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Analysis of mutation profiles in extranodal NK/T-cell lymphoma: clinical and prognostic correlations

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Abstract

The molecular pathogenesis of extranodal NK/T-cell lymphoma (NKTCL) remains obscured despite the next-generation sequencing (NGS) studies explored on ever larger cohorts in the last decade. We addressed the highly variable mutation frequencies reported among previous studies with comprehensive amplicon coverage and enhanced sequencing depth to achieve higher genomic resolution for novel genetic discovery and comparative mutational profiling of the oncogenesis of NKTCL. Targeted exome sequencing was conducted to interrogate 415 cancer-related genes in a cohort of 36 patients with NKTCL, and a total of 548 single nucleotide variants (SNVs) and 600 Copy number variances (CNVs) were identified. Recurrent amplification of the MCL1 (67%) and PIM1 (56%) genes was detected in a dominant majority of patients in our cohort. Functional mapping of genetic aberrations revealed that an enrichment of mutations in the JAK-STAT signaling pathway, including the cytokine receptor LIFR (copy number loss) upstream of JAK3, STAT3 (activating SNVs), and downstream effectors of MYC, PIM1 and MCL1 (copy number gains). RNA in situ hybridization showed the significant consistence of MCL1 RNA level and copy number of MCL1 gene. We further correlated molecular and clinical parameters with overall survival (OS) of these patients. When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of LIFR gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of LIFR gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR.

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Acknowledgements

The authors thank Ms. Ling Huang for help with the tumor samples processing and DNA extraction. We thank Dr. Chi-Kuan Chen for the pathology review at MacKay Memorial Hospital. We also thank Drs. Shang-Yun Liu and Yi-Ting Yang (ACT genomics) for initial bioinformatic analysis of the NGS raw data.

Funding

This work was supported by a grant from the National Science and Technology Council, Taipei, Taiwan (NSTC 111-2314-B195-007) to Y.-C. C. and intramural funding from the Department of Medical Research, MacKay Memorial Hospital (MMH-110-75 and MMH-111-70) to Y.-C. C.

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Author notes

  1. Yu-Cheng Chang and Hui-Jen Tsai contributed equally to this study.

Authors and Affiliations

  1. Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Yu-Cheng Chang & Sung-Hsin Kuo

  2. Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan

    Yu-Cheng Chang, Nai-Wen Su, Ying-Wen Su, Yi-Fang Chang, Caleb Gon-Shen Chen, Johnson Lin, Ming-Chih Chang & Ken-Hong Lim

  3. Department of Medicine, MacKay Medical College, New Taipei City, Taiwan

    Yu-Cheng Chang, Nai-Wen Su, Ying-Wen Su, Yi-Fang Chang, Caleb Gon-Shen Chen, Ming-Chih Chang & Ken-Hong Lim

  4. Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan

    Yu-Cheng Chang, To-Yu Huang, Nai-Wen Su, Ying-Wen Su, Yi-Fang Chang, Caleb Gon-Shen Chen & Ken-Hong Lim

  5. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    Hui-Jen Tsai

  6. Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan

    Hui-Jen Tsai

  7. Department of Nursing, Nursing, and Management, MacKay Junior College of Medicine, New Taipei City, Taiwan

    Ying-Wen Su & Caleb Gon-Shen Chen

  8. Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan

    Caleb Gon-Shen Chen

  9. ACT Genomics Co., Ltd, Taipei, Taiwan

    Shu-Jen Chen & Hua-Chien Chen

  10. Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan

    Kung-Chao Chang

  11. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    Sung-Hsin Kuo

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  1. Yu-Cheng Chang
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Contributions

Y.-C. C., H.-J. T., K.-H.L. and K.-C.C. conceived and designed the study; Y.-C. C., H.-J. T., N.-W.S., Y.-W.S., Y.-F.C., C.G.-S.C., J.L., M.-C.C., K.-H.L. and K.-C.C provided study materials or patient care; Y.-C. C., H.-J. T., T.-Y.H., N.-W.S., Y.-W.S., Y.-F.C., C.G.-S.C., J.L., M.-C.C., S.-J.C., H.-C.C., K.-H.L., K.-C.C. and S.-H.K. analyzed and interpreted the data; S.-J.C. and H.-C.C. reviewed the NGS raw data and initial analysis reports; Y.-C. C., H.-J. T.-Y.H., K.-H.L. and S.-H.K. wrote the manuscript; and all authors provided final approval of the manuscript. Conflict-of-interest disclosure Drs. Shu-Jen Chen and Hua-Chien Chen are employees of ACT Genomics Co., Ltd, Taipei, Taiwan. All the other authors declare no competing financial interests.

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Correspondence to Ken-Hong Lim, Kung-Chao Chang or Sung-Hsin Kuo.

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Drs. Shu-Jen Chen and Hua-Chien Chen are employees of ACT Genomics Co., Ltd, Taipei, Taiwan. All the other authors declare no competing financial interests.

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Chang, YC., Tsai, HJ., Huang, TY. et al. Analysis of mutation profiles in extranodal NK/T-cell lymphoma: clinical and prognostic correlations. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05698-9

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