and Obstetrics, the People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, Hubei, China
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20
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Kase AM, Copland III JA, Tan W. Novel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer. Onco Targets Ther 2020; 13:10499-10513. [PMID: 33116629 PMCID: PMC7576355 DOI: 10.2147/ott.s266085] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 09/18/2020] [Indexed: 12/15/2022] Open
Abstract
The majority of patients with castrate-resistant prostate cancer will have metastatic disease at the time of diagnosis. Investigative efforts on new therapeutics for this patient population have improved with the development of androgen signaling inhibitors, such as abiraterone and enzalutamide, and PARP inhibitors, such as rucaparib and olaparib, to accompany the previously FDA-approved docetaxel, cabazitaxel, sipuleucel-T, and Radium 223. However, new therapeutic strategies are necessary to prolong survival as progression after these agents is inevitable. CDK4/6 inhibitors have advanced the field of estrogen receptor positive breast cancer treatment and are being investigated in prostate cancer given the role of androgen receptor signaling effects on the cell cycle. Response to CDK4/6 inhibitors may be predicted by the tumors' genomic profile and may provide insight into combinatory therapy with CDK4/6 inhibitors in order to delay resistance or provide synergistic effects. Here, we review the use of CDK4/6 inhibitors in prostate cancer and potential combinations based on known resistance mechanisms to CDK4/6 inhibitors, prostate cancer regulatory pathways, and prostate-cancer-specific genomic alterations.
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Affiliation(s)
- Adam M Kase
- Mayo Clinic Florida Division of Hematology Oncology, Jacksonville, FL32224, USA
| | - John A Copland III
- Mayo Clinic Florida Department of Cancer Biology, Jacksonville, FL32224, USA
| | - Winston Tan
- Mayo Clinic Florida Division of Hematology Oncology, Jacksonville, FL32224, USA
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21
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The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing. Cancers (Basel) 2020; 12:cancers12092717. [PMID: 32971841 PMCID: PMC7563196 DOI: 10.3390/cancers12092717] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/13/2020] [Accepted: 09/17/2020] [Indexed: 02/07/2023] Open
Abstract
p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the 'guardian of the genome' and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of the current standard of care and marginal benefit of newly approved therapies. Presently, the endeavors focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.
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22
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Frequency of the TP53 p.R337H mutation in a Brazilian cohort of pediatric patients with solid tumors. Mol Biol Rep 2020; 47:6439-6443. [PMID: 32671623 DOI: 10.1007/s11033-020-05655-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/08/2020] [Indexed: 02/06/2023]
Abstract
TP53 p.R337H germline mutation is highly prevalent in the Southern region of Brazil. We sought to investigate TP53 p.R337H mutation in pediatric tumor samples from a population settled in a geographic area of high prevalence for this variant. Mutation assessment and genetic counseling for carriers/relatives were provided. 6/57 tumor samples were heterozygous for TP53 p.R337H. As expected, a high frequency was observed within adrenocortical tumors (3/3) and choroid plexus carcinomas (2/2). Interestingly, the TP53 R337H mutation was found in one case of pediatric rhabdomyosarcoma with Li-Fraumeni pedigree. Our finding expands the spectrum of childhood cancer associated with this germline mutation.
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23
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Guo CC, Majewski T, Zhang L, Yao H, Bondaruk J, Wang Y, Zhang S, Wang Z, Lee JG, Lee S, Cogdell D, Zhang M, Wei P, Grossman HB, Kamat A, Duplisea JJ, Ferguson JE, Huang H, Dadhania V, Gao J, Dinney C, Weinstein JN, Baggerly K, McConkey D, Czerniak B. Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer. Cell Rep 2020; 27:1781-1793.e4. [PMID: 31067463 DOI: 10.1016/j.celrep.2019.04.048] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/28/2019] [Accepted: 04/10/2019] [Indexed: 12/17/2022] Open
Abstract
Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.
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Affiliation(s)
- Charles C Guo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tadeusz Majewski
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Li Zhang
- Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA
| | - Hui Yao
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jolanta Bondaruk
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yan Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shizhen Zhang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ziqiao Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - June Goo Lee
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sangkyou Lee
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David Cogdell
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Miao Zhang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Peng Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - H Barton Grossman
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ashish Kamat
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - James Edward Ferguson
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - He Huang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vipulkumar Dadhania
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jianjun Gao
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Colin Dinney
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John N Weinstein
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keith Baggerly
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David McConkey
- Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Bogdan Czerniak
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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24
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Cordani M, Butera G, Pacchiana R, Masetto F, Mullappilly N, Riganti C, Donadelli M. Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells. Biomolecules 2020; 10:biom10030361. [PMID: 32111081 PMCID: PMC7175157 DOI: 10.3390/biom10030361] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/14/2020] [Accepted: 02/20/2020] [Indexed: 12/16/2022] Open
Abstract
The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene.
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Affiliation(s)
- Marco Cordani
- IMDEA Nanociencia, Ciudad Universitaria de Cantoblanco, 28049 Madrid, Spain;
| | - Giovanna Butera
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy; (G.B.); (R.P.); (F.M.); (N.M.)
| | - Raffaella Pacchiana
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy; (G.B.); (R.P.); (F.M.); (N.M.)
| | - Francesca Masetto
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy; (G.B.); (R.P.); (F.M.); (N.M.)
| | - Nidula Mullappilly
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy; (G.B.); (R.P.); (F.M.); (N.M.)
| | - Chiara Riganti
- Department of Oncology, University of Torino, 10126 Torino, Italy;
| | - Massimo Donadelli
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy; (G.B.); (R.P.); (F.M.); (N.M.)
- Correspondence: ; Tel.: +39-045-8027281; Fax: +39-045-8027170
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25
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Cooper MM, Loiseau C, Doolan DL. Casting a Wide Net around Immunity to Malaria Catches p53. Immunity 2019; 51:603-605. [PMID: 31618652 DOI: 10.1016/j.immuni.2019.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The mechanisms underlying acquisition of naturally acquired immunity to malaria are poorly understood. In this issue of Immunity, Tran and colleagues (2019) demonstrate that systems immunology is a powerful tool to decipher molecular and cellular components contributing to this immunity.
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Affiliation(s)
- Martha M Cooper
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4870, Australia
| | - Claire Loiseau
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4870, Australia
| | - Denise L Doolan
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4870, Australia.
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26
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Ooizumi Y, Kojima K, Igarashi K, Tanaka Y, Harada H, Yokota K, Kaida T, Ishii S, Tanaka T, Yokoi K, Nishizawa N, Washio M, Ushiku H, Katoh H, Kosaka Y, Mieno H, Hosoda K, Watanabe M, Katada C, Hiki N, Yamashita K. Comprehensive Exploration to Identify Predictive DNA Markers of ΔNp63/SOX2 in Drug Resistance in Human Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 2019; 26:4814-4825. [PMID: 31529309 DOI: 10.1245/s10434-019-07795-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND OBP-801 is a novel histone deacetylase inhibitor being developed as an anticancer drug. In this study, we explored genes to predict drug resistance in human cancer. METHODS OBP-801 resistance was assessed in 37 strains of human cancer cell lines. Expression microarrays harboring 54,675 genes were used to focus on candidate genes, which were validated for both functional and clinical relevance in esophageal squamous cell carcinoma (ESCC). RESULTS OBP-801 is sensitive to esophageal, gastric, and thyroid cancer, and resistant to some esophageal and colorectal cancers. We therefore used ESCC to explore genes. Comprehensive exploration focused on ΔNp63/SOX2, which were both genetically and epigenetically overexpressed in ESCC. Genomic amplifications of ΔNp63/SOX2 were tightly correlated each other (r = 0.81). Importantly, genomic amplification of ΔNp63/SOX2 in the resected tumors after neoadjuvant chemotherapy was significantly associated with histological grade of response (G1). Forced expression of either of these two genes did not induce each other, suggesting that their functional relevances were independent and showed robust drug resistance in OBP-801, as well as 5-fluorouracil. Furthermore, ΔNp63 could exert a potent oncogenic potential. RNA interference of ΔNp63 supported its oncological properties, as well as drug resistance. CONCLUSION Comprehensive exploration of genes involved in anticancer drug residence could identify critical oncogenes of ΔNp63/SOX2 that would predict chemotherapy response in ESCC.
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Affiliation(s)
- Yosuke Ooizumi
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keita Kojima
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kazuharu Igarashi
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoko Tanaka
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiroki Harada
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kazuko Yokota
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeshi Kaida
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Satoru Ishii
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Toshimichi Tanaka
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keigo Yokoi
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Nobuyuki Nishizawa
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Marie Washio
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hideki Ushiku
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiroshi Katoh
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshimasa Kosaka
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiroaki Mieno
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kei Hosoda
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Masahiko Watanabe
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Chikatoshi Katada
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Naoki Hiki
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keishi Yamashita
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. .,Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
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27
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Chung AK, OuYang CN, Liu H, Chao M, Luo JD, Lee CY, Lu YJ, Chung IC, Chen LC, Wu SM, Tsang NM, Chang KP, Hsu CL, Li HP, Chang YS. Targeted sequencing of cancer-related genes in nasopharyngeal carcinoma identifies mutations in the TGF-β pathway. Cancer Med 2019; 8:5116-5127. [PMID: 31328403 PMCID: PMC6718742 DOI: 10.1002/cam4.2429] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 12/18/2022] Open
Abstract
Approximately, 25% of nasopharyngeal carcinoma (NPC) patients develop recurrent disease. NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein‐Barr virus (EBV). We envisioned that in‐depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty‐three NPC paired tumor/adjacent normal or peripheral blood mononuclear cell samples were deep‐sequenced (>1000×) with respect to a panel of 409 cancer‐related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK/RAS/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF‐κB, and TGF‐β pathways. In addition, patients harbored CNV among 409 cancer‐related genes and missense mutations in TGF‐β/SMAD signaling were associated with poor overall survival and poor recurrence‐free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD‐dependent TGF‐β signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2/3 and activation of downstream TGF‐β‐mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF‐β signaling contributes to exacerbating the NPC pathogenesis.
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Affiliation(s)
- An-Ko Chung
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Chun-Nan OuYang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Hsuan Liu
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Molecular Medicine Research Center, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Department of Biochemistry, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, Republic of China
| | - Mei Chao
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Department of Microbiology and Immunology, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, Republic of China
| | - Ji-Dung Luo
- Molecular Medicine Research Center, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Bioinformatics Center, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Cheng-Yang Lee
- Research Information Session, Office of Information Technology, Taipei Medical University, Taipei City, Taiwan, Republic of China
| | - Yen-Jung Lu
- ACT Genomics, Co. Ltd., Taipei City, Taiwan, Republic of China
| | - I-Che Chung
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Molecular Medicine Research Center, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Lih-Chyang Chen
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, Republic of China
| | - Shao-Min Wu
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Ngan-Ming Tsang
- Department of Radiation, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Kai-Ping Chang
- Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Cheng-Lung Hsu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Hsin-Pai Li
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Molecular Medicine Research Center, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Department of Microbiology and Immunology, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City, Taiwan, Republic of China
| | - Yu-Sun Chang
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Molecular Medicine Research Center, Chang Gung University, Taoyuan City, Taiwan, Republic of China.,Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City, Taiwan, Republic of China
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Hosoda K, Watanabe M, Yamashita K. Re-emerging role of macroscopic appearance in treatment strategy for gastric cancer. Ann Gastroenterol Surg 2019; 3:122-129. [PMID: 30923781 PMCID: PMC6422795 DOI: 10.1002/ags3.12218] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 09/16/2018] [Accepted: 09/22/2018] [Indexed: 12/22/2022] Open
Abstract
Pathological outcomes are definitely the most important prognostic factors in gastric cancer, but they can be obtained only after surgical resection. Use of preoperative adjuvant chemotherapy is becoming widespread for aggressive human cancer, so clinical factors such as macroscopic features are important as they are highly predictive for patient prognosis. In gastric cancer, the macroscopic type represents a distinct prognosis; Type 0 represents early gastric cancer with excellent prognosis, but, among advanced tumors, giant Type III and Type IV tumors have a dismal prognosis. Japan Clinical Oncology Group (JCOG) Stomach Cancer Study Group adopted macroscopic features as high-risk entities in clinical trials. It makes sense for risk classification to use macroscopic phenotypes because The Cancer Genome Atlas (TCGA) Network has lately subcategorized different histologies associated with specific macroscopic types by the molecular features of the whole genome. Dismal prognosis of Type IV gastric cancer is notorious, but similar prognosis was seen in giant Type III gastric cancer defined as 8 cm or beyond, both of which are unique for their propensity of peritoneal dissemination. In this review, clinical relevance including prognosis of such macroscopic high-risk features will be separately debated in the context of precision medicine and updated prognostic outcomes will be presented under the present standard therapy of curative surgery followed by postoperative S-1 chemotherapy. Moreover, promising emerging novel therapeutic strategies including trimodal potent regimens or intraperitoneal chemotherapy will be described for such aggressive gastric cancer.
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Affiliation(s)
- Kei Hosoda
- Department of SurgeryKitasato University School of MedicineSagamiharaJapan
| | - Masahiko Watanabe
- Department of SurgeryKitasato University School of MedicineSagamiharaJapan
| | - Keishi Yamashita
- Department of SurgeryKitasato University School of MedicineSagamiharaJapan
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical FrontiersKitasato University School of MedicineSagamiharaJapan
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TP73 G4C14-A4T14 polymorphism and cancer susceptibility: evidence from 36 case-control studies. Biosci Rep 2018; 38:BSR20181452. [PMID: 30420492 PMCID: PMC6294616 DOI: 10.1042/bsr20181452] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 10/26/2018] [Accepted: 11/08/2018] [Indexed: 11/24/2022] Open
Abstract
G4C14-A4T14 polymorphism of TP73 gene has been reported with a potential association in cancer risks through affected cell homeostasis; however the results were not consistent. We performed a comprehensive meta-analysis to explore the associations between G4C14-A4T14 polymorphism and cancer susceptibility. Extensive retrieve was performed in PubMed, EMBASE, Google Scholar, Web of Science, Wanfang database and CNKI database up to May 20, 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were conducted to evaluate the overall strength of the associations in five genetic models, as well as in subgroup analyses. Q-test, false-positive report probability analysis and trial sequential analysis, Egger’s test and Begg’s funnel plot were applied to evaluate the robustness of the results. In silico analysis was managed to demonstrate the relationship of TP73 expression correlated with cancer tissues. Finally, 36 case–control studies with a total of 9493 cancer cases and 13,157 healthy controls were enrolled into the meta-analysis. The pooled results present a significantly higher risk of G4C14-A4T14 polymorphism in all the five genetic models, as well as in the subgroups of Caucasian, cervical cancer, colorectal cancer, H-B subgroup and comfort to Hardy–Weinberg equilibrium subgroup. In silico analysis revealed that the expression of TP73 in cervical cancer tissue is higher than it in corresponding normal tissue, as well as in cervical cancer. All in all, TP73 G4C14-A4T14 polymorphism causes an upgrade cancer risk, especially in Caucasian population. G4C14-A4T14 polymorphism might be a potential biomarker for judging the tumorigenesis of cervical cancer and colorectal cancer.
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