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image of Identification and Validation of NDRG2 as a Biomarker for Follicular Lymphoma

Abstract

Introduction

Follicular lymphoma (FL) is the most prevalent form of indolent lymphoma, characterized by intermittent relapse and remission periods. This study aims to identify potential biomarker genes for FL and elucidate their roles in the disease.

Methods

FL-related microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify potential hub genes. Various machine learning algorithms were applied to improve gene selection accuracy and predictive performance. Mendelian randomization (MR) analysis was carried out to identify genes with causal relationships to FL. Functional enrichment analysis was performed to explore the underlying mechanisms. Finally, the identified biomarker gene was validated in clinical samples using quantitative real-time PCR.

Results

A total of 60 hub genes were identified through differential expression analysis and WGCNA. Subsequently, 11 characteristic genes were identified using machine learning algorithms. MR analysis revealed 173 genes with causal effects on FL, leading to the identification of one key co-expressed gene, N-myc downstream-regulated gene 2 (), as a potential biomarker for FL. demonstrated strong predictive performance. Functional enrichment analysis revealed significant associations between and immune-related pathways in FL. Validation in clinical samples confirmed the relevance of as a biomarker.

Discussion

The integration of machine learning and MR successfully identified as a promising biomarker with a causal relationship to FL. Validation in clinical samples reinforced the reliability of these findings in clinical practice.

Conclusion

By combining machine learning, MR, and experimental validation, was identified and validated as a promising biomarker for FL.

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2025-10-29
2025-12-18
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References

  1. Carbone A. Roulland S. Gloghini A. Younes A. von Keudell G. López-Guillermo A. Fitzgibbon J. Follicular lymphoma. Nat. Rev. Dis. Primers. 2019 5 1 83 10.1038/s41572‑019‑0132‑x 31831752
    [Google Scholar]
  2. Jacobsen E. Follicular lymphoma: 2023 update on diagnosis and management. Am. J. Hematol. 2022 97 12 1638 1651 10.1002/ajh.26737 36255040
    [Google Scholar]
  3. Fischer T. Zing N.P.C. Chiattone C.S. Federico M. Luminari S. Transformed follicular lymphoma. Ann. Hematol. 2018 97 1 17 29 10.1007/s00277‑017‑3151‑2 29043381
    [Google Scholar]
  4. Dreyling M. Ghielmini M. Rule S. Salles G. Ladetto M. Tonino S.H. Herfarth K. Seymour J.F. Jerkeman M. Newly diagnosed and relapsed follicular lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2021 32 3 298 308 10.1016/j.annonc.2020.11.008 33249059 ESMO Guidelines Committee
    [Google Scholar]
  5. Gordon M.J. Smith M.R. Nastoupil L.J. Follicular lymphoma: The long and winding road leading to your cure? Blood. Rev. 2023 57 100992 10.1016/j.blre.2022.100992 35908982
    [Google Scholar]
  6. Welaya K. Casulo C. Follicular lymphoma. Hematol. Oncol. Clin. North. Am. 2019 33 4 627 638 10.1016/j.hoc.2019.03.003 31229159
    [Google Scholar]
  7. Matasar M.J. Luminari S. Barr P.M. Barta S.K. Danilov A.V. Hill B.T. Phillips T.J. Jerkeman M. Magagnoli M. Nastoupil L.J. Persky D.O. Okosun J. Follicular lymphoma: Recent and emerging therapies, treatment strategies, and remaining unmet needs. Oncologist 2019 24 11 e1236 e1250 10.1634/theoncologist.2019‑0138 31346132
    [Google Scholar]
  8. Carracedo-Reboredo P. Liñares-Blanco J. Rodríguez-Fernández N. Cedrón F. Novoa F.J. Carballal A. Maojo V. Pazos A. Fernandez-Lozano C. A review on machine learning approaches and trends in drug discovery. Comput. Struct. Biotechnol. J. 2021 19 4538 4558 10.1016/j.csbj.2021.08.011 34471498
    [Google Scholar]
  9. Greener J.G. Kandathil S.M. Moffat L. Jones D.T. A guide to machine learning for biologists. Nat. Rev. Mol. Cell. Biol. 2022 23 1 40 55 10.1038/s41580‑021‑00407‑0 34518686
    [Google Scholar]
  10. Ng S. Masarone S. Watson D. Barnes M.R. The benefits and pitfalls of machine learning for biomarker discovery. Cell. Tissue. Res. 2023 394 1 17 31 10.1007/s00441‑023‑03816‑z 37498390
    [Google Scholar]
  11. Dreval K. Hilton L.K. Cruz M. Shaalan H. Ben-Neriah S. Boyle M. Collinge B. Coyle K.M. Duns G. Farinha P. Grande B.M. Meissner B. Pararajalingam P. Rushton C.K. Slack G.W. Wong J. Mungall A.J. Marra M.A. Connors J.M. Steidl C. Scott D.W. Morin R.D. Genetic subdivisions of follicular lymphoma defined by distinct coding and noncoding mutation patterns. Blood 2023 142 6 561 573 10.1182/blood.2022018719 37084389
    [Google Scholar]
  12. de Jesus F.M. Yin Y. Mantzorou-Kyriaki E. Kahle X.U. de Haas R.J. Yakar D. Glaudemans A.W.J.M. Noordzij W. Kwee T.C. Nijland M. Machine learning in the differentiation of follicular lymphoma from diffuse large B-cell lymphoma with radiomic [18F]FDG PET/CT features. Eur. J. Nucl. Med. Mol. Imaging. 2022 49 5 1535 1543 10.1007/s00259‑021‑05626‑3 34850248
    [Google Scholar]
  13. Mosquera Orgueira A. Cid López M. Peleteiro Raíndo A. Abuín Blanco A. Díaz Arias J.Á. González Pérez M.S. Antelo Rodríguez B. Bao Pérez L. Ferreiro Ferro R. Aliste Santos C. Pérez Encinas M.M. Fraga Rodríguez M.F. Cerchione C. Mozas P. Bello López J.L. Personally tailored survival prediction of patients with follicular lymphoma using machine learning transcriptome-based models. Front. Oncol. 2022 11 705010 10.3389/fonc.2021.705010 35083135
    [Google Scholar]
  14. Li C. Patil V. Rasmussen K.M. Yong C. Chien H.C. Morreall D. Humpherys J. Sauer B.C. Burningham Z. Halwani A.S. Predicting survival in veterans with follicular lymphoma using structured electronic health record information and machine learning. Int. J. Environ. Res. Public. Health. 2021 18 5 2679 10.3390/ijerph18052679 33799968
    [Google Scholar]
  15. Zorman M. Sánchez de la Rosa J.L. Dinevski D. Classification of follicular lymphoma images: A holistic approach with symbol-based machine learning methods. Wien. Klin. Wochenschr. 2011 123 23-24 700 709 10.1007/s00508‑011‑0091‑z 22138763
    [Google Scholar]
  16. Emdin C.A. Khera A.V. Kathiresan S. Mendelian randomization. JAMA 2017 318 19 1925 1926 10.1001/jama.2017.17219 29164242
    [Google Scholar]
  17. Birney E. Mendelian Randomization. Cold. Spring. Harb. Perspect. Med. 2022 12 4 a041302 34872952
    [Google Scholar]
  18. Richmond R.C. Davey Smith G. Mendelian randomization: Concepts and scope. Cold. Spring. Harb. Perspect. Med. 2022 12 1 a040501 10.1101/cshperspect.a040501 34426474
    [Google Scholar]
  19. Zhang H. Pros and cons of Mendelian randomization. Fertil. Steril. 2023 119 6 913 916 10.1016/j.fertnstert.2023.03.029 36990264
    [Google Scholar]
  20. Zhu Y. Gan X. Qin R. Lin Z. Identification of six diagnostic biomarkers for chronic Lymphocytic Leukemia based on machine learning algorithms. J. Oncol. 2022 2022 1 19 10.1155/2022/3652107 36467501
    [Google Scholar]
  21. Huang S. Cai N. Pacheco P.P. Narrandes S. Wang Y. Xu W. Applications of Support Vector Machine (SVM) learning in cancer genomics. Cancer. Genomics. Proteomics. 2018 15 1 41 51 10.21873/cgp.20063 29275361
    [Google Scholar]
  22. Rigatti S.J. Random forest. J. Insur. Med. 2017 47 1 31 39 10.17849/insm‑47‑01‑31‑39.1 28836909
    [Google Scholar]
  23. McNeish D.M. Using Lasso for predictor selection and to assuage overfitting: A method long overlooked in behavioral sciences. Multivariate. Behav. Res. 2015 50 5 471 484 10.1080/00273171.2015.1036965 26610247
    [Google Scholar]
  24. Võsa U. Claringbould A. Westra H.J. Bonder M.J. Deelen P. Zeng B. Kirsten H. Saha A. Kreuzhuber R. Yazar S. Brugge H. Oelen R. de Vries D.H. van der Wijst M.G.P. Kasela S. Pervjakova N. Alves I. Favé M.J. Agbessi M. Christiansen M.W. Jansen R. Seppälä I. Tong L. Teumer A. Schramm K. Hemani G. Verlouw J. Yaghootkar H. Sönmez Flitman R. Brown A. Kukushkina V. Kalnapenkis A. Rüeger S. Porcu E. Kronberg J. Kettunen J. Lee B. Zhang F. Qi T. Hernandez J.A. Arindrarto W. Beutner F. ’t Hoen P.A.C. van Meurs J. van Dongen J. van Iterson M. Swertz M.A. Jan Bonder M. Dmitrieva J. Elansary M. Fairfax B.P. Georges M. Heijmans B.T. Hewitt A.W. Kähönen M. Kim Y. Knight J.C. Kovacs P. Krohn K. Li S. Loeffler M. Marigorta U.M. Mei H. Momozawa Y. Müller-Nurasyid M. Nauck M. Nivard M.G. Penninx B.W.J.H. Pritchard J.K. Raitakari O.T. Rotzschke O. Slagboom E.P. Stehouwer C.D.A. Stumvoll M. Sullivan P. ’t Hoen P.A.C. Thiery J. Tönjes A. van Dongen J. van Iterson M. Veldink J.H. Völker U. Warmerdam R. Wijmenga C. Swertz M. Andiappan A. Montgomery G.W. Ripatti S. Perola M. Kutalik Z. Dermitzakis E. Bergmann S. Frayling T. van Meurs J. Prokisch H. Ahsan H. Pierce B.L. Lehtimäki T. Boomsma D.I. Psaty B.M. Gharib S.A. Awadalla P. Milani L. Ouwehand W.H. Downes K. Stegle O. Battle A. Visscher P.M. Yang J. Scholz M. Powell J. Gibson G. Esko T. Franke L. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat. Genet. 2021 53 9 1300 1310 10.1038/s41588‑021‑00913‑z 34475573 BIOS Consortium i2QTL Consortium
    [Google Scholar]
  25. Burgess S. Butterworth A. Thompson S.G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 2013 37 7 658 665 10.1002/gepi.21758 24114802
    [Google Scholar]
  26. Erblich T. Montoto S. Treating relapsed follicular lymphoma. Expert. Rev. Hematol. 2018 11 5 403 410 10.1080/17474086.2018.1453801 29542329
    [Google Scholar]
  27. Link B.K. Transformation of follicular lymphoma – Why does it happen and can it be prevented? Best. Pract. Res. Clin. Haematol. 2018 31 1 49 56 10.1016/j.beha.2017.10.005 29452666
    [Google Scholar]
  28. Cahill K.E. Smith S.M. Follicular lymphoma: A focus on current and emerging therapies. Oncology 2022 36 2 97 106 10.46883/2022.25920946 35180337
    [Google Scholar]
  29. Binson V.A. Thomas S. Subramoniam M. Arun J. Naveen S. Madhu S. A review of machine learning algorithms for biomedical applications. Ann. Biomed. Eng. 2024 52 5 1159 1183 10.1007/s10439‑024‑03459‑3 38383870
    [Google Scholar]
  30. Haug C.J. Drazen J.M. Artificial intelligence and machine learning in clinical medicine, 2023. N. Engl. J. Med. 2023 388 13 1201 1208 10.1056/NEJMra2302038 36988595
    [Google Scholar]
  31. Nayarisseri A. Khandelwal R. Tanwar P. Madhavi M. Sharma D. Thakur G. Speck-Planche A. Singh S.K. Curr. Drug. Targets. 2021 22 6 631 655 10.2174/18735592MTEzsMDMnz 33397265
    [Google Scholar]
  32. Zhu Y. Liu J. Wang B. Integrated approach for biomarker discovery and mechanistic insights into the co-pathogenesis of type 2 Diabetes mellitus and non-hodgkin lymphoma. Diabetes. Metab. Syndr. Obes. 2025 18 267 282 10.2147/DMSO.S503449 39906693
    [Google Scholar]
  33. Zheng J. Baird D. Borges M.C. Bowden J. Hemani G. Haycock P. Evans D.M. Smith G.D. Recent developments in Mendelian randomization studies. Curr. Epidemiol. Rep. 2017 4 4 330 345 10.1007/s40471‑017‑0128‑6 29226067
    [Google Scholar]
  34. Chen L.G. Tubbs J.D. Liu Z. Thach T.Q. Sham P.C. Mendelian randomization: Causal inference leveraging genetic data. Psychol. Med. 2024 54 8 1461 1474 10.1017/S0033291724000321 38639006
    [Google Scholar]
  35. Zhu Y. Jin X. Liu J. Yang W. Identification and functional investigation of hub genes associated with Follicular lymphoma. Biochem. Genet. 2024 38802691
    [Google Scholar]
  36. Zhu Y. Zhao J. Li Z. Chen Y. Identification of senescence-related biomarkers for osteoporosis based on microarray analysis, Mendelian randomization, and experimental validation. Mamm. Genome. 2025 10.1007/s00335‑025‑10116‑0 40411576
    [Google Scholar]
  37. Hu W. Fan C. Jiang P. Ma Z. Yan X. Di S. Jiang S. Li T. Cheng Y. Yang Y. Emerging role of N-myc downstream-regulated gene 2 (NDRG2) in cancer. Oncotarget 2016 7 1 209 223 10.18632/oncotarget.6228 26506239
    [Google Scholar]
  38. Kim G. Lim S. Kim K.D. N-myc downstream-regulated gene 2 (NDRG2) function as a positive regulator of apoptosis: A new insight into NDRG2 as a tumor suppressor. Cells. 2021 10 10 2649 10.3390/cells10102649 34685629
    [Google Scholar]
  39. Lee K.W. Lim S. Kim K.D. The function of N-Myc downstream-regulated gene 2 (NDRG2) as a negative regulator in tumor cell metastasis. Int. J. Mol. Sci. 2022 23 16 9365 9365 10.3390/ijms23169365 36012631
    [Google Scholar]
  40. Liu N. Wang L. Liu X. Yang Q. Zhang J. Zhang W. Wu Y. Shen L. Zhang Y. Yang A. Han H. Zhang J. Yao L. Promoter methylation, mutation, and genomic deletion are involved in the decreased NDRG2 expression levels in several cancer cell lines. Biochem. Biophys. Res. Commun. 2007 358 1 164 169 10.1016/j.bbrc.2007.04.089 17470364
    [Google Scholar]
  41. Morishita K. Nakahata S. Ichikawa T. Pathophysiological significance of N-myc downstream-regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation. Cancer. Sci. 2021 112 1 22 30 10.1111/cas.14716 33128318
    [Google Scholar]
  42. Gu A. Xu J. Ye J. Zhang C. Low NDRG2 expression predicts poor prognosis in solid tumors. Medicine. 2020 99 41 e22678 10.1097/MD.0000000000022678 33031336
    [Google Scholar]
  43. Hu W. Yang Y. Fan C. Ma Z. Deng C. Li T. Lv J. Yao W. Gao J. Clinical and pathological significance of N-Myc downstream-regulated gene 2 (NDRG2) in diverse human cancers. Apoptosis. 2016 21 6 675 682 10.1007/s10495‑016‑1244‑3 27113371
    [Google Scholar]
  44. Reznik S.E. Tiwari A.K. Chavda V. Ashby C.R. The delivery of N-myc downstream-regulated gene 2 (NDRG2) self-amplifying mRNA via modified lipid nanoparticles as a potential treatment for drug-resistant and metastatic cancers. Med. Rev. 2024 4 3 235 238 10.1515/mr‑2024‑0004 38919399
    [Google Scholar]
  45. Wu S. Zhang J. Chen S. Zhou X. Liu Y. Hua H. Qi X. Mao Y. Young K.H. Lu T. Low NDRG2, regulated by the MYC/MIZ-1 complex and methylation, predicts poor outcomes in DLBCL patients. Ann. Hematol. 2024 103 8 2877 2892 10.1007/s00277‑024‑05829‑2 38842567
    [Google Scholar]
  46. Xu T. Zheng Z. Zhao W. Advances in the multi-omics landscape of Follicular lymphoma. Int. J. Biol. Sci. 2023 19 6 1955 1967 10.7150/ijbs.80401 37063433
    [Google Scholar]
  47. Radtke A.J. Roschewski M. The Follicular lymphoma tumor microenvironment at single-cell and spatial resolution. Blood 2024 143 12 1069 1079 10.1182/blood.2023020999 38194685
    [Google Scholar]
  48. Xu-Monette Z.Y. Zhou J. Young K.H. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood 2018 131 1 68 83 10.1182/blood‑2017‑07‑740993 29118007
    [Google Scholar]
  49. Laurent C. Dietrich S. Tarte K. Cell crosstalk within lymphoma tumor microenvironment: Follicular lymphoma as a paradigm. Blood 2024 143 12 1080 1090 10.1182/blood.2023021000 38096368
    [Google Scholar]
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  • Article Type:
    Research Article
Keywords: Follicular lymphoma ; machine learning ; NDRG2 ; immunity ; biomarker ; Mendelian randomization
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