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Genomic Alterations and MYD88MUT Variant Mapping in Patients with Diffuse Large B-Cell Lymphoma and Response to Ibrutinib

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Abstract

Background

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous malignancy. Following front-line immunochemotherapy, 30–40% of DLBCL patients develop relapsed or refractory (r/r) disease, which can be treated with ibrutinib. It has been previously reported that MYD88MUT affects the response to ibrutinib in patients with r/r DLBCL.

Objective

Here, we aimed to gather understanding of MYD88MUT in r/r DLBCL patients and to evaluate its influence on response to ibrutinib.

Patients and Methods

In this study, tissue samples from DLBCL patients (n = 212) were retrospectively collected and sequenced by target-capturing panels of either 413 or 112 genes that are frequently mutated in non-Hodgkin’s lymphoma. Sixty patients with MYD88 mutations and available clinical information were included for further analysis.

Results

Seven MYD88MUT variants were identified, L265P (65.0%, n = 39), S219C (13.3%, n = 8), S243N (8.3%, n = 5), P258L (6.7%, n = 4), F283V (1.7%, n = 1), P141R (1.7%, n = 1), and V217F (1.7%, n = 1). One patient had MYD88 amplification. In addition, mutations in PIM1 (67%, n = 40), IGH fusion (48%, n = 29), CD79B (43%, n = 26), KMT2D (30%, n = 18), and TP53 (27%, n = 17) were identified. For patients with L265P, IRF4 (p = 0.011) was frequently mutated. Otherwise, TET2 (p = 0.016), NOTCH2 (p = 0.044), MET (p = 0.037), SOCS1 (p = 0.011), TNFRSF14 (p = 0.011), EZH2 (p = 0.037), and BCL6 (p < 0.001) mutations were associated with MYD88MUT non-L265P variants. The incidence rate of MYD88MUT L265P was significantly higher with central nervous system involvement (p = 0.034). Four out of nine MYD88MUT patients responded to ibrutinib containing treatment, and this included those with MYD88MUT/CD79BWT.

Conclusions

This study adds clinical observations with MYD88MUT patients, further helping to understand the genetic features and possible correlation of MYD88MUT with response to ibrutinib.

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Acknowledgements

We thank all the patients, their families, and all the investigators who participated in the study.

Author information

Author notes

  1. Shiyu Jiang and Yan Qin contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China

    Shiyu Jiang, Yan Qin, Lin Gui, Peng Liu, Jianliang Yang, Sheng Yang, Xiaohui He, Shengyu Zhou & Yuankai Shi

  2. Department of Medical Oncology, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215001, Jiangsu Province, China

    Hongxin Jiang

  3. Department of Pathology, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215001, Jiangsu Province, China

    Biao Liu

  4. Geneplus-Beijing, Beijing, 102206, China

    Xinhua Du & Yuting Yi

  5. Burning Rock Biotech, Guangzhou, Guangdong, China

    Jing Lin

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  1. Shiyu Jiang
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Contributions

YKS, YQ, and SYJ conceptualized and designed the study. YKS, SYJ, YQ, LG, HXJ, BL, JLY, SY, XHH, and SYZ reviewed the literature, collected data, and interpreted the findings. SYJ, XHD, YTY, and JL performed statistical analysis. YKS, YQ, and SYJ drafted the manuscript. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Yuankai Shi.

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Funding

This study was supported by the National Key Technology Support Program (2014BAI09B12), National New Drug Innovation Program (2017ZX09304015), Beijing-Tianjin-Hebei Cooperation Program for basic research under Grant H2018206591, and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001).

Conflict of Interest

Jing Lin is an employee of Burning Rock Biotech. Xinhua Du and Yuting Yi are employees of Geneplus-Beijing. Shiyu Jiang, Yan Qin, Lin Gui, Peng Liu, Hongxin Jiang, Biao Liu, Jianliang Yang, Sheng Yang, Xiaohui He, Shengyu Zhou, and Yuankai Shi declare that they have no conflicts of interest that might be relevant to the contents of this article.

Ethics Approval and Consent to Participate

The study was approved by the Review Board of Cancer Institute and Hospital, Chinese Academy of Medical Sciences and conducted in accordance with the Declaration of Helsinki. Consent to publish was obtained from the participants for reporting individual patient data.

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Jiang, S., Qin, Y., Gui, L. et al. Genomic Alterations and MYD88MUT Variant Mapping in Patients with Diffuse Large B-Cell Lymphoma and Response to Ibrutinib. Targ Oncol 15, 221–230 (2020). https://doi.org/10.1007/s11523-020-00710-4

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  • DOI: https://doi.org/10.1007/s11523-020-00710-4

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