Rintu Thomas, John Michael Jerome, Kimiko L. Krieger, Naghmana Ashraf, David R. Rowley
Prostate cancer remains the most commonly diagnosed and the second leading cause of cancer-related deaths in men in the United States. The neoplastic transformation of prostate epithelia, concomitant with modulations in the stromal compartment, known as reactive stromal response, is critical for the growth, development, and progression of prostate cancer. Reactive stroma typifies an emergent response to disrupted tissue homeostasis commonly observed in wound repair and pathological conditions such as cancer. Despite the significance of reactive stroma in prostate cancer pathobiology, our understanding of the ontogeny, phenotypic and functional heterogeneity, and reactive stromal regulation of the immune microenvironment in prostate cancer remains limited. Traditionally characterized to have an immunologically "cold" tumor microenvironment, prostate cancer presents significant challenges for advancing immunotherapy compared to other solid tumors. This review explores the detrimental role of reactive stroma in prostate cancer, particularly its immunomodulatory function. Understanding the molecular characteristics and dynamic transcriptional program of the reactive stromal populations in tandem with tumor progression could offer insights into enhancing immunotherapy efficacy against prostate cancer.
{"title":"The reactive stroma response regulates the immune landscape in prostate cancer","authors":"Rintu Thomas, John Michael Jerome, Kimiko L. Krieger, Naghmana Ashraf, David R. Rowley","doi":"10.20517/jtgg.2024.15","DOIUrl":"https://doi.org/10.20517/jtgg.2024.15","url":null,"abstract":"Prostate cancer remains the most commonly diagnosed and the second leading cause of cancer-related deaths in men in the United States. The neoplastic transformation of prostate epithelia, concomitant with modulations in the stromal compartment, known as reactive stromal response, is critical for the growth, development, and progression of prostate cancer. Reactive stroma typifies an emergent response to disrupted tissue homeostasis commonly observed in wound repair and pathological conditions such as cancer. Despite the significance of reactive stroma in prostate cancer pathobiology, our understanding of the ontogeny, phenotypic and functional heterogeneity, and reactive stromal regulation of the immune microenvironment in prostate cancer remains limited. Traditionally characterized to have an immunologically \"cold\" tumor microenvironment, prostate cancer presents significant challenges for advancing immunotherapy compared to other solid tumors. This review explores the detrimental role of reactive stroma in prostate cancer, particularly its immunomodulatory function. Understanding the molecular characteristics and dynamic transcriptional program of the reactive stromal populations in tandem with tumor progression could offer insights into enhancing immunotherapy efficacy against prostate cancer.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"56 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141807009","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}
Prostate cancer stands as the most prevalent cancer globally, constituting 21% of all cancer diagnoses in male patients. Urgent optimization of prostate cancer care is essential, given that this disease claims 345,000 lives every year. These innovative approaches hold substantial promise for both researchers and patients, representing a beacon of hope in the inhibitory act against prostate cancer. Prostate cancer's gradual advancement deems it suitable for immune therapy, but trials in metastatic cases show limited effectiveness, likely due to compromised immunity. Hindered by defective cellular responses, an immune-suppressive microenvironment, emerging evidence and breakthroughs, such as CAR-T therapy, inspire cautious optimism for advanced prostate cancer immunotherapy. Tumors utilize tactics to escape immune recognition, promoting the proliferation of MDSCs, Treg cells, and TAMs. Immunotherapy targets prostate cancer by mostly expressed target proteins and overexpressed target proteins. Immune cells play a role in tumor development and metastasis in advanced prostate cancer. Modulating the tumor microenvironment presents therapeutic possibilities. Certain prostate cancer types exhibit potential responses to immune checkpoint inhibitors, yet obstacles remain, necessitating additional research for enhanced efficacy. Immunotherapy faces hurdles in prostate cancer—limited inflammation, scarce antigens, and a resistant microenvironment. Grasping resistance intricacies is pivotal. The identification of DNA's helical structure propelled global progress in disease treatment through gene therapy. Choosing gene therapy vectors is critical; viruses are potent but toxic, while nonviral options, though less toxic, encounter barriers affecting transfection. In the realm of prostate cancer treatment, immunotherapy and gene therapy are emerging as increasingly viable options.
{"title":"New approaches and prospects of immunotherapy and gene therapy for prostate cancer","authors":"Roshni Bibi, Koustav Sarkar","doi":"10.20517/jtgg.2023.50","DOIUrl":"https://doi.org/10.20517/jtgg.2023.50","url":null,"abstract":"Prostate cancer stands as the most prevalent cancer globally, constituting 21% of all cancer diagnoses in male patients. Urgent optimization of prostate cancer care is essential, given that this disease claims 345,000 lives every year. These innovative approaches hold substantial promise for both researchers and patients, representing a beacon of hope in the inhibitory act against prostate cancer. Prostate cancer's gradual advancement deems it suitable for immune therapy, but trials in metastatic cases show limited effectiveness, likely due to compromised immunity. Hindered by defective cellular responses, an immune-suppressive microenvironment, emerging evidence and breakthroughs, such as CAR-T therapy, inspire cautious optimism for advanced prostate cancer immunotherapy. Tumors utilize tactics to escape immune recognition, promoting the proliferation of MDSCs, Treg cells, and TAMs. Immunotherapy targets prostate cancer by mostly expressed target proteins and overexpressed target proteins. Immune cells play a role in tumor development and metastasis in advanced prostate cancer. Modulating the tumor microenvironment presents therapeutic possibilities. Certain prostate cancer types exhibit potential responses to immune checkpoint inhibitors, yet obstacles remain, necessitating additional research for enhanced efficacy. Immunotherapy faces hurdles in prostate cancer—limited inflammation, scarce antigens, and a resistant microenvironment. Grasping resistance intricacies is pivotal. The identification of DNA's helical structure propelled global progress in disease treatment through gene therapy. Choosing gene therapy vectors is critical; viruses are potent but toxic, while nonviral options, though less toxic, encounter barriers affecting transfection. In the realm of prostate cancer treatment, immunotherapy and gene therapy are emerging as increasingly viable options.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140365790","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}
Mollie R. Dewsbury, Iain P. Hargreaves, Heather M. Morgan, Karolina M. Stepien
A significant portion of patients who are afflicted with lysosomal storage diseases (LSDs) encounter neurological manifestations, including cognitive issues and developmental delay, seizures, psychiatric issues, and an overall neurodegenerative decline. In order to enhance the development of effective therapies for these symptoms, it is imperative that we allude to the neuropathophysiology that underlies these manifestations. These distinct neurological and developmental features are particularly evident in patients with Alpha-Mannosidosis (AM), a type of LSD. However, there is limited published information regarding the mechanisms and pathophysiology of these presentations in patients with this condition. Although the precise impact of lysosomal storage on the biogenesis and functioning of neuronal cells has not been clearly defined, recent studies have placed emphasis on the significance of synaptic defects influencing this dysfunction. These defects encompass changes in synaptic spines, proteins, and vesicles, as well as postsynaptic densities that potentially precipitate functional disruptions in synaptic transmission and neurodegeneration. Ultimately, this cascade is thought to result in extensive neuronal loss and, consequently, the onset of cognitive manifestations. Uncovering the effects on synaptic components in LSDs with neurological symptoms like AM will enable a better understanding of disease progression. It will also allow us to identify critical targets for therapeutic intervention and the determination of optimal time frames for targeted treatments, as well as the effects of these treatments on mitochondrial function. The available therapeutic modalities in AM are not a definitive cure for affected patients, but rather an attempt to reduce the symptomatic severity in their presentation, while aiming to regress/slow down disease progression. This review will aim to discuss and rationalize the current treatment approaches in place for AM patients in relation to their effects on the improvement of neurocognitive symptoms in affected AM individuals.
{"title":"Molecular basis of neurocognitive dysfunction and psychosis in Alpha-Mannosidosis","authors":"Mollie R. Dewsbury, Iain P. Hargreaves, Heather M. Morgan, Karolina M. Stepien","doi":"10.20517/jtgg.2023.58","DOIUrl":"https://doi.org/10.20517/jtgg.2023.58","url":null,"abstract":"A significant portion of patients who are afflicted with lysosomal storage diseases (LSDs) encounter neurological manifestations, including cognitive issues and developmental delay, seizures, psychiatric issues, and an overall neurodegenerative decline. In order to enhance the development of effective therapies for these symptoms, it is imperative that we allude to the neuropathophysiology that underlies these manifestations. These distinct neurological and developmental features are particularly evident in patients with Alpha-Mannosidosis (AM), a type of LSD. However, there is limited published information regarding the mechanisms and pathophysiology of these presentations in patients with this condition. Although the precise impact of lysosomal storage on the biogenesis and functioning of neuronal cells has not been clearly defined, recent studies have placed emphasis on the significance of synaptic defects influencing this dysfunction. These defects encompass changes in synaptic spines, proteins, and vesicles, as well as postsynaptic densities that potentially precipitate functional disruptions in synaptic transmission and neurodegeneration. Ultimately, this cascade is thought to result in extensive neuronal loss and, consequently, the onset of cognitive manifestations. Uncovering the effects on synaptic components in LSDs with neurological symptoms like AM will enable a better understanding of disease progression. It will also allow us to identify critical targets for therapeutic intervention and the determination of optimal time frames for targeted treatments, as well as the effects of these treatments on mitochondrial function. The available therapeutic modalities in AM are not a definitive cure for affected patients, but rather an attempt to reduce the symptomatic severity in their presentation, while aiming to regress/slow down disease progression. This review will aim to discuss and rationalize the current treatment approaches in place for AM patients in relation to their effects on the improvement of neurocognitive symptoms in affected AM individuals.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"11 S11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140224672","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}
Kara Schmidt, Andrea L. Gropman, T. Sadeghin, T. A. Jackson, C. Samango-Sprouse
Aim: 47,XXY (KS) is the most frequently occurring sex chromosome aneuploidy (SCA) with an incidence rate of 1:500 to 1:650 live male births. 47,XXY is characterized by androgen insufficiency and hypogonadism, diminished phallus size, hypotonia, and increased stature. This investigation examines the relationship between Early Hormonal Treatment (EHT) and growth in boys with 47,XXY from birth to 5 years. Methods: A cohort of 134 males with 47,XXY was seen as part of a natural history study and anthropometric measurements were completed at each evaluation for height (HGT), weight (WGT), and head circumference (HC). Data was analyzed for these factors in the group receiving testosterone as EHT (T group) and a no treatment (No-T) control group. Results: Significant differences in HC were observed between the T group and No-T group for birth to 12 months. There was no other significant difference in HC for boys between the ages of 13 to 60 months. Only significant differences were observed in the birth to 12 months group for HGT between the T group and No-T group. There were only significant differences in WGT in the birth to 12-month age range between the T group and the No-T group, as well as in the 12-24-month age range. Conclusion: EHT is not associated with reducing or advancing growth in children with 47,XXY over 2 years old. After 24 months of age there is no discernible difference between boys with 47,XXY with EHT and without EHT.
{"title":"An extensive investigation of the anthropometric measurements in males with 47,XXY (Klinefelter Syndrome) from birth to five years of age and the impact of early hormonal treatment (EHT)","authors":"Kara Schmidt, Andrea L. Gropman, T. Sadeghin, T. A. Jackson, C. Samango-Sprouse","doi":"10.20517/jtgg.2023.43","DOIUrl":"https://doi.org/10.20517/jtgg.2023.43","url":null,"abstract":"Aim: 47,XXY (KS) is the most frequently occurring sex chromosome aneuploidy (SCA) with an incidence rate of 1:500 to 1:650 live male births. 47,XXY is characterized by androgen insufficiency and hypogonadism, diminished phallus size, hypotonia, and increased stature. This investigation examines the relationship between Early Hormonal Treatment (EHT) and growth in boys with 47,XXY from birth to 5 years.\u0000 Methods: A cohort of 134 males with 47,XXY was seen as part of a natural history study and anthropometric measurements were completed at each evaluation for height (HGT), weight (WGT), and head circumference (HC). Data was analyzed for these factors in the group receiving testosterone as EHT (T group) and a no treatment (No-T) control group.\u0000 Results: Significant differences in HC were observed between the T group and No-T group for birth to 12 months. There was no other significant difference in HC for boys between the ages of 13 to 60 months. Only significant differences were observed in the birth to 12 months group for HGT between the T group and No-T group. There were only significant differences in WGT in the birth to 12-month age range between the T group and the No-T group, as well as in the 12-24-month age range.\u0000 Conclusion: EHT is not associated with reducing or advancing growth in children with 47,XXY over 2 years old. After 24 months of age there is no discernible difference between boys with 47,XXY with EHT and without EHT.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"16 21","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140409438","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}
Amman Bhasin, Patrick J. Mille, Aditya Eturi, Andrew Iskander, William Tester, Kevin K. Zarrabi
Prostate cancer remains the most common malignancy among men in the United States. Advancements in androgen receptor signaling blockade have led to landmark approvals for its use in patients with locally advanced and metastatic disease. However, additional novel therapeutic strategies for both hormone-sensitive and castration-resistant diseases remain ongoing areas of study. Thus, we turn to the growth of immuno-oncology, which has led to improved treatment outcomes for a variety of hematologic and solid tumor malignancies. Prostate cancers have shown only modest results with immune checkpoint inhibition in published trials, and innovative strategies are now looking into enhancing cytotoxic T-cell activity against cancer cells. This review provides a thorough evaluation of tumor-associated antigens that are integrated into novel chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Our review will evaluate the most recent advancements in immunotherapies, while also illustrating major obstacles and underlying limiting factors.
前列腺癌仍然是美国男性最常见的恶性肿瘤。雄激素受体信号传导阻断技术的进步使其在局部晚期和转移性疾病患者中的应用获得了里程碑式的批准。然而，针对激素敏感性和阉割抵抗性疾病的其他新型治疗策略仍是我们正在研究的领域。因此，我们转向免疫肿瘤学的发展，免疫肿瘤学已经改善了各种血液和实体肿瘤恶性肿瘤的治疗效果。在已发表的试验中，前列腺癌对免疫检查点抑制的治疗效果一般，目前正在研究增强细胞毒性 T 细胞对癌细胞活性的创新策略。本综述将对整合到新型嵌合抗原受体 T 细胞和双特异性 T 细胞吸引疗法中的肿瘤相关抗原进行全面评估。我们的综述将评估免疫疗法的最新进展，同时还将说明主要障碍和潜在的限制因素。
{"title":"Tumor-associated antigen targets for novel immune-based strategies in prostate cancer","authors":"Amman Bhasin, Patrick J. Mille, Aditya Eturi, Andrew Iskander, William Tester, Kevin K. Zarrabi","doi":"10.20517/jtgg.2023.46","DOIUrl":"https://doi.org/10.20517/jtgg.2023.46","url":null,"abstract":"Prostate cancer remains the most common malignancy among men in the United States. Advancements in androgen receptor signaling blockade have led to landmark approvals for its use in patients with locally advanced and metastatic disease. However, additional novel therapeutic strategies for both hormone-sensitive and castration-resistant diseases remain ongoing areas of study. Thus, we turn to the growth of immuno-oncology, which has led to improved treatment outcomes for a variety of hematologic and solid tumor malignancies. Prostate cancers have shown only modest results with immune checkpoint inhibition in published trials, and innovative strategies are now looking into enhancing cytotoxic T-cell activity against cancer cells. This review provides a thorough evaluation of tumor-associated antigens that are integrated into novel chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Our review will evaluate the most recent advancements in immunotherapies, while also illustrating major obstacles and underlying limiting factors.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"82 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139798774","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}
Amman Bhasin, Patrick J. Mille, Aditya Eturi, Andrew Iskander, William Tester, Kevin K. Zarrabi
Prostate cancer remains the most common malignancy among men in the United States. Advancements in androgen receptor signaling blockade have led to landmark approvals for its use in patients with locally advanced and metastatic disease. However, additional novel therapeutic strategies for both hormone-sensitive and castration-resistant diseases remain ongoing areas of study. Thus, we turn to the growth of immuno-oncology, which has led to improved treatment outcomes for a variety of hematologic and solid tumor malignancies. Prostate cancers have shown only modest results with immune checkpoint inhibition in published trials, and innovative strategies are now looking into enhancing cytotoxic T-cell activity against cancer cells. This review provides a thorough evaluation of tumor-associated antigens that are integrated into novel chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Our review will evaluate the most recent advancements in immunotherapies, while also illustrating major obstacles and underlying limiting factors.
前列腺癌仍然是美国男性最常见的恶性肿瘤。雄激素受体信号传导阻断技术的进步使其在局部晚期和转移性疾病患者中的应用获得了里程碑式的批准。然而，针对激素敏感性和阉割抵抗性疾病的其他新型治疗策略仍是我们正在研究的领域。因此，我们转向免疫肿瘤学的发展，免疫肿瘤学已经改善了各种血液和实体肿瘤恶性肿瘤的治疗效果。在已发表的试验中，前列腺癌对免疫检查点抑制的治疗效果一般，目前正在研究增强细胞毒性 T 细胞对癌细胞活性的创新策略。本综述将对整合到新型嵌合抗原受体 T 细胞和双特异性 T 细胞吸引疗法中的肿瘤相关抗原进行全面评估。我们的综述将评估免疫疗法的最新进展，同时还将说明主要障碍和潜在的限制因素。
{"title":"Tumor-associated antigen targets for novel immune-based strategies in prostate cancer","authors":"Amman Bhasin, Patrick J. Mille, Aditya Eturi, Andrew Iskander, William Tester, Kevin K. Zarrabi","doi":"10.20517/jtgg.2023.46","DOIUrl":"https://doi.org/10.20517/jtgg.2023.46","url":null,"abstract":"Prostate cancer remains the most common malignancy among men in the United States. Advancements in androgen receptor signaling blockade have led to landmark approvals for its use in patients with locally advanced and metastatic disease. However, additional novel therapeutic strategies for both hormone-sensitive and castration-resistant diseases remain ongoing areas of study. Thus, we turn to the growth of immuno-oncology, which has led to improved treatment outcomes for a variety of hematologic and solid tumor malignancies. Prostate cancers have shown only modest results with immune checkpoint inhibition in published trials, and innovative strategies are now looking into enhancing cytotoxic T-cell activity against cancer cells. This review provides a thorough evaluation of tumor-associated antigens that are integrated into novel chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Our review will evaluate the most recent advancements in immunotherapies, while also illustrating major obstacles and underlying limiting factors.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"226 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139858721","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}
{"title":"Personalised genomic medicine is shaping the future of healthcare","authors":"Annie T. W. Chu, Brian H. Y. Chung","doi":"10.20517/jtgg.2023.47","DOIUrl":"https://doi.org/10.20517/jtgg.2023.47","url":null,"abstract":"","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140481988","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}
Alyssa I. Clay-Gilmour, Julia Cooper, Junke Wang, Qianqian Zhu, Loreall Pooler, Xin Sheng, Christopher Haiman, Stephen R. Spellman, Marcelo Pasquini, Philip McCarthy, Pamela L. Brock, Leigha Senter-Jamieson, Theresa E. Hahn, Lara Sucheston-Campbell
Aims: The revised 2022 World Health Organization classification recognizes myeloid neoplasms with associated germline predisposition as a defined subcategory, underscoring the clinical significance of likely pathogenic (LPV) and pathogenic (PV) germline variation in these diseases. To better understand the role of LPV/PV in blood or marrow transplants (BMT), a curative therapy for myeloid neoplasms, we measure their frequency and association with mortality in two cohorts of donor-recipient pairs. Methods: LPV/PV frequencies in 665 cancer-related genes were measured using exomechip genotyping data in 1990 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and their unrelated donors, registered with the Center for International Blood and Marrow Transplant Research. Cox proportional hazard models were used to test variant association with recipient mortality one-year post-transplant. Results: Thirteen autosomal dominant (AD) LPV/PV in eight genes were found in 2.8% of patients and 2.2% of donors; those linked to autosomal recessive conditions appeared in 11.1% of patients and 11% of donors. The most common AD LPV/PV mutations in recipients were found in DDX41 (n = 18). For donors, the most frequent AD PVs occurred in CHEK2 (n = 21) and Fanconi Anemia (FA) genes (n = 7). DDX41 and CHEK2 variation did not correlate with patient survival, but patients with donors with an LPV/PVs in an FA gene had lower survival (HR = 2.38, 95%CI: 1.06-5.31, P = 0.035) than patients whose donors did not have an FA LPV/PV. Conclusion: We identified LPVs/PVs in cancer genes in donors and recipients and are the first to show an association of donor FA PVs with mortality after BMT.
{"title":"Pathogenic and likely pathogenic germline variation in patients with myeloid malignancies and their unrelated HLA-matched hematopoietic stem cell donors","authors":"Alyssa I. Clay-Gilmour, Julia Cooper, Junke Wang, Qianqian Zhu, Loreall Pooler, Xin Sheng, Christopher Haiman, Stephen R. Spellman, Marcelo Pasquini, Philip McCarthy, Pamela L. Brock, Leigha Senter-Jamieson, Theresa E. Hahn, Lara Sucheston-Campbell","doi":"10.20517/jtgg.2023.31","DOIUrl":"https://doi.org/10.20517/jtgg.2023.31","url":null,"abstract":"Aims: The revised 2022 World Health Organization classification recognizes myeloid neoplasms with associated germline predisposition as a defined subcategory, underscoring the clinical significance of likely pathogenic (LPV) and pathogenic (PV) germline variation in these diseases. To better understand the role of LPV/PV in blood or marrow transplants (BMT), a curative therapy for myeloid neoplasms, we measure their frequency and association with mortality in two cohorts of donor-recipient pairs.\u0000 Methods: LPV/PV frequencies in 665 cancer-related genes were measured using exomechip genotyping data in 1990 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and their unrelated donors, registered with the Center for International Blood and Marrow Transplant Research. Cox proportional hazard models were used to test variant association with recipient mortality one-year post-transplant.\u0000 Results: Thirteen autosomal dominant (AD) LPV/PV in eight genes were found in 2.8% of patients and 2.2% of donors; those linked to autosomal recessive conditions appeared in 11.1% of patients and 11% of donors. The most common AD LPV/PV mutations in recipients were found in DDX41 (n = 18). For donors, the most frequent AD PVs occurred in CHEK2 (n = 21) and Fanconi Anemia (FA) genes (n = 7). DDX41 and CHEK2 variation did not correlate with patient survival, but patients with donors with an LPV/PVs in an FA gene had lower survival (HR = 2.38, 95%CI: 1.06-5.31, P = 0.035) than patients whose donors did not have an FA LPV/PV.\u0000 Conclusion: We identified LPVs/PVs in cancer genes in donors and recipients and are the first to show an association of donor FA PVs with mortality after BMT.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"23 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139595829","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}
Juliana CN. Chan, Chow Elaine, A. Kong, Elaine Cheung, Tony O, Cadmon K. P. Lim, B. Fan, Sandra Tsoi, Yingnan Fan, Mai Shi, Risa Ozaki, Ronald C W Ma, A. Luk
Young-onset type 2 diabetes (YOD), defined as diabetes diagnosis before age 40, has an aggressive clinical course with premature mortality, in part due to long disease duration and lack of evidence to guide diagnosis and management. Autoimmune type 1 diabetes, maturity-onset diabetes of the young (MODY), and latent autoimmune diabetes in adults (LADA) are subtypes of diabetes in young people, which, however, cannot fully explain their complex clinical course. Similarly, family members carrying the same rare genetic variant of monogenic diabetes can have different presentations and outcomes. Ancestral heterogeneity, ecological transition, inter-ethnic differences in genomic architecture, and variations in living environment, lifestyles, access to care, and timeliness of diagnosis and treatment can influence the age of diagnosis and exposure to these cardiometabolic-renal risk factors. Despite the wealth of literature on genetic associations with diabetes, the familial cosegregation of rare variants and their relevance to YOD remains uncertain. This perspective was motivated by decades of clinical observations and learnings from an ongoing randomized controlled trial that uses biogenetic markers to classify patients with YOD for improving outcomes. Apart from highlighting the need to use family-based studies to improve the precision of diagnosis, we discussed atypical causes for diabetic ketoacidosis and the importance of lifecourse and psychosocial-behavioral factors in patients with YOD. Apart from detailed clinical evaluation, we propose using plasma C peptide, homeostasis model of assessment (HOMA) indexes, autoantibodies, and polygenic risk scores to stratify risk, classify diabetes subtypes, and personalize treatment in YOD. To achieve these goals, we advocate changing the practice environment and team structure to enable physicians to use the insights they learn from patients and their family members to implement precision medicine and improve the outlook of these high-risk individuals.
年轻发病的 2 型糖尿病（YOD）是指在 40 岁之前诊断出糖尿病的患者，其临床病程较长，死亡率较高，部分原因是病程较长以及缺乏指导诊断和管理的证据。自身免疫性 1 型糖尿病、成熟期发病的青年糖尿病（MODY）和成人潜伏自身免疫性糖尿病（LADA）是青年糖尿病的亚型，但这些亚型并不能完全解释其复杂的临床病程。同样，携带相同罕见基因变异的单基因糖尿病家族成员也会有不同的表现和结局。祖先的异质性、生态过渡、基因组结构的种族间差异，以及生活环境、生活方式、就医途径、诊断和治疗的及时性等方面的差异，都会影响诊断年龄和接触这些心脏代谢-肾脏风险因素的机会。尽管有关糖尿病遗传关联的文献很多，但罕见变异的家族共聚及其与 YOD 的相关性仍不确定。数十年的临床观察和正在进行的一项随机对照试验的经验教训促使我们提出了这一观点，该试验利用生物遗传标记对 YOD 患者进行分类，以改善预后。除了强调需要利用基于家庭的研究来提高诊断的准确性外，我们还讨论了糖尿病酮症酸中毒的非典型病因以及 YOD 患者的生命历程和心理社会行为因素的重要性。除了详细的临床评估外，我们还建议使用血浆 C 肽、平衡状态评估模型（HOMA）指数、自身抗体和多基因风险评分来对 YOD 进行风险分层、糖尿病亚型分类和个性化治疗。为了实现这些目标，我们主张改变实践环境和团队结构，使医生能够利用从患者及其家庭成员那里了解到的信息，实施精准医疗，改善这些高危人群的前景。
{"title":"Multifaceted nature of young-onset diabetes - can genomic medicine improve the precision of diagnosis and management?","authors":"Juliana CN. Chan, Chow Elaine, A. Kong, Elaine Cheung, Tony O, Cadmon K. P. Lim, B. Fan, Sandra Tsoi, Yingnan Fan, Mai Shi, Risa Ozaki, Ronald C W Ma, A. Luk","doi":"10.20517/jtgg.2023.36","DOIUrl":"https://doi.org/10.20517/jtgg.2023.36","url":null,"abstract":"Young-onset type 2 diabetes (YOD), defined as diabetes diagnosis before age 40, has an aggressive clinical course with premature mortality, in part due to long disease duration and lack of evidence to guide diagnosis and management. Autoimmune type 1 diabetes, maturity-onset diabetes of the young (MODY), and latent autoimmune diabetes in adults (LADA) are subtypes of diabetes in young people, which, however, cannot fully explain their complex clinical course. Similarly, family members carrying the same rare genetic variant of monogenic diabetes can have different presentations and outcomes. Ancestral heterogeneity, ecological transition, inter-ethnic differences in genomic architecture, and variations in living environment, lifestyles, access to care, and timeliness of diagnosis and treatment can influence the age of diagnosis and exposure to these cardiometabolic-renal risk factors. Despite the wealth of literature on genetic associations with diabetes, the familial cosegregation of rare variants and their relevance to YOD remains uncertain. This perspective was motivated by decades of clinical observations and learnings from an ongoing randomized controlled trial that uses biogenetic markers to classify patients with YOD for improving outcomes. Apart from highlighting the need to use family-based studies to improve the precision of diagnosis, we discussed atypical causes for diabetic ketoacidosis and the importance of lifecourse and psychosocial-behavioral factors in patients with YOD. Apart from detailed clinical evaluation, we propose using plasma C peptide, homeostasis model of assessment (HOMA) indexes, autoantibodies, and polygenic risk scores to stratify risk, classify diabetes subtypes, and personalize treatment in YOD. To achieve these goals, we advocate changing the practice environment and team structure to enable physicians to use the insights they learn from patients and their family members to implement precision medicine and improve the outlook of these high-risk individuals.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":"94 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139612420","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}
With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology of this psychiatric disorder remains elusive. There is an evident genetic component of schizophrenia, with heritability estimates lying at 60%-80%. While genome-wide association studies have identified 120 gene loci associated with schizophrenia risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The recent emergence of whole exome sequencing (WES) technologies has facilitated the identification of rare sequence variants, including some protein-truncating variants that have significant effects on risk. Three key large-scale WES studies have demonstrated that rare sequence variants in the genes SETD1A , CACNA1G , CUL1 , GRIA3 , GRIN2A , HERC1 , RB1CC1 , SP4 , TRIO , XPO7 , and AKAP11 confer substantial risk for schizophrenia. These genes are highly expressed in central nervous system neurons and their products participate in diverse molecular functions including synaptic transmission, transcriptional regulation, and ubiquitin ligation. The understanding of these functional roles illuminates putative molecular mechanisms which may lead to schizophrenia-like phenotypes. It will also be possible to develop model systems in which the effects of impaired function of these genes can be further explored. Genetic studies of rare variants to date suggest that glutamatergic system dysregulation, chromatin modification, and the ubiquitin-proteasome system play key roles in schizophrenia aetiology.
{"title":"What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?","authors":"Lea Heinzer, David H. Curtis","doi":"10.20517/jtgg.2023.39","DOIUrl":"https://doi.org/10.20517/jtgg.2023.39","url":null,"abstract":"With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology of this psychiatric disorder remains elusive. There is an evident genetic component of schizophrenia, with heritability estimates lying at 60%-80%. While genome-wide association studies have identified 120 gene loci associated with schizophrenia risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The recent emergence of whole exome sequencing (WES) technologies has facilitated the identification of rare sequence variants, including some protein-truncating variants that have significant effects on risk. Three key large-scale WES studies have demonstrated that rare sequence variants in the genes SETD1A , CACNA1G , CUL1 , GRIA3 , GRIN2A , HERC1 , RB1CC1 , SP4 , TRIO , XPO7 , and AKAP11 confer substantial risk for schizophrenia. These genes are highly expressed in central nervous system neurons and their products participate in diverse molecular functions including synaptic transmission, transcriptional regulation, and ubiquitin ligation. The understanding of these functional roles illuminates putative molecular mechanisms which may lead to schizophrenia-like phenotypes. It will also be possible to develop model systems in which the effects of impaired function of these genes can be further explored. Genetic studies of rare variants to date suggest that glutamatergic system dysregulation, chromatin modification, and the ubiquitin-proteasome system play key roles in schizophrenia aetiology.","PeriodicalId":508462,"journal":{"name":"Journal of Translational Genetics and Genomics","volume":" 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139625299","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：