In this study, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making classic Hodgkin Lymphoma (cHL) particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate hazard ratios (HRs) circulating tumor DNA (ctDNA) shedding to be shaped by <a href="https://www.ncbi.nlm.nih.gov/gene/?term=1776">DNASE1L3</a>, 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 <a href="https://www.ncbi.nlm.nih.gov/gene/3566">IL4R</a>-mutations that are dependent on <a href="https://www.ncbi.nlm.nih.gov/gene/3596">IL13</a> signaling and therapeutically targetable with <a href="https://www.ncbi.nlm.nih.gov/gene/3566">IL4R</a> blocking antibodies. Finally, 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.Methods utilized include a) targeted genotyping of baseline plasma samples, b) whole exome sequencing (WES) of baseline plasma samples, c) epigenetic expression inference from cell-free DNA-sequencing (EPIC-Seq) to infer gene expression from cell-free DNA (cfDNA) fragmentation profiles, d) ctDNA tracking in on-treatment samples, e) RNA-Sequencing, and f) Phased variant Enrichment and Detection Sequencing (PhasED-Seq).All patients were treated at cancer centers across Europe and North America between 2011 and 2020. The following 3 cancer centers, Stanford (CA, USA), Bellinzona [Confoederatio Helvetica (CH) or Switzerland], and Leuven (Belgium), were included. The 6 clinical trial collectives included in this study are the Phase III trial AHOD1331 trial (<a href="https://clinicaltrials.gov/study/NCT02166463">NCT02166463</a>) and the Phase II cHOD17 study (<a href="https://clinicaltrials.gov/study/NCT03755804">NCT03755804</a>) for enrolled pediatric patients, the Phase III AHL2011 (<a href="http://clinicaltrials.gov/study/NCT01358747">NCT01358747</a>), the Phase II BREACH trial (<a href="https://clinicaltrials.gov/study/NCT02292979">NCT02292979</a>), a pilot study evaluating concurrent Pembrolizumab with AVD (Doxorubicin, also known as Adriamycin, Vinblastine, and Dacarbazine; <a href="https://clinicaltrials.gov/study/NCT03331341">NCT03331341</a>), and a Phase II study evaluating PVAB (Prednisone, Vinblastine, Doxorubicin and Bendamustine; <a href="https://clinicaltrials.gov/study/NCT02414568">NCT02414568</a>) in older patients (61 years and older). In addition, lymph node specimens from a biorepository at <a href="https://www.stjude.org/">St. Jude Children's Research Hospital</a> (TN, USA) were included.

Circulating Genomic Determinants of Treatment Failure in Hodgkin Lymphoma

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