AbstractRecent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from the European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-NDC assay.

。我们通过使用EuroClonality（EC）-NDC分析对外周血DNA进行靶向测序，对来自欧洲MCL网络试验的180名患者进行了全面的基因组表征。

The IGH::CCND1 fusion was identified in 94% of patients, clonal IGH-V-(D)-J rearrangements in all, and 79% had ≥1 somatic gene mutation. The top mutated genes were ATM, TP53, KMT2D, SAMHD1, BIRC3 and NFKBIE. Copy number variations (CNVs) were detected in 83% of patients with RB1, ATM, CDKN2A/B and TP53 being the most frequently deleted and KLF2, CXCR4, CCND1, MAP2K1 and MYC the top amplified genes.

在94%的患者中发现了IGH：：CCND1融合，总共克隆了IGH-V-（D）-J重排，79%的患者具有≥1个体细胞基因突变。突变频率最高的基因是ATM、TP53、KMT2D、SAMHD1、BIRC3和NFKBIE。在83%的RB1、ATM、CDKN2A/B和TP53患者中检测到拷贝数变异（CNV），而KLF2、CXCR4、CCND1、MAP2K1和MYC是扩增频率最高的基因。

CNVs and mutations were more frequently observed in older patients with adverse impact on prognosis. TP53mut, NOTCH1mut, FAT1mut TRAF2del, CDKN2A/Bdel and MAP2K1amp were linked to inferior failure-free (FFS) and overall survival (OS), while TRAF2mut, EGR2del and BCL2amp related to inferior OS only. Genetic complexity (≥3 CNVs) observed in 51% of analysed patients was significantly associated with impaired FFS and OS.

在对预后有不利影响的老年患者中，更常观察到CNV和突变。TP53mut，NOTCH1mut，FAT1mut TRAF2del，CDKN2A/Bdel和MAP2K1amp与较差的无故障（FFS）和总体生存（OS）相关，而TRAF2mut，EGR2del和BCL2amp仅与较差的OS相关。在51%的分析患者中观察到的遗传复杂性（≥3 CNV）与FFS和OS受损显着相关。

We demonstrate that targeted sequencing from peripheral blood and bone marrow reliably detects diagnostically and prognostically important genetic factors in MCL patients, facilitating genetic characterization in clinical routine..

我们证明，从外周血和骨髓中进行靶向测序可以可靠地检测MCL患者的诊断和预后重要遗传因素，从而促进临床常规中的遗传表征。。

IntroductionMantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin’s lymphoma (NHL) comprising 5–7% of all cases of B-cell NHL and is clinically considered as aggressive with a poor long-term prognosis. MCL is characterized by the rapid growth of abnormal B-cells in the mantle zone of the lymph node caused by the upregulation of the cell-cycle regulator protein cyclin-D1 driven by an IGH::CCND1 gene fusion [1, 2].

引言套细胞淋巴瘤（MCL）是一种罕见的非霍奇金淋巴瘤（NHL）亚型，占所有B细胞NHL病例的5-7%，临床上被认为是侵袭性的，长期预后较差。MCL的特征是由IGH：：CCND1基因融合驱动的细胞周期调节蛋白cyclin-D1上调引起的淋巴结套区异常B细胞的快速生长[1，2]。

MCL can be categorized into three subtypes: conventional (cMCL) with aggressive behaviour, high genomic instability and overexpression of SOX11, the less common leukemic non-nodal (nn)MCL with an indolent behaviour, downregulation of SOX11 [3,4,5] and lower treatment pressure, and the blastoid variant with high cell proliferation and rapidly progressing clinical course [6].

MCL可分为三种亚型：具有侵袭性行为的常规（cMCL），高基因组不稳定性和SOX11的过表达，具有惰性行为的较不常见的白血病非淋巴结（nn）MCL，SOX11的下调[3,4,5]和较低的治疗压力，以及具有高细胞增殖和快速进展的临床过程的类胚变体（6）。

MCL can be divided into different molecular subgroups based on specific genetic mutations and aberrations [7], with most affected genes involved in signalling pathways such as cell-cycle or apoptosis regulation. Early treatment failure is associated with specific genetic abnormalities in MCL, namely mutations of KMT2D and TP53 [8], deletions of RB1, CDKN2A (p16), TP53 and CDKN1B [9], as well as a high-risk MCL international prognostic index (MIPI)-c or high p53 expression [10].

MCL可以根据特定的基因突变和畸变分为不同的分子亚组，受影响最大的基因参与信号通路，如细胞周期或凋亡调控。早期治疗失败与MCL的特定遗传异常有关，即KMT2D和TP53突变，RB1、CDKN2A（p16）、TP53和CDKN1B缺失，以及高风险MCL国际预后指数（MIPI）-c或高p53表达（10）。

This cannot be overcome by intensive treatment with immune-chemotherapy, high-dose cytarabine and autologous stem cell transplantation (ASCT) [11, 12]. With the availability of novel drugs and immune therapies like CAR-T-cell treatment, comprehensive and rapid molecular characterization of MCL is attracting attention in the era of precision medicine to better assign patients to an optimal treatment approach.

这不能通过免疫化疗，高剂量阿糖胞苷和自体干细胞移植（ASCT）的强化治疗来克服[11，12]。随着CAR-T细胞治疗等新药和免疫疗法的出现，在精准医学时代，MCL的全面和快速分子表征正在引起人们的关注，以更好地将患者分配到最佳治疗方法。

However, detection of different genomic aberrations requires a methodical portfolio ranging from histopat.

然而，检测不同的基因组畸变需要一个从histopat到histopat的有条不紊的组合。

Data availability

数据可用性

Curated genomic variants of each patient is available in Supplementary Tables 4 and 5. The raw sequencing data analysed in this study is available from the corresponding author on a reasonable request.

补充表4和5中提供了每位患者的精选基因组变异。本研究中分析的原始测序数据可根据合理的要求从通讯作者处获得。

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Download referencesAcknowledgementsWe thank the patients and their families and the European Mantle Cell Lymphoma network for providing the samples for analysis from the MCL Younger and MCL Elderly trials.FundingOpen Access funding enabled and organized by Projekt DEAL.Author informationAuthor notesThese authors contributed equally: David Gonzalez de Castro, Eva Hoster, Christiane PottAuthors and AffiliationsSecond Medical Department, University Hospital Schleswig-Holstein, Kiel, GermanyMouhamad Khouja, Karol Pal, Binaya Regmi, Martin Schwarz, Nikos Darzentas & Christiane PottInstitute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Munich, GermanyLinmiao Jiang & Eva HosterCenter of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech RepublicKarol PalThe Patrick G Johnston Centre for Cancer Research, Queens University Belfast, Belfast, UKPeter James Stewart & David Gonzalez de CastroDepartment of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, GermanyBinaya RegmiDepartment of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Kiel, GermanyWolfram KlapperDepartment of Medicine III, University Hospital, Ludwig-Maximilian-University, Munich, GermanyStefan K.

下载参考文献致谢我们感谢患者及其家属和欧洲套细胞淋巴瘤网络提供MCL Younger和MCL Elders试验的样本进行分析。资金开放获取资金由Projekt交易启用和组织。作者信息作者注意到这些作者做出了同样的贡献：David Gonzalez de Castro，Eva Hoster，Christiane PottAuthors和附属机构石勒苏益格-荷尔斯泰因大学医院第二医学部，基尔，GermanyMouhamad Khouja，Karol Pal，Binaya Regmi，Martin Schwarz，Nikos Darzentas＆Christiane Pottas医学信息处理，生物测量和流行病学研究所（IBE），慕尼黑大学医学院，慕尼黑，GermanyLinmiao Jiang＆Eva HosterCenter of Molecular Medicine，中欧理工学院，马萨里克大学，布尔诺，捷克共和国卡罗尔帕尔Patrick G Johnston癌症研究中心NS贝尔法斯特大学，贝尔法斯特，英国彼得·詹姆斯·斯图尔特和大卫·冈萨雷斯·德·卡斯特罗德，亚琛大学医院，亚琛大学医院，亚琛大学医院，GermanyBinaya RegmidDepartment of Pathology，Hematopathology Section and Lymph Node Registry，石勒苏益格-荷尔斯坦大学医院，基尔，GermanyWolfram Klapper医学系III，德国慕尼黑路德维希·马克西米利安大学大学医院。

Alig & Martin DreylingDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsHanneke C. Kluin-NelemansDepartment of Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, FranceOlivier HermineINSERM U1163 and CNRS 8254, Imagine Institute, Université Sorbonne Paris Cité, Paris, FranceOlivier HermineAuthorsMouhamad KhoujaView .

Alig＆Martin Dreyling格罗宁根大学医学中心血液学系，格罗宁根格罗宁根大学，荷兰Shanneke C.Kluin Nelemans血液学系，Hôpital Necker，巴黎笛卡尔大学巴黎公共医院，巴黎，弗朗西奥·奥利维尔·赫敏内瑟姆U1163和CNRS 8254，巴黎索邦大学巴黎分校想象研究所，巴黎，弗朗西奥·奥利维尔·赫敏作家Mouhamad KhoujaView。

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PubMed Google ScholarConsortiaOn behalf of the European Mantle Cell Lymphoma NetworkMouhamad Khouja, Linmiao Jiang, Wolfram Klapper, Stefan K. Alig, Hanneke C. Kluin-Nelemans, Olivier Hermine, Martin Dreyling, Eva Hoster & Christiane PottContributionsMK and CP conceived the study, wrote the manuscript; CP provided patient samples; EH and LJ provided clinical data and performed statistical analysis; BR and PJS performed sequencing; MK, KP, MS, ND, PJS, and DG provided bioinformatic support and performed variant annotations; CP, DG, EH and MD supervised the study and data analysis; all authors read, revised and approved the manuscript.Corresponding authorCorrespondence to.

PubMed Google ScholarConsortiaOn代表欧洲套细胞淋巴瘤网络Mouhamad Khouja，Linmiao Jiang，Wolfram Klapper，Stefan K.Alig，Hanneke C.Kluin Nelemans，Olivier Hermine，Martin Dreyling，Eva Hoster＆Christiane PottributionsMK和CP构思了这项研究，撰写了手稿；CP提供了患者样本；EH和LJ提供了临床数据并进行了统计分析；BR和PJS进行了测序；MK，KP，MS，ND，PJS和DG提供了生物信息学支持并进行了变体注释；CP，DG，EH和MD监督了研究和数据分析；所有作者都阅读，修订并批准了手稿。。

Christiane Pott.Ethics declarations

克里斯蒂安·波特。道德宣言

Competing interests

相互竞争的利益

MK, LJ, KP, PJS, BR, MS, WK, SKCA, HCKN, OH, ND, EH, CP: No COI., MD Research Support: Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, Roche, Speaker Honoraria: AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, Roche, Advisory Board: Abbvie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/loxo, Novartis, Roche, D.G: founder and holds stock on Univ8.

MK、LJ、KP、PJS、BR、MS、WK、SKCA、HCKN、OH、ND、EH、CP：无COI。，MD研究支持：Abbvie，拜耳，BMS/Celgene，Gilead/Kite，Janssen，Lilly，Roche，演讲者荣誉：阿斯利康，Beigene，Gilead/Kite，Janssen，Lilly，Novartis，Roche，咨询委员会：Abbvie，AstraZeneca，Beigene，BMS/Celgene，Gilead/Kite，Janssen，Lilly/loxo，Novartis，Roche，D.G：创始人并持有Univ8的股票。

Genomics Ltd..

基因组学有限公司。。

Ethics approval

道德认可

Both clinical trials were led according to the Declaration of Helsinki. All patients gave their written informed consent after have been informed about the purpose and investigational nature of the trial. Prior to initiation, the clinical trial including molecular analysis received approval by the ethics committee of the medical faculty of the Christian-Albrechts-University of Kiel, Germany with the reference number B226/04..

两项临床试验均根据赫尔辛基宣言进行。所有患者在被告知试验的目的和研究性质后均签署了书面知情同意书。在开始之前，包括分子分析在内的临床试验已获得德国基尔基督教阿尔布雷希茨大学医学院伦理委员会的批准，参考号为B226/04。。

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Reprints and permissionsAbout this articleCite this articleKhouja, M., Jiang, L., Pal, K. et al. Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials.

转载和许可本文引用本文Khouja，M.，Jiang，L.，Pal，K。等人。通过靶向测序进行的综合遗传分析可确定套细胞淋巴瘤的危险因素并预测患者预后：EU-MCL网络试验的结果。

Leukemia (2024). https://doi.org/10.1038/s41375-024-02375-8Download citationReceived: 26 April 2024Revised: 29 July 2024Accepted: 06 August 2024Published: 16 September 2024DOI: https://doi.org/10.1038/s41375-024-02375-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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B-cell lymphomaCancer geneticsCancer genomicsGenetics research

B细胞淋巴瘤遗传学研究