Iatrogenic amyloidosis results from medical therapeutic interventions, leading to the misfolding and aggregation of proteins into amyloid fibrils or to their direct deposition in different tissues. This review aims to provide a comprehensive overview of the iatrogenic amyloidosis pathology, underlying the possible molecular mechanisms, associated pathological manifestations, and clinical implications within modern medicine. By conducting a systematic analysis of the current literature, this paper highlights the diverse instances of iatrogenic amyloidosis triggered by medical procedures such as dialysis, organ and tissue transplantation, and therapeutic drugs. Exploring the intricate molecular pathways and contributing factors involved in protein misfolding and amyloidogenesis, and uncovering the pathological consequences observed in various tissues and organs, allows us to establish appropriate nomenclature and to gain a more profound understanding of the condition, working towards improved medical interventions and treatments.
{"title":"Exploring the Molecular Pathology of Iatrogenic Amyloidosis","authors":"Bernardo Bonilauri","doi":"10.3390/jmp5020016","DOIUrl":"https://doi.org/10.3390/jmp5020016","url":null,"abstract":"Iatrogenic amyloidosis results from medical therapeutic interventions, leading to the misfolding and aggregation of proteins into amyloid fibrils or to their direct deposition in different tissues. This review aims to provide a comprehensive overview of the iatrogenic amyloidosis pathology, underlying the possible molecular mechanisms, associated pathological manifestations, and clinical implications within modern medicine. By conducting a systematic analysis of the current literature, this paper highlights the diverse instances of iatrogenic amyloidosis triggered by medical procedures such as dialysis, organ and tissue transplantation, and therapeutic drugs. Exploring the intricate molecular pathways and contributing factors involved in protein misfolding and amyloidogenesis, and uncovering the pathological consequences observed in various tissues and organs, allows us to establish appropriate nomenclature and to gain a more profound understanding of the condition, working towards improved medical interventions and treatments.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":"47 39","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141384501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Vigliar, Claudio Bellevicine, Gennaro Acanfora, Allan Argueta Morales, Anna Maria Carillo, Domenico Cozzolino, Mariantonia Nacchio, C. Luca, P. Pisapia, María D Lozano, S. Roy-Chowdhuri, G. Troncone
Over the past decade, molecular cytopathology has emerged as a relevant area of modern pathology. Notably, in patients with advanced-stage cancer, cytological samples could be the only material available for diagnosis and molecular biomarker testing to identify patients suitable for targeted therapies. As a result, the contemporary cytopathologist’s role extends beyond morphological assessments to include critical skills such as evaluating the adequacy of the cytological samples and managing these specimens for molecular testing. This case collection can be a valuable source of insight, especially for young pathologists, who should learn to combine the opportunities offered by molecular biology with the basis of morphological evaluation.
{"title":"How Molecular and Ancillary Tests Can Help in Challenging Cytopathology Cases: Insights from the International Molecular Cytopathology Meeting","authors":"E. Vigliar, Claudio Bellevicine, Gennaro Acanfora, Allan Argueta Morales, Anna Maria Carillo, Domenico Cozzolino, Mariantonia Nacchio, C. Luca, P. Pisapia, María D Lozano, S. Roy-Chowdhuri, G. Troncone","doi":"10.3390/jmp5020015","DOIUrl":"https://doi.org/10.3390/jmp5020015","url":null,"abstract":"Over the past decade, molecular cytopathology has emerged as a relevant area of modern pathology. Notably, in patients with advanced-stage cancer, cytological samples could be the only material available for diagnosis and molecular biomarker testing to identify patients suitable for targeted therapies. As a result, the contemporary cytopathologist’s role extends beyond morphological assessments to include critical skills such as evaluating the adequacy of the cytological samples and managing these specimens for molecular testing. This case collection can be a valuable source of insight, especially for young pathologists, who should learn to combine the opportunities offered by molecular biology with the basis of morphological evaluation.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":"92 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141268044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mukesh Kumar Yadav, Zeeshan Ahmed Khan, Jing-Hua Wang, AbuZar Ansari
The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially in pregnancy, HBD may result in increased maternal and fetal morbidity and mortality. Maternal HBD is a burden to the fetus’s growth, complicates fetal development, and risks the mother’s life. In fetal programming, the maternal mechanism is significantly disturbed by multiple factors (especially diet) that influence the development of the fetus and increase the frequency of metabolic diseases later in life. Additionally, maternal under-nutrition or over-nutrition (especially in high-fat, high-carbohydrate, or protein-rich diets) lead to dysregulation in gut hormones (CCK, GLP-1, etc.), microbiota metabolite production (SCFA, LPS, TMA, etc.), neurotransmitters (POMC, NPY, etc.), and hepatobiliary signaling (insulin resistance, TNF-a, SREBPs, etc.), which significantly impact fetal programming. Recently, biotherapeutics have provided a new horizon for treating HBD during fetal programming to save the lives of the mother and fetus. This review focuses on how maternal impaired hepatobiliary metabolic signaling leads to disease transmission to the fetus mediated through the gut–brain axis.
{"title":"Impact of Gut–Brain Axis on Hepatobiliary Diseases in Fetal Programming","authors":"Mukesh Kumar Yadav, Zeeshan Ahmed Khan, Jing-Hua Wang, AbuZar Ansari","doi":"10.3390/jmp5020014","DOIUrl":"https://doi.org/10.3390/jmp5020014","url":null,"abstract":"The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially in pregnancy, HBD may result in increased maternal and fetal morbidity and mortality. Maternal HBD is a burden to the fetus’s growth, complicates fetal development, and risks the mother’s life. In fetal programming, the maternal mechanism is significantly disturbed by multiple factors (especially diet) that influence the development of the fetus and increase the frequency of metabolic diseases later in life. Additionally, maternal under-nutrition or over-nutrition (especially in high-fat, high-carbohydrate, or protein-rich diets) lead to dysregulation in gut hormones (CCK, GLP-1, etc.), microbiota metabolite production (SCFA, LPS, TMA, etc.), neurotransmitters (POMC, NPY, etc.), and hepatobiliary signaling (insulin resistance, TNF-a, SREBPs, etc.), which significantly impact fetal programming. Recently, biotherapeutics have provided a new horizon for treating HBD during fetal programming to save the lives of the mother and fetus. This review focuses on how maternal impaired hepatobiliary metabolic signaling leads to disease transmission to the fetus mediated through the gut–brain axis.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":"23 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140967267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nikki Higa, L. Welter, Liya Xu, A. Kolatkar, K. Bramlett, Ole V. Gjoerup, Ryon P Graf, Richard S P Huang, Rebecca J. Leary, Young Lee, Jeremy Perkins, Adam Riker, Angad P Singh, Lorraine Tafra, Carol Kaplan Tweed, C. Shriver, James B. Hicks, Peter Kuhn
The chief goal of the Blood Profiling Atlas in Cancer (BloodPAC) consortium is to promote collaborative efforts that support the development and implementation of liquid biopsy tests. Here, we report the results of a pilot study conducted by three BloodPAC members that aimed to demonstrate a multisite liquid biopsy testing framework using longitudinal blood specimens from 38 patients with metastatic breast cancer. Three laboratories receiving identical samples from two clinical sites each applied a different targeted sequencing platform to analyze mutations in cell-free DNA (cfDNA). The resulting mutational profiles reflected common breast cancer alterations, including clinically actionable mutations for 40% of hormone- receptor-positive patients. In 12 genes with shared target regions across sequencing panels, perfect inter-assay concordance was also observed for mutations detected above the lowest common assay limit of detection. Whole-genome copy number profiling of cfDNA and circulating tumor cells (CTCs) further revealed marked heterogeneity in copy number alterations and cfDNA tumor fractions across patients. Additionally, comparison of tumor fraction and CTC abundance demonstrated the complementary nature of cfDNA and CTC analyses. Overall, the framework described in this study may serve as a resource for future trials aiming to identify multimodal liquid biopsy biomarkers to guide clinical care.
{"title":"Liquid Biopsy Profiling with Multiple Tests in Patients with Metastatic Breast Cancer","authors":"Nikki Higa, L. Welter, Liya Xu, A. Kolatkar, K. Bramlett, Ole V. Gjoerup, Ryon P Graf, Richard S P Huang, Rebecca J. Leary, Young Lee, Jeremy Perkins, Adam Riker, Angad P Singh, Lorraine Tafra, Carol Kaplan Tweed, C. Shriver, James B. Hicks, Peter Kuhn","doi":"10.3390/jmp5020013","DOIUrl":"https://doi.org/10.3390/jmp5020013","url":null,"abstract":"The chief goal of the Blood Profiling Atlas in Cancer (BloodPAC) consortium is to promote collaborative efforts that support the development and implementation of liquid biopsy tests. Here, we report the results of a pilot study conducted by three BloodPAC members that aimed to demonstrate a multisite liquid biopsy testing framework using longitudinal blood specimens from 38 patients with metastatic breast cancer. Three laboratories receiving identical samples from two clinical sites each applied a different targeted sequencing platform to analyze mutations in cell-free DNA (cfDNA). The resulting mutational profiles reflected common breast cancer alterations, including clinically actionable mutations for 40% of hormone- receptor-positive patients. In 12 genes with shared target regions across sequencing panels, perfect inter-assay concordance was also observed for mutations detected above the lowest common assay limit of detection. Whole-genome copy number profiling of cfDNA and circulating tumor cells (CTCs) further revealed marked heterogeneity in copy number alterations and cfDNA tumor fractions across patients. Additionally, comparison of tumor fraction and CTC abundance demonstrated the complementary nature of cfDNA and CTC analyses. Overall, the framework described in this study may serve as a resource for future trials aiming to identify multimodal liquid biopsy biomarkers to guide clinical care.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":" 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140997792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Type 2 diabetes mellitus (T2DM) accounts for one-sixth of deaths globally, whereas cancer is the second leading cause of death in the U.S. T2DM is a known risk factor for many cancers. Reactive oxygen species (ROS)-altered metabolic and signaling pathways link T2DM to cancer. These reprogrammed metabolic and signaling pathways contribute to diabetic complications, impact the redox balance (oxidative stress), and have differential roles in the early and late stages of cancer. A respiratory chain that is highly reduced (as under hyperglycemic conditions) or if reduced cofactors accumulate, ROS are greatly elevated. ROS may cause mutations in mitochondrial DNA (mtDNA) that result in further ROS elevations. The amplification of ROS results in the activation of PKC, an overarching signaling pathway that activates MAPK with a subsequent regulation in several factors that result in pathophysiological manifestations of T2DM and cancer. An upregulation in PKC leads to a deregulation in NF-kß, which regulates the PKB/P13/Akt pathway and orchestrates the cell survival, growth, proliferation, and glucose metabolism manifested in cancer. It also affects Insulin Receptor Substrate (IRS-1), decreasing insulin-stimulated glucose transport and glucose uptake, disrupting subsequent cell signaling pathways contributing to the development of T2DM. Dyslipidemia is a hallmark of T2DM and cancer. ROS-induced lipid peroxidation leads to systemic inflammation, producing inflammatory prostaglandins, cytokines, and chemokines that result in tumor proliferation, rapid tumor growth, and modulation of immunity. The dual role of ROS in the early and late stages of cancer makes antioxidant therapy precarious and may be responsible for controversial results. A system that delivers an antioxidant directly to mitochondria may be useful in inhibiting the formation of ROS early during the pre-diabetic stage, whereas antioxidant therapy must be halted in later stages to retard metastasis.
{"title":"Oxidative Stress and ROS Link Diabetes and Cancer","authors":"Homer S. Black","doi":"10.3390/jmp5010007","DOIUrl":"https://doi.org/10.3390/jmp5010007","url":null,"abstract":"Type 2 diabetes mellitus (T2DM) accounts for one-sixth of deaths globally, whereas cancer is the second leading cause of death in the U.S. T2DM is a known risk factor for many cancers. Reactive oxygen species (ROS)-altered metabolic and signaling pathways link T2DM to cancer. These reprogrammed metabolic and signaling pathways contribute to diabetic complications, impact the redox balance (oxidative stress), and have differential roles in the early and late stages of cancer. A respiratory chain that is highly reduced (as under hyperglycemic conditions) or if reduced cofactors accumulate, ROS are greatly elevated. ROS may cause mutations in mitochondrial DNA (mtDNA) that result in further ROS elevations. The amplification of ROS results in the activation of PKC, an overarching signaling pathway that activates MAPK with a subsequent regulation in several factors that result in pathophysiological manifestations of T2DM and cancer. An upregulation in PKC leads to a deregulation in NF-kß, which regulates the PKB/P13/Akt pathway and orchestrates the cell survival, growth, proliferation, and glucose metabolism manifested in cancer. It also affects Insulin Receptor Substrate (IRS-1), decreasing insulin-stimulated glucose transport and glucose uptake, disrupting subsequent cell signaling pathways contributing to the development of T2DM. Dyslipidemia is a hallmark of T2DM and cancer. ROS-induced lipid peroxidation leads to systemic inflammation, producing inflammatory prostaglandins, cytokines, and chemokines that result in tumor proliferation, rapid tumor growth, and modulation of immunity. The dual role of ROS in the early and late stages of cancer makes antioxidant therapy precarious and may be responsible for controversial results. A system that delivers an antioxidant directly to mitochondria may be useful in inhibiting the formation of ROS early during the pre-diabetic stage, whereas antioxidant therapy must be halted in later stages to retard metastasis.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":"114 48","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140089393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Roy Khalife, Tara M. Love, Lara Sucheston-Campbell, Michael J. Clark, Helle Sorensen, Shuba Krishna, Anthony Magliocco
Variant annotation is an important step in deciphering the functional impact of genomic variants and their association with diseases. In this study, we analyzed 80 pan-cancer cases that underwent comprehensive genomic testing and compared the auto-classified variant tiers among four globally-available software solutions for variant interpretation from Roche, SOPHiA GENETICS, QIAGEN, and Genoox. The results revealed striking differences in tier classifications, which are believed to be a result of several factors, including subjectivity in the AMP/ASCO/CAP guidelines, threshold settings for variant allele frequencies and population allele frequencies, as well as variation in disease ontologies. Although the software tools described here provide a time-saving and repeatable process for interpretation of genomic data, it is crucial to understand the nuances and various settings for these solutions, as they can strongly influence variant tier classifications and downstream management.
{"title":"Comparing Classifications from Multiple Variant Annotation Software Solutions Using Real-World Next Generation Sequencing Data from Oncology Testing","authors":"Roy Khalife, Tara M. Love, Lara Sucheston-Campbell, Michael J. Clark, Helle Sorensen, Shuba Krishna, Anthony Magliocco","doi":"10.3390/jmp5010006","DOIUrl":"https://doi.org/10.3390/jmp5010006","url":null,"abstract":"Variant annotation is an important step in deciphering the functional impact of genomic variants and their association with diseases. In this study, we analyzed 80 pan-cancer cases that underwent comprehensive genomic testing and compared the auto-classified variant tiers among four globally-available software solutions for variant interpretation from Roche, SOPHiA GENETICS, QIAGEN, and Genoox. The results revealed striking differences in tier classifications, which are believed to be a result of several factors, including subjectivity in the AMP/ASCO/CAP guidelines, threshold settings for variant allele frequencies and population allele frequencies, as well as variation in disease ontologies. Although the software tools described here provide a time-saving and repeatable process for interpretation of genomic data, it is crucial to understand the nuances and various settings for these solutions, as they can strongly influence variant tier classifications and downstream management.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":" 464","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140092472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jessica Alejandra Zapata-García, L. Jave-Suárez, A. Aguilar-Lemarroy
The RYK gene encodes a receptor-like tyrosine kinase crucial for several biological processes, including development, tissue homeostasis, and cancer. This study utilized data from the Cancer Genome Atlas Project (TCGA) to evaluate RYK expression at both mRNA and protein levels in various cancers, determine its prognostic significance, and explore its involvement in cancer-related signaling pathways. Elevated levels of RYK mRNA were identified in cholangiocarcinoma (CHOL), pancreatic adenocarcinoma (PAAD), glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), brain lower grade glioma (LGG), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LICH), esophageal carcinoma (ESCA), and colon adenocarcinoma (COAD), while RYK protein levels were observed to be increased in colon adenocarcinoma (COAD), GBM, LICH, cervical and endocervical adenocarcinoma (CESC), and breast invasive carcinoma (BRCA). Additionally, RYK overexpression correlated with poorer prognosis in several cancers, including PAAD, LICH, BRCA, ESCA, COAD, and CESC. Furthermore, RYK showed a positive correlation with the upregulation of multiple receptors and coreceptors in the WNT signaling pathway in various types of cancer. In terms of cancer-related signaling pathways, RYK was found to potentially interact with DNA damage, TSC/mTOR, PI3K/AKT, EMT, RTK, RAS/MAPK, ER hormone, AR hormone, and the cell cycle. This study provides new and previously unreported insights into the role of RYK in cancer biology.
{"title":"Delving into the Role of Receptor-like Tyrosine Kinase (RYK) in Cancer: In Silico Insights into Its Diagnostic and Prognostic Utility","authors":"Jessica Alejandra Zapata-García, L. Jave-Suárez, A. Aguilar-Lemarroy","doi":"10.3390/jmp5010005","DOIUrl":"https://doi.org/10.3390/jmp5010005","url":null,"abstract":"The RYK gene encodes a receptor-like tyrosine kinase crucial for several biological processes, including development, tissue homeostasis, and cancer. This study utilized data from the Cancer Genome Atlas Project (TCGA) to evaluate RYK expression at both mRNA and protein levels in various cancers, determine its prognostic significance, and explore its involvement in cancer-related signaling pathways. Elevated levels of RYK mRNA were identified in cholangiocarcinoma (CHOL), pancreatic adenocarcinoma (PAAD), glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), brain lower grade glioma (LGG), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LICH), esophageal carcinoma (ESCA), and colon adenocarcinoma (COAD), while RYK protein levels were observed to be increased in colon adenocarcinoma (COAD), GBM, LICH, cervical and endocervical adenocarcinoma (CESC), and breast invasive carcinoma (BRCA). Additionally, RYK overexpression correlated with poorer prognosis in several cancers, including PAAD, LICH, BRCA, ESCA, COAD, and CESC. Furthermore, RYK showed a positive correlation with the upregulation of multiple receptors and coreceptors in the WNT signaling pathway in various types of cancer. In terms of cancer-related signaling pathways, RYK was found to potentially interact with DNA damage, TSC/mTOR, PI3K/AKT, EMT, RTK, RAS/MAPK, ER hormone, AR hormone, and the cell cycle. This study provides new and previously unreported insights into the role of RYK in cancer biology.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":"54 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139860460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jessica Alejandra Zapata-García, L. Jave-Suárez, A. Aguilar-Lemarroy
The RYK gene encodes a receptor-like tyrosine kinase crucial for several biological processes, including development, tissue homeostasis, and cancer. This study utilized data from the Cancer Genome Atlas Project (TCGA) to evaluate RYK expression at both mRNA and protein levels in various cancers, determine its prognostic significance, and explore its involvement in cancer-related signaling pathways. Elevated levels of RYK mRNA were identified in cholangiocarcinoma (CHOL), pancreatic adenocarcinoma (PAAD), glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), brain lower grade glioma (LGG), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LICH), esophageal carcinoma (ESCA), and colon adenocarcinoma (COAD), while RYK protein levels were observed to be increased in colon adenocarcinoma (COAD), GBM, LICH, cervical and endocervical adenocarcinoma (CESC), and breast invasive carcinoma (BRCA). Additionally, RYK overexpression correlated with poorer prognosis in several cancers, including PAAD, LICH, BRCA, ESCA, COAD, and CESC. Furthermore, RYK showed a positive correlation with the upregulation of multiple receptors and coreceptors in the WNT signaling pathway in various types of cancer. In terms of cancer-related signaling pathways, RYK was found to potentially interact with DNA damage, TSC/mTOR, PI3K/AKT, EMT, RTK, RAS/MAPK, ER hormone, AR hormone, and the cell cycle. This study provides new and previously unreported insights into the role of RYK in cancer biology.
{"title":"Delving into the Role of Receptor-like Tyrosine Kinase (RYK) in Cancer: In Silico Insights into Its Diagnostic and Prognostic Utility","authors":"Jessica Alejandra Zapata-García, L. Jave-Suárez, A. Aguilar-Lemarroy","doi":"10.3390/jmp5010005","DOIUrl":"https://doi.org/10.3390/jmp5010005","url":null,"abstract":"The RYK gene encodes a receptor-like tyrosine kinase crucial for several biological processes, including development, tissue homeostasis, and cancer. This study utilized data from the Cancer Genome Atlas Project (TCGA) to evaluate RYK expression at both mRNA and protein levels in various cancers, determine its prognostic significance, and explore its involvement in cancer-related signaling pathways. Elevated levels of RYK mRNA were identified in cholangiocarcinoma (CHOL), pancreatic adenocarcinoma (PAAD), glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), brain lower grade glioma (LGG), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LICH), esophageal carcinoma (ESCA), and colon adenocarcinoma (COAD), while RYK protein levels were observed to be increased in colon adenocarcinoma (COAD), GBM, LICH, cervical and endocervical adenocarcinoma (CESC), and breast invasive carcinoma (BRCA). Additionally, RYK overexpression correlated with poorer prognosis in several cancers, including PAAD, LICH, BRCA, ESCA, COAD, and CESC. Furthermore, RYK showed a positive correlation with the upregulation of multiple receptors and coreceptors in the WNT signaling pathway in various types of cancer. In terms of cancer-related signaling pathways, RYK was found to potentially interact with DNA damage, TSC/mTOR, PI3K/AKT, EMT, RTK, RAS/MAPK, ER hormone, AR hormone, and the cell cycle. This study provides new and previously unreported insights into the role of RYK in cancer biology.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":"181 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139800792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Landon Pastushok, S. Sarda, K. Mochoruk, Wayne Hill, Loni Pickle, Michelle A. Toro, Carolina Gonzalez, Stephanie Ostresh, T. Looney, Chenchen Yang, Julie Stakiw, Mark J. Bosch, Hadi Goubran, C. Geyer, G. Lowman, J. Decoteau
B-cell neoplasms possess clonal B-cell receptor rearrangements (BCR clonotype lineages) that can be identified by sequencing the B-cell repertoire for use in diagnostics, risk stratification, and high-sensitivity monitoring. BCR somatic hypermutation (SHM) can result in clonality detection failure from point mutations in PCR primer binding regions, often necessitating splitting samples into multiple reactions which increases test costs, turnaround times, and sample requirements. We evaluated the Oncomine BCR Pan-Clonality Assay, a novel single-tube PCR reaction that simultaneously amplifies all BCR loci for next-generation DNA sequencing, using neoplastic B-cell lines and clinical research samples from multiple myeloma (MM) patients, a plasma cell neoplasm associated with high SHM levels. The assay showed a linear detection range down to 1 ng of clonal DNA input, sensitivity to 10−6 in a polyclonal background, and high reproducibility. Clonotype lineages were identified in 42/45 (93%) MM samples. Ion Reporter software packaged with the assay permitted straightforward identification of MM subgroups. As expected, SHM was identified in 94% of MM cases, but several unexpected subgroups were identified including biased IGHV3-11 or IGHV4-34 usage in 20% of MM samples, and two cases with very low levels of SHM. Evidence of intraclonal diversity/ongoing SHM was identified in 18% of samples, suggesting a possible germinal center origin for some MM cases. The single-tube Oncomine BCR Pan-Clonality assay efficiently detects BCR clonotype lineages at rates comparable to existing multiple reaction assays and permits their characterization for cell of origin studies and lymphoma classification.
B 细胞肿瘤具有克隆 B 细胞受体重排（BCR 克隆型系），可通过对 B 细胞重排进行测序来识别，用于诊断、风险分层和高灵敏度监测。BCR体细胞高突变（SHM）会导致PCR引物结合区的点突变造成克隆检测失败，通常需要将样本分成多个反应，这增加了检测成本、周转时间和样本要求。我们使用来自多发性骨髓瘤（MM）患者的肿瘤性 B 细胞系和临床研究样本对 Oncomine BCR 泛克隆性检测进行了评估，这是一种新型的单管 PCR 反应，可同时扩增所有 BCR 基因座以进行下一代 DNA 测序。该检测方法的线性检测范围可低至 1 纳克克隆 DNA 输入量，在多克隆背景下灵敏度可达 10-6，重现性高。在 42/45 个（93%）MM 样本中确定了克隆型系。与该检测法配套的 Ion Reporter 软件可直接鉴定 MM 亚群。不出所料，94% 的 MM 病例中都鉴定出了 SHM，但也鉴定出了几个意想不到的亚组，包括 20% 的 MM 样本中偏向使用 IGHV3-11 或 IGHV4-34，以及两个 SHM 水平很低的病例。在18%的样本中发现了克隆内多样性/持续SHM的证据，这表明一些MM病例可能起源于生殖中心。单管 Oncomine BCR 泛克隆性测定能有效检测 BCR 克隆型系，其检测率与现有的多反应测定相当，并能为细胞起源研究和淋巴瘤分类确定其特征。
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Landon Pastushok, S. Sarda, K. Mochoruk, Wayne Hill, Loni Pickle, Michelle A. Toro, Carolina Gonzalez, Stephanie Ostresh, T. Looney, Chenchen Yang, Julie Stakiw, Mark J. Bosch, Hadi Goubran, C. Geyer, G. Lowman, J. Decoteau
B-cell neoplasms possess clonal B-cell receptor rearrangements (BCR clonotype lineages) that can be identified by sequencing the B-cell repertoire for use in diagnostics, risk stratification, and high-sensitivity monitoring. BCR somatic hypermutation (SHM) can result in clonality detection failure from point mutations in PCR primer binding regions, often necessitating splitting samples into multiple reactions which increases test costs, turnaround times, and sample requirements. We evaluated the Oncomine BCR Pan-Clonality Assay, a novel single-tube PCR reaction that simultaneously amplifies all BCR loci for next-generation DNA sequencing, using neoplastic B-cell lines and clinical research samples from multiple myeloma (MM) patients, a plasma cell neoplasm associated with high SHM levels. The assay showed a linear detection range down to 1 ng of clonal DNA input, sensitivity to 10−6 in a polyclonal background, and high reproducibility. Clonotype lineages were identified in 42/45 (93%) MM samples. Ion Reporter software packaged with the assay permitted straightforward identification of MM subgroups. As expected, SHM was identified in 94% of MM cases, but several unexpected subgroups were identified including biased IGHV3-11 or IGHV4-34 usage in 20% of MM samples, and two cases with very low levels of SHM. Evidence of intraclonal diversity/ongoing SHM was identified in 18% of samples, suggesting a possible germinal center origin for some MM cases. The single-tube Oncomine BCR Pan-Clonality assay efficiently detects BCR clonotype lineages at rates comparable to existing multiple reaction assays and permits their characterization for cell of origin studies and lymphoma classification.
B 细胞肿瘤具有克隆 B 细胞受体重排（BCR 克隆型系），可通过对 B 细胞重排进行测序来识别，用于诊断、风险分层和高灵敏度监测。BCR体细胞高突变（SHM）会导致PCR引物结合区的点突变造成克隆检测失败，通常需要将样本分成多个反应，这增加了检测成本、周转时间和样本要求。我们使用来自多发性骨髓瘤（MM）患者的肿瘤性 B 细胞系和临床研究样本对 Oncomine BCR 泛克隆性检测进行了评估，这是一种新型的单管 PCR 反应，可同时扩增所有 BCR 基因座以进行下一代 DNA 测序。该检测方法的线性检测范围可低至 1 纳克克隆 DNA 输入量，在多克隆背景下灵敏度可达 10-6，重现性高。在 42/45 个（93%）MM 样本中确定了克隆型系。与该检测法配套的 Ion Reporter 软件可直接鉴定 MM 亚群。不出所料，94% 的 MM 病例中都鉴定出了 SHM，但也鉴定出了几个意想不到的亚组，包括 20% 的 MM 样本中偏向使用 IGHV3-11 或 IGHV4-34，以及两个 SHM 水平很低的病例。在18%的样本中发现了克隆内多样性/持续SHM的证据，这表明一些MM病例可能起源于生殖中心。单管 Oncomine BCR 泛克隆性测定能有效检测 BCR 克隆型系，其检测率与现有的多反应测定相当，并能为细胞起源研究和淋巴瘤分类确定其特征。
{"title":"A Novel Single-Tube Next Generation Sequencing Assay for B-Cell Receptor Clonality Testing","authors":"Landon Pastushok, S. Sarda, K. Mochoruk, Wayne Hill, Loni Pickle, Michelle A. Toro, Carolina Gonzalez, Stephanie Ostresh, T. Looney, Chenchen Yang, Julie Stakiw, Mark J. Bosch, Hadi Goubran, C. Geyer, G. Lowman, J. Decoteau","doi":"10.3390/jmp5010004","DOIUrl":"https://doi.org/10.3390/jmp5010004","url":null,"abstract":"B-cell neoplasms possess clonal B-cell receptor rearrangements (BCR clonotype lineages) that can be identified by sequencing the B-cell repertoire for use in diagnostics, risk stratification, and high-sensitivity monitoring. BCR somatic hypermutation (SHM) can result in clonality detection failure from point mutations in PCR primer binding regions, often necessitating splitting samples into multiple reactions which increases test costs, turnaround times, and sample requirements. We evaluated the Oncomine BCR Pan-Clonality Assay, a novel single-tube PCR reaction that simultaneously amplifies all BCR loci for next-generation DNA sequencing, using neoplastic B-cell lines and clinical research samples from multiple myeloma (MM) patients, a plasma cell neoplasm associated with high SHM levels. The assay showed a linear detection range down to 1 ng of clonal DNA input, sensitivity to 10−6 in a polyclonal background, and high reproducibility. Clonotype lineages were identified in 42/45 (93%) MM samples. Ion Reporter software packaged with the assay permitted straightforward identification of MM subgroups. As expected, SHM was identified in 94% of MM cases, but several unexpected subgroups were identified including biased IGHV3-11 or IGHV4-34 usage in 20% of MM samples, and two cases with very low levels of SHM. Evidence of intraclonal diversity/ongoing SHM was identified in 18% of samples, suggesting a possible germinal center origin for some MM cases. The single-tube Oncomine BCR Pan-Clonality assay efficiently detects BCR clonotype lineages at rates comparable to existing multiple reaction assays and permits their characterization for cell of origin studies and lymphoma classification.","PeriodicalId":506404,"journal":{"name":"Journal of Molecular Pathology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139869517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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