Dharnidharka Vikas R, Wylie Kristine M, Wylie Todd N, Ruzinova Marianna B, Goss Charles W, Storch Gregory A, Mehta-Shah Neha, Byers Derek, Walther Leslie, Jaza Lujain, Gu Hongjie, Agarwal Mansi, Green Michael, Moore Erika, Swerdlow Steven H, Silveira Fernanda, Marks Lianna J, Gratzinger Dita, Bagg Adam, Law Soi Cheng, Gandhi Maher
Washington University School of Medicine, St. Louis, MO.
UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.
Transplant Direct. 2024 Oct 28;10(11):e1723. doi: 10.1097/TXD.0000000000001723. eCollection 2024 Nov.
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.
移植后淋巴细胞增生性疾病（PTLD）仍然是移植中令人恐惧的并发症，具有显著的发病率和死亡率。致癌性EB病毒（EBV）是50%-80%病例中的关键致病驱动因素。众多预后指标，包括多种临床、流行病学和肿瘤特征，如EBV肿瘤阳性，并不总是与患者较差的生存率相关，这表明EBV基因组变异在决定预后方面可能发挥作用。然而，与人类基因组变异相比，用于确定病毒基因组变异是否致病的精准医学工具非常有限。此外，针对性研究尚未发现EBV阴性PTLD中有特定的病毒病原体。我们正在使用新型前沿技术，从福尔马林固定、石蜡包埋存档或冷冻的PTLD组织或血浆中提取病毒核酸，以无偏倚的方式使用宏基因组鸟枪法测序（MSS）同时检测所有脊椎动物病毒。我们正在从多个移植中心收集此类样本，以实现以下具体目标并填补以下知识空白：（1）验证我们的新观察结果，即MSS检测PTLD组织中环病毒阳性（并经PCR确认）可作为PTLD诊断后移植受者死亡率较高的生物标志物；（2）通过对多个病毒组进行无偏倚的MSS并经其他技术确认，确定其他致癌病毒在EBV阴性PTLD中的作用；（3）开发必要的计算、算法和软件分析工具，以确定EBV基因组变异与PTLD中较差表现或结局之间的关联。研究完成将有助于改善患者护理，并可能为新疗法提供途径。
