PO.MCB08.04 · 分子与细胞生物学

基于游离DNA的基因组分析揭示血管内大B细胞淋巴瘤独特的全基因组图景与时序

Cell free DNA based genomic analysis revealed the distinct whole genome landscape and chronology of intravascular large B cell lymphoma

编号 5932 展板 20 时间 4/21 02:00–05:00 区域 Section 21 主讲 Takuto Mori, MD

分会场 Genetic and Transcriptomic Dissection of Cancer Evolution

该海报暂无可下载的资料 AACR 官方页面

作者与单位 Authors & Affiliations

Takuto Mori¹, Kazuyuki Shimada², Kaito Mimura¹, Suguru Fukuhara³, Koji Izutsu³, Daisuke Kawauchi⁴, Yoshitaka Narita⁴, Akiko Miyagi Maeshima⁵, Ryosuke Koyamada⁶, Nobuhiro Hiramoto⁷, Hirona Maeda⁸, Nobuyuki Kakiuchi⁸, Ai Okada⁹, Kenichi Chiba⁹, Yuichi Shiraishi⁹, Akifumi Takaori−Kondo¹⁰, Seishi Ogawa⁸, Akihiro Tomita¹¹, Kenichi Yoshida¹

¹Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan,²Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan,³Department of Hematology, National Cancer Center Research Institute, Tokyo, Japan,⁴Department of Neurosurgery and Neuro-Oncology, National Cancer Center Research Institute, Tokyo, Japan,⁵Diagnostic Pathology, National Cancer Center Research Institute, Tokyo, Japan,⁶Department of Hematology, St. Luke International Hospital, Tokyo, Japan,⁷Department of Hematology, Kobe city medical center general hospital, Kobe, Japan,⁸Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan,⁹Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan,¹⁰Department of Hematology, Kyoto University, Kyoto, Japan,¹¹Department of Hematology, Fujita Health University School of Medicine, Tokyo, Japan

摘要 Abstract

中文摘要

活检中肿瘤细胞的稀缺阻碍了对血管内大B细胞淋巴瘤（IVLBCL）的基因组分析，这是一种以肿瘤在血管内选择性生长为特征的侵袭性淋巴瘤。我们此前工作证明了游离DNA（cfDNA）在基因组研究中的效用，其可能有助于揭示IVLBCL的遗传改变，而这些改变可能不同于相关淋巴瘤亚型，如免疫豁免部位大B细胞淋巴瘤（IP-LBCL）。为全面表征IVLBCL的突变图景，我们对36份IVLBCL样本进行了全基因组和全外显子组测序，这些样本来源于cfDNA（n=32）和患者来源异种移植（n=4），并对25份来自IP-LBCL的活检或手术样本（包括12例中枢神经系统淋巴瘤和13例睾丸淋巴瘤）进行了测序，比较了它们的基因组谱。IVLBCL的大多数cfDNA来源于肿瘤细胞（中位数88.8%；范围55-98%）。最频繁突变的基因为PIM1、MYD88、CD79B、TBL1XR1、MPEG1和ETV6。突变signature分析显示，成簇突变（如kataegis）由激活诱导的胞苷脱氨酶（AID）引起。然而，总体而言，驱动突变如MYD88突变不受AID活性影响。拷贝数（CN）分析显示反复出现的臂级改变，如9p和3p的杂合性缺失（LOH）、1q获得及6q缺失。至于局灶性CN改变和/或结构变异（SV），在IVLBCL中频繁观察到累及CDKN2A、TOX、PRDM1和CD58的缺失，以及累及CD274/PDCD1LG2的局灶性扩增或多种类型的SV。时序分析表明，MYD88突变和靶向CDKN2A的9p LOH在肿瘤演化的早期阶段获得。比较IVLBCL和IP-LBCL，大多数遗传异常（包括早期MYD88突变和9p改变）是共有的，但两者之间有若干病变存在显著差异。RAC2编码突变在IVLBCL中富集（33% vs 0%）。就免疫通路而言，一个显著差异是CD274/PDCD1LG2异常的频率，其见于约40%的IVLBCL，但在IP-LBCL中仅罕见地检出（4%）。相比之下，B2M异常在IP-LBCL中比IVLBCL更频繁。尽管IVLBCL中最早的驱动突变和CN异常与IP-LBCL相似，但我们的发现提示，IVLBCL中独特观察到的免疫逃逸相关遗传改变可能反映了其与肿瘤微环境的独特相互作用，并有助于将IVLBCL与IP-LBCL区分开来。

查看英文原文 English 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.

利益披露 Disclosure

T. Mori, None. K. Shimada, Chugai Other, consulting fees. Eli Lilly Other, consulting fees. AbbVie Other, consulting fees, honoraria. BeiGene Other, consulting fees. Genmab Other, consulting fees, honoraria. Daiichi Sankyo Other, consulting fees,honoraria. Ohara Other, consulting fees, Other, consulting fees. Takeda Other, honoraria, Other, honoraria. Kyowa Kirin Other, honoraria, Other, honoraria. CSL Behring Other, honoraria, Other, honoraria. Eisai Other, honoraria, Other, honoraria. Chugai Other, honoraria, Other, honoraria. Daiichi Sankyo Other, honoraria, Other, honoraria. Janssen Other, honoraria, Other, honoraria. Bristol-Myers Squibb Other, honoraria, Other, honoraria. Nippon Shinyaku Other, honoraria, Other, honoraria. Ono Other, honoraria, Other, honoraria. Gilead Other, honoraria, Other, honoraria. Novartis Other, honoraria, Other, honoraria. Meiji Seika Pharma Other, honoraria, Other, honoraria. K. Mimura, None. S. Fukuhara, Chugai ), Other, Honoraria. LOXO Oncology ). Mitsubishi Tanabe ). AbbVie ), Other, Honoraria. BeiOne ), Other, Honoraria. Bristol Myers Squibb ). Janssen Other, Honoraria. AstraZeneca Other, Honoraria. Genmab Other, Honoraria. Ono Pharmaceutical Other, Honoraria. Eli Lilly Other, Honoraria. Nihon Shinyaku Other, Honoraria. Otsuka Other, Honoraria. Takeda Other, Honoraria. K. Izutsu, MSD ), Other, honorarium. AstraZeneca ), Other, honorarium. AbbVie ), Other, honorarium. Incyte ). Symbio ), Other, honorarium. Bristol Myers Squibb ), Other, honorarium. Bayer ). Pfizer ), Other, honorarium. Janssen ), Other, honorarium. Yakult ). Kyowa Kirin ), Other, honorarium. Daiichi Sankyo ), Other, honorarium. Chugai ), Other, honorarium. Beigene ), Other, honorarium. Genmab ), Other, honorarium. LOXO Oncology ), Other, honorarium. Otsuka ), Other. Regeneron ). Gile a d/Kite ). Nihon Shinyaku Other, honorarium. D. Kawauchi, None. Y. Narita, Ono Pharmaceutical company ), Other, honorarium. Servier ), Other, honorarium. Eisai ), Other, honorarium. Sumitomo Pharma ), Other, honorarium. Novocure ), Other, honorarium. A. M. Maeshima, None.. R. Koyamada, None.. N. Hiramoto, None.. H. Maeda, None.. N. Kakiuchi, None.. A. Okada, None.. K. Chiba, None.. Y. Shiraishi, None. A. Takaori−Kondo, abbVie GK Other, Honoraria. AstraZeneca K.K. Other, Honoraria. Bristol-Myers Squibb Co. Other, Honoraria. CHUGAI PHARMACEUTICAL Co., Ltd. Other, Honoraria. Gilead Sciences, Inc. Other, Honoraria. Janssen Pharmaceutical K.K. Other, Honoraria. Novartis Pharma K.K. Other, Honoraria. S. Ogawa, Chordia Therapeutics Inc. ), Other, Consulting fees. Eisai Co., Ltd. ), Other, Consulting fees. Nanpuh Hospital ). Montage Bio, INC. Other, Consulting fees. Asahi Genomics Inc. Stock. A. Tomita, None.. K. Yoshida, None.

← 返回 AACR 2026 检索