AbstractBackground: Primary mediastinal large B-cell lymphoma (PMBCL), arising from thymic medullary B cells, shares molecular features with classic Hodgkin lymphoma (cHL), including activation of JAK/STAT and Nuclear Factor Kappa B (NF-ƙB) pathways, as well as PD-L1 mediated immune evasion. Much of the molecular characterization relied on availability of tissue samples. Cell-free DNA (cfDNA) has emerged as a promising non-invasive approach for molecular profiling in lymphomas. In this study, we characterized the molecular features of PMBCL and cHL in the Chinese population utilizing both tissue-based and liquid biopsies.Methods: Tissue and/or plasma samples from a total of 35 PMBCL patients, 52 cHL patients and 81 DLBCL patients that were subjected to targeted next-generation sequencing (NGS) using a 475 cancer-related gene panel were included in the analysis.Results: Analysis of matched tumor and plasma samples from 38 cHL patients revealed 152 (28.10%) overlapping genetic alterations, with a higher number of mutations detected in the plasma compared to tissue (Total=472 vs. 221; Median=11 vs. 3 per patient, P<0.01). Of these, 320 (59.15%) were unique to the plasma, whereas 69 (12.15%) were only found in the tissue. Mutant allele frequencies (MAFs) were also lower in the tissue than in the plasma, with a median of 1.71% vs 2.99% (P<0.01). In 18 PMBCL patients, who had paired plasma and tumor samples, similar number of genetic alterations were detected (Total=347 vs. 411; Median=19.5 vs. 21 per patient, P=0.09). Of these, 273 (56.29%) alterations were shared variants, 74 (15.28%) were unique to the plasma sample and 138 (28.45%) were unique to the tissue. MAFs were higher in the tissue compared with the plasma (23.35% vs. 8.78%, P<0.01). Comparisons of mutational profiles among PMBCL, cHL, and DLBCL showed similar mutational profiles between PMBCL and cHL. The most frequently detected genetic alterations in PMBCL and cHL were STAT6 (68.57% vs. 40.38%), SOCS1 (57.14% vs. 57.69%), ACTB (48.57% vs. 23.08%), B2M (48.57% vs. 42.31%), and TNFAIP3 (34.29% vs. 40.38%). On the contrary, the frequencies of STAT6 (68.57% vs. 6.17%, P <0.01), SOCS1 (57.14% vs. 18.52%, P<0.05), and ACTB (48.57% vs. 9.88%, P<0.05) were markedly different comparing PMBCL and DLBCL. Meanwhile, the more common genetic alterations in DLBCL, such as MYD88 (33.33% vs. 0.00%, P<0.01), BCL6 (33.33% vs. 11.43%, P=0.06), BCL2 (20.99% vs. 2.86%, P<0.05), and CDKN2A (24.69% vs. 2.86%, P<0.05) were rarely detected in PMBCL patients.Conclusion: Our findings support that ctDNA in PMBCL and cHL may be an attractive source of genetic materials to assess tumor genomics and guide treatment decisions, especially in cHL with only 1% Hodgkin and Reed/Sternberg (HRS) cells. We also demonstrate for the first time in the Chinese population that PMBCL and cHL shared comparable mutational profiles, which were different from that of DLBCL.Citation Format: Xiaonan Wang, Lu Shen, Liuqing Zhu, Jiani C. Yin, Haimeng Tang, Yang Shao. Genomic characterization of PMBCL, cHL and DLBCL utilizing tissue and liquid biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 939.