美国斯坦福大学Ash A. Alizadeh和斯坦福大学医学中心Maximilian Diehn共同合作，近期取得重要工作进展。他们研究提出通过非侵入性基因组分析确定不同的霍奇金淋巴瘤亚型的策略。相关研究成果2023年12月11日在线发表于《自然》杂志上。

据介绍，恶性霍奇金和Reed-Sternberg（HRS）细胞的缺乏阻碍了基于组织的经典霍奇金淋巴瘤（cHL）的全面基因组分析。相比之下，由于循环肿瘤DNA（ctDNA）水平相对较高，液体活组织检查显示出对cHL进行分子分析的前景。

研究人员发现在大多数情况下，突变在血浆中的表现超过了在肿瘤中的整体表现，这使得cHL特别适合于非侵入性分析。利用cHL肿瘤的单细胞转录谱，研究人员证明HRS ctDNA脱落是由DNASE1L3形成的，其肿瘤微环境源性表达的增加驱动了高ctDNA浓度。利用这一见解，研究人员对366名患者进行了全面的分析，揭示了两种不同的cHL基因组亚型，它们具有特征性的临床和预后相关性，以及不同的转录和免疫特征。

此外，研究人员鉴定了一类新的截短型IL4R突变，其依赖于IL13信号传导，并可通过IL4R阻断抗体进行治疗靶向。最后，使用PhasED-Seq，研究人员证明了治疗前和治疗中ctDNA水平在纵向细化cHL风险预测和检测放射学隐匿性最小残留疾病方面的临床价值。

总之，这些结果支持了无创策略在cHL基因分型和动态监测以及捕获具有诊断、预后和治疗潜力的分子不同亚型方面的实用性。

附：英文原文

Title: Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling

Author: Alig, Stefan K., Esfahani, Mohammad Shahrokh, Garofalo, Andrea, Li, Michael Yu, Rossi, Cdric, Flerlage, Tim, Flerlage, Jamie E., Adams, Ragini, Binkley, Michael S., Shukla, Navika, Jin, Michael C., Olsen, Mari, Telenius, Adle, Mutter, Jurik A., Schroers-Martin, Joseph G., Sworder, Brian J., Rai, Shinya, King, Daniel A., Schultz, Andre, Bgeholz, Jan, Su, Shengqin, Kathuria, Karan R., Liu, Chih Long, Kang, Xiaoman, Strohband, Maya J., Langfitt, Deanna, Pobre-Piza, Kristine Faye, Surman, Sherri, Tian, Feng, Spina, Valeria, Tousseyn, Thomas, Buedts, Lieselot, Hoppe, Richard, Natkunam, Yasodha, Fornecker, Luc-Matthieu, Castellino, Sharon M., Advani, Ranjana, Rossi, Davide, Lynch, Ryan, Ghesquires, Herv, Casasnovas, Olivier, Kurtz, David M., Marks, Lianna J., Link, Michael P., Andr, Marc, Vandenberghe, Peter, Steidl, Christian, Diehn, Maximilian, Alizadeh, Ash A.

Issue&Volume: 2023-12-11

Abstract: The scarcity of malignant Hodgkin and Reed-Sternberg (HRS) cells hamper tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). Liquid biopsies, in contrast, show promise for molecular profiling of cHL due to relatively high circulating tumor DNA (ctDNA) levels1–4. Here, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate HRS ctDNA shedding to be shaped by DNASE1L3, whose increased tumor microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R-mutations that are dependent on IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, using PhasED-Seq5 we demonstrate the clinical value of pre- and on-treatment ctDNA levels for longitudinally refining cHL risk prediction, and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL as well as capturing molecularly distinct subtypes with diagnostic, prognostic, and therapeutic potential.

DOI: 10.1038/s41586-023-06903-x

Source: https://www.nature.com/articles/s41586-023-06903-x