PO.MCB08.04 · 分子与细胞生物学

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

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作者与单位

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

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.

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