BACKGROUND: Previous studies have suggested that, after acquisition of t(11;14), mantle cell lymphoma (MCL) pathogenesis may proceed via several different genetic second hits, which may shape different mutational profiles of clinically manifest lymphoma. The most prevalent second hit in MCL includes ATM aberrations, accounting for about half of patients with newly diagnosed MCL. As ATM and TP53 mutations tend to be exclusive in MCL, we retrospectively analyzed the prognostic role of ATM deletions and/or mutations in patients with newly diagnosed MCL, both in the entire cohort and in a subcohort of patients with wild-type TP53. METHODS: To investigate deletions and mutations of ATM and TP53 in newly diagnosed MCL, we used fluorescence in situ hybridization and next-generation sequencing. To assess relationships between variables, non-parametric (Spearman) and chi-square tests were used. The Kruskal-Wallis test was used to analyze differences in continuous variables between two groups of patients. For survival analyses, the standard Kaplan-Meier estimator and log-rank test were employed. Univariate and multivariate Cox proportional hazard models were used to examine the prognostic value of various factors on patient survival. RESULTS: We analyzed 187 patients with MCL (a median follow-up of 3.6 years). Eighty-one (43%) and 75 (40%) patients had ATM and TP53 aberrations, respectively. Of note, three (9%) patients with mutated ATM harbored a germline mutation. Patients with TP53 aberration had shorter survival rates. Although ATM deletion did not correlate with progression-free survival (PFS) in the entire cohort, it was associated with shorter PFS (hazard ratio 2.25, p = 0.01) in patients with wild-type TP53. A higher frequency of ATM deletion correlated with shorter PFS. Patients with ATM mutation (and wild-type TP53) had a trend toward better PFS (albeit not statistically significant). Moreover, patients with a higher variant allele frequency of ATM mutation tended to have longer PFS. CONCLUSIONS: ATM deletion is an important predictor of prognosis in MCL patients and should be routinely examined, especially in those with wild-type TP53. In contrast, an isolated ATM mutation may predict a better prognosis in the context of standard immunochemotherapy.

1st Department of Internal Medicine Department of Hematology 1st Faculty of Medicine University General Hospital Charles University Prague Czech Republic

Centre of Oncocytogenomics Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine General University Hospital Charles University Prague Czech Republic

Department of Clinical and Molecular Pathology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Czech Republic

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Czech Republic

Department of Immunology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Czech Republic

Department of Mathematical Analysis and Applications of Mathematics Faculty of Science Palacky University Olomouc Czech Republic

Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

Zobrazit více v PubMed

Ahmed M, Zhang L, Nomie K, Lam L, Wang M. Gene mutations and actionable genetic lesions in mantle cell lymphoma. Oncotarget. 2016;7(36):58638–48. PubMed PMC

Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IBDO, Berti E, et al. The 5th edition of the world health organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720–48. PubMed PMC

Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, de Oliveira Araujo IB, Berti E et al. Correction: The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms Leukemia. 2022;36(7):1720–1748. Leukemia. 2023;37(9):1944–51. PubMed PMC

Aukema SM, Hoster E, Rosenwald A, Canoni D, Delfau-Larue MH, Rymkiewicz G, et al. Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL network. Blood. 2018;131(4):417–20. PubMed

Berkson J. Limitations of the application of fourfold table analysis to hospital data. Biometrics Bull. 1946;2(3):47. PubMed

Camacho E, Hernández L, Hernández S, Tort F, Bellosillo B, Beà S, et al. ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances. Blood. 2002;99(1):238–44. PubMed

Che Y, Liu Y, Yao Y, Hill HA, Li Y, Cai Q, et al. Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations. Blood Cancer J. 2023;13(1):27. PubMed PMC

Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. Mol Cancer Ther. 2016;15(8):1781–91. PubMed

Dreyling M, Campo E, Hermine O, Jerkeman M, Le Gouill S, Rule S, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv62–71. PubMed

Delfau-Larue MH, Klapper W, Berger F, Jardin F, Briere J, Salles G, et al. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015;126(5):604–11. PubMed

Eskelund CW, Dahl C, Hansen JW, Westman M, Kolstad A, Pedersen LB, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130(17):1903–10. PubMed

Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from PubMed

Greiner TC, Dasgupta C, Ho VV, Weisenburger DD, Smith LM, Lynch JC, et al. Mutation and genomic deletion status of PubMed PMC

Halldórsdóttir AM, Lundin A, Murray F, Mansouri L, Knuutila S, Sundström C, et al. Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia. 2011;25(12):1904–8. PubMed

Herrmann A, Hoster E, Zwingers T, Brittinger G, Engelhard M, Meusers P, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. JCO. 2009;27(4):511–8. PubMed

Huang Z, Chavda VP, Bezbaruah R, Dhamne H, Yang DH, Zhao HB. CAR t-cell therapy for the management of mantle cell lymphoma. Mol Cancer. 2023;22(1):67. PubMed PMC

Imai T, Yamauchi M, Seki N, Sugawara T, Saito T, Matsuda Y, et al. Identification and characterization of a new gene physically linked to the ATM gene. Genome Res. 1996;6(5):439–47. PubMed

Jiang Y, Chen HC, Su X, Thompson PA, Liu X, Do KA, et al. ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2). Blood Cancer J. 2016;6(9):e465–465. PubMed PMC

Kalla C, Scheuermann MO, Kube I, Schlotter M, Mertens D, Döhner H, et al. Analysis of 11q22–q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B. Eur J Cancer. 2007;43(8):1328–35. PubMed

Karolová J, Kazantsev D, Svatoň M, Tušková L, Forsterová K, Maláriková D, et al. Sequencing-based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy. Am J Hematol. 2023;98(10):1627–36. PubMed

Koff JL, Kositsky R, Jaye DL, Churnetski MC, Baird K, O’Leary CB, et al. Mutations of

Lampson BL, Gupta A, Tyekucheva S, Mashima K, Petráčková A, Wang Z, et al. Rare germline PubMed PMC

Lowndes NF, Murguia JR. Sensing and responding to DNA damage. Curr Opin Genet Dev. 2000;10(1):17–25. PubMed

López C, Silkenstedt E, Dreyling M, Beà S. Biological and clinical determinants shaping heterogeneity in mantle cell lymphoma. Blood Adv. 2024;8(14):3652–64. PubMed PMC

Lozano-Santos C, García-Vela JA, Pérez-Sanz N, Nova-Gurumeta S, Fernandez-Cuevas B, Gomez-Lozano N, et al. Biallelic PubMed

Malarikova D, Berkova A, Obr A, Blahovcova P, Svaton M, Forsterova K, et al. Concurrent TP53 and CDKN2A gene aberrations in newly diagnosed mantle cell lymphoma correlate with chemoresistance and call for innovative upfront therapy. Cancers. 2020;12(8):2120. PubMed PMC

Mareckova A, Malcikova J, Tom N, Pal K, Radova L, Salek D, et al. ATM and TP53 mutations show mutual exclusivity but distinct clinical impact in mantle cell lymphoma patients. Leuk Lymphoma. 2019;60(6):1420–8. PubMed

Mavrou A, Tsangaris GT, Roma E, Kolialexi A. The ATM gene and ataxia telangiectasia. Anticancer Res. 2008;28(1B):401–5. PubMed

Meissner B, Kridel R, Lim RS, Rogic S, Tse K, Scott DW, et al. The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma. Blood. 2013;121(16):3161–4. PubMed

Obr A, Prochazka V, Papajik T, Klener P, Janikova A, Salek D, et al. Maintenance rituximab in newly diagnosed mantle cell lymphoma patients: a real world analysis from the Czech lymphoma study group registry PubMed

Obr A, Procházka V, Jirkuvová A, Urbánková H, Kriegova E, Schneiderová P, et al. TP53 mutation and complex karyotype portends a dismal prognosis in patients with mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(11):762–8. PubMed

Obr A, Klener P, Furst T, Kriegova E, Zemanova Z, Urbankova H et al. A high PubMed

Petrackova A, Manakova J, Nesnadna R, Kubova Z, Papajik T, Kriegova E. Rare germline PubMed PMC

Petrackova A, Savara J, Turcsanyi P, Gajdos P, Papajik T, Kriegova E. Rare germline PubMed

Reiman A, Srinivasan V, Barone G, Last JI, Wootton LL, Davies EG, et al. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. Br J Cancer. 2011;105(4):586–91. PubMed PMC

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Sci. 2015;17(5):405–24. PubMed PMC

Rossi D, Ferrero S, Bruscaggin A, Ghione P, Di Rocco A, Spina V, et al. A molecular model for the prediction of progression free survival in young mantle cell lymphoma patients treated with Cytarabine-Based high dose sequential chemotherapy and autologous stem cell transplantation: results from the MCL0208 phase III trial from Fondazione Italiana linfomi (FIL). Blood. 2015;126(23):336–336.

Rozenbaum M, Fluss R, Marcu-Malina V, Sarouk I, Meir A, Elitzur S, et al. Genotoxicity associated with retroviral CAR transduction of PubMed PMC

Salek D, Vesela P, Boudova L, Janikova A, Klener P, Vokurka S, et al. Retrospective analysis of 235 unselected patients with mantle cell lymphoma confirms prognostic relevance of mantle cell lymphoma international prognostic index and Ki-67 in the era of rituximab: long-term data from the Czech lymphoma project database. Leuk Lymphoma. 2014;55(4):802–10. PubMed

Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268(5218):1749–53. PubMed

Sakhdari A, Ok CY, Patel KP, Kanagal-Shamanna R, Yin CC, Zuo Z, et al. TP53 mutations are common in mantle cell lymphoma, including the indolent leukemic non-nodal variant. Ann Diagn Pathol. 2019;41:38–42. PubMed

Salaverria I, Zettl A, Beà S, Moreno V, Valls J, Hartmann E, et al. Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression–based proliferation signature. JCO. 2007;25(10):1216–22. PubMed PMC

Shiloh Y. ATM and ATR: networking cellular responses to DNA damage. Curr Opin Genet Dev. 2001;11(1):71–7. PubMed

Skowronska A, Parker A, Ahmed G, Oldreive C, Davis Z, Richards S, et al. Biallelic PubMed

Stakyte K, Rotheneder M, Lammens K, Bartho JD, Grädler U, Fuchß T, et al. Molecular basis of human ATM kinase inhibition. Nat Struct Mol Biol. 2021;28(10):789–98. PubMed

Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by Ataxia–Telangiectasia. N Engl J Med. 1991;325(26):1831–6. PubMed

Sun L, Wang RC, Zhang Q, Guo LL. ATM mutations as an independent prognostic factor and potential biomarker for immune checkpoint therapy in endometrial cancer. Pathology. 2020;216(8):153032. PubMed

Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d’Enghien C, Brousse N, et al. Incidence, presentation, and prognosis of malignancies in Ataxia-Telangiectasia: A report from the French National registry of primary immune deficiencies. JCO. 2015;33(2):202–8. PubMed

Sturm I, Bosanquet AG, Hermann S, Güner D, Dörken B, Daniel PT. Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy. Cell Death Differ. 2003;10(4):477–84. PubMed

Seymour JF, Kipps TJ, Eichhorst BF, D’Rozario J, Owen CJ, Assouline S, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8):839–50. PubMed PMC

Usui Y, Iwasaki Y, Matsuo K, Endo M, Kamatani Y, Hirata M, et al. Association between germline pathogenic variants in cancer-predisposing genes and lymphoma risk. Cancer Sci. 2022;113(11):3972–9. PubMed PMC

Webb F, Morey A, Mahler-Hinder C, Georgousopoulou E, Koo R, Pati N, et al. Comprehensive FISH testing using FFPE tissue microarray of primary lymph node tissue identifies secondary cytogenetic abnormalities in mantle cell lymphoma. Cancer Genet. 2023;274–275:75–83. PubMed

Yazinski SA, Comaills V, Buisson R, Genois MM, Nguyen HD, Ho CK, et al. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev. 2017;31(3):318–32. PubMed PMC

Zhang J, Jima D, Moffitt AB, Liu Q, Czader M, Hsi ED, et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014;123(19):2988–96. PubMed PMC

https://www.ncbi.nlm.nih.gov/genome/gdv/browser/genome/?id=GCF_000001405.40