Abstract The scarcity of tumor cells in biopsies has hampered genomic analysis of intravascular large B-cell lymphoma (IVLBCL), an aggressive lymphoma characterized by selective tumor growth within vessels. The utility of cell-free DNA (cfDNA) for genomic studies, demonstrated in our previous work, may help reveal the genetic alterations of IVLBCL, which might differ from those of related subtypes of lymphoma subtypes, such as immune-privileged large B-cell lymphoma (IP-LBCL).To comprehensively characterize the mutational landscape of IVLBCL, we performed whole-genome and whole-exome sequencing of 36 IVLBCL samples, which are derived from cfDNA (n = 32) and patient-derived xenografts (n = 4), as well as 25 biopsy or surgical samples from IP-LBCL, including 12 central nervous system and 13 testicular lymphomas, and compared their genomic profiles.The majority of cfDNA from IVLBCL was derived from tumor cells (median, 88.8%; range, 55-98%). Most frequently mutated genes were PIM1, MYD88, CD79B, TBL1XR1, MPEG1, and ETV6. Mutational signature analysis showed that clustered mutations, such as kataegis, were caused by activation-induced cytidine deaminase (AID). However, in general, driver mutations such as MYD88 mutations were not affected by AID activity. Copy number (CN) analysis showed recurrent arm-level changes such as loss-of-heterozygosity (LOH) of 9p and 3p, gain of 1q, and deletion of 6q. As for focal CN changes and/or structural variants (SVs), deletions involving CDKN2A, TOX, PRDM1, and CD58, as well as focal amplification or multiple types of SVs involving CD274/PDCD1LG2, were frequently observed in IVLBCL. Timing analysis indicated that MYD88 mutations and 9p LOH targeting CDKN2A were acquired at early stages of tumor evolution.Comparing IVLBCL and IP-LBCL, most genetic abnormalities, including early MYD88 mutations and 9p changes, were shared, but several lesions differed significantly between the two. RAC2 coding mutations were enriched in IVLBCL (33% vs 0%). As for immune pathway, one of the notable differences was the frequency of CD274/PDCD1LG2 abnormalities, which were observed in about 40% of IVLBCL but were rarely detected in 4% of IP-LBCL. In contrast, B2M abnormalities were more frequent in IP-LBCL than IVLBCL. Although the earliest driver mutations and CN abnormalities in IVLBCL are similar to those in IP-LBCL, our findings suggest that the immune-evasion-related genetic alterations uniquely observed in IVLBCL may reflect its distinct interactions with the tumor microenvironment and could help distinguish IVLBCL from IP-LBCL. Citation Format: Takuto Mori, Kazuyuki Shimada, Kaito Mimura, Suguru Fukuhara, Koji Izutsu, Daisuke Kawauchi, Yoshitaka Narita, Akiko Miyagi Maeshima, Ryosuke Koyamada, Nobuhiro Hiramoto, Hirona Maeda, Nobuyuki Kakiuchi, Ai Okada, Kenichi Chiba, Yuichi Shiraishi, Akifumi Takaori−Kondo, Seishi Ogawa, Akihiro Tomita, Kenichi Yoshida. Cell free DNA based genomic analysis revealed the distinct whole genome landscape and chronology of intravascular large B cell lymphoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5932.
Mori et al. (Fri,) studied this question.