Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses: A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring

Cancers, vol. 14, pp. 5152

Abstract

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients.

Authors 18

1. Anne M.R. Schrader corresponding Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

2. Ruben A. L. de Groen Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

3. Rein Willemze Aachen Department of Dermatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

4. Patty M. Jansen Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

5. Koen D. Quint Aachen Department of Dermatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

6. Arjen Cleven Aachen Department of Pathology, Leiden University Medical Center

   University Medical Center Groningen · Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Department of Pathology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands

7. Tom van Wezel Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

8. Ronald van Eijk Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

9. Dina Ruano Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

10. Hendrik Veelken Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

11. Cornelis P. Tensen Aachen Department of Dermatology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

12. Karen J. Neelis Aachen Department of Radiotherapy, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiotherapy, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

13. Laurien A. Daniels Aachen Department of Radiotherapy, Leiden University Medical Center

    Leiden University Medical Center · Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers

    Affiliation as printed

    Department of Radiotherapy, Amsterdam University Medical Center, Location Amsterdam Medical Center, 1105 AZ Amsterdam, The Netherlands

    Department of Radiotherapy, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

14. Esther I. Hauben

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of Pathology, University Hospitals Leuven, 3000 Leuven, Belgium

15. Feng Jung Sherida H. Woei-A-Jin

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of General Medical Oncology, University Hospitals Leuven, 3000 Leuven, Belgium

16. Anne-Marie Busschots

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of Dermatology, University Hospitals Leuven, 3000 Leuven, Belgium

17. Maarten H. Vermeer Aachen Department of Dermatology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

18. Joost S.P. Vermaat corresponding Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands