The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol
Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%–80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiol...
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Wolters Kluwer
2024-11-01
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| Series: | Transplantation Direct |
| Online Access: | http://journals.lww.com/transplantationdirect/fulltext/10.1097/TXD.0000000000001723 |
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| author | Vikas R. Dharnidharka, MD, MPH Kristine M. Wylie, PhD Todd N. Wylie, BS Marianna B. Ruzinova, MD, PhD Charles W. Goss, PhD Gregory A. Storch, MD Neha Mehta-Shah, MD Derek Byers, MD Leslie Walther, RN Lujain Jaza, MD Hongjie Gu, MS Mansi Agarwal, PhD, MPH Michael Green, MD, MPH Erika Moore, MD Steven H. Swerdlow, MD Fernanda Silveira, MD Lianna J. Marks, MD Dita Gratzinger, MD Adam Bagg, MD Soi Cheng Law, PhD Maher Gandhi, MD |
| author_facet | Vikas R. Dharnidharka, MD, MPH Kristine M. Wylie, PhD Todd N. Wylie, BS Marianna B. Ruzinova, MD, PhD Charles W. Goss, PhD Gregory A. Storch, MD Neha Mehta-Shah, MD Derek Byers, MD Leslie Walther, RN Lujain Jaza, MD Hongjie Gu, MS Mansi Agarwal, PhD, MPH Michael Green, MD, MPH Erika Moore, MD Steven H. Swerdlow, MD Fernanda Silveira, MD Lianna J. Marks, MD Dita Gratzinger, MD Adam Bagg, MD Soi Cheng Law, PhD Maher Gandhi, MD |
| author_sort | Vikas R. Dharnidharka, MD, MPH |
| collection | DOAJ |
| description | Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%–80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome. However, the precision medicine tools for determining if a viral genome variant is pathogenic are very limited compared with human genome variants. Further, targeted studies have not implicated a specific viral etiological agent in EBV-negative PTLD. Using novel cutting-edge technologies, we are extracting viral nucleic acids from formalin-fixed, paraffin-embedded archived, or frozen PTLD tissues or plasma, to test for all vertebrate viruses simultaneously in an unbiased fashion, using metagenomic shotgun sequencing (MSS). We are collecting such samples from multiple transplant centers to address the following specific aims and close the following knowledge gaps: (1) Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by PCR) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; (2) determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral groupings, confirmed by other techniques; and (3) develop the necessary computational, algorithmic and software analytic tools required to determine association of EBV genome variants with worse presentations or outcomes in PTLD. Study completion will contribute to better patient care and may provide avenues for novel therapies. |
| format | Article |
| id | doaj-art-428e9dfd237045e18df0376bfbfc2718 |
| institution | Kabale University |
| issn | 2373-8731 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wolters Kluwer |
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| series | Transplantation Direct |
| spelling | doaj-art-428e9dfd237045e18df0376bfbfc27182024-11-26T08:06:28ZengWolters KluwerTransplantation Direct2373-87312024-11-011011e172310.1097/TXD.0000000000001723202411000-00010The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and ProtocolVikas R. Dharnidharka, MD, MPH0Kristine M. Wylie, PhD1Todd N. Wylie, BS2Marianna B. Ruzinova, MD, PhD3Charles W. Goss, PhD4Gregory A. Storch, MD5Neha Mehta-Shah, MD6Derek Byers, MD7Leslie Walther, RN8Lujain Jaza, MD9Hongjie Gu, MS10Mansi Agarwal, PhD, MPH11Michael Green, MD, MPH12Erika Moore, MD13Steven H. Swerdlow, MD14Fernanda Silveira, MD15Lianna J. Marks, MD16Dita Gratzinger, MD17Adam Bagg, MD18Soi Cheng Law, PhD19Maher Gandhi, MD201 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.1 Washington University School of Medicine, St. Louis, MO.2 UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA.3 University of Pittsburgh School of Medicine, Pittsburgh.3 University of Pittsburgh School of Medicine, Pittsburgh.3 University of Pittsburgh School of Medicine, Pittsburgh.4 Stanford University School of Medicine, Palo Alto, CA.4 Stanford University School of Medicine, Palo Alto, CA.5 University of Pennsylvania, Philadelphia, PA.6 Mater Research, University of Queensland, Woolloongabba.6 Mater Research, University of Queensland, Woolloongabba.Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%–80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome. However, the precision medicine tools for determining if a viral genome variant is pathogenic are very limited compared with human genome variants. Further, targeted studies have not implicated a specific viral etiological agent in EBV-negative PTLD. Using novel cutting-edge technologies, we are extracting viral nucleic acids from formalin-fixed, paraffin-embedded archived, or frozen PTLD tissues or plasma, to test for all vertebrate viruses simultaneously in an unbiased fashion, using metagenomic shotgun sequencing (MSS). We are collecting such samples from multiple transplant centers to address the following specific aims and close the following knowledge gaps: (1) Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by PCR) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; (2) determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral groupings, confirmed by other techniques; and (3) develop the necessary computational, algorithmic and software analytic tools required to determine association of EBV genome variants with worse presentations or outcomes in PTLD. Study completion will contribute to better patient care and may provide avenues for novel therapies.http://journals.lww.com/transplantationdirect/fulltext/10.1097/TXD.0000000000001723 |
| spellingShingle | Vikas R. Dharnidharka, MD, MPH Kristine M. Wylie, PhD Todd N. Wylie, BS Marianna B. Ruzinova, MD, PhD Charles W. Goss, PhD Gregory A. Storch, MD Neha Mehta-Shah, MD Derek Byers, MD Leslie Walther, RN Lujain Jaza, MD Hongjie Gu, MS Mansi Agarwal, PhD, MPH Michael Green, MD, MPH Erika Moore, MD Steven H. Swerdlow, MD Fernanda Silveira, MD Lianna J. Marks, MD Dita Gratzinger, MD Adam Bagg, MD Soi Cheng Law, PhD Maher Gandhi, MD The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol Transplantation Direct |
| title | The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol |
| title_full | The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol |
| title_fullStr | The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol |
| title_full_unstemmed | The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol |
| title_short | The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol |
| title_sort | post transplant lymphoproliferative disorders metagenomic shotgun microbial sequencing ptld msms study methods and protocol |
| url | http://journals.lww.com/transplantationdirect/fulltext/10.1097/TXD.0000000000001723 |
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