Clonal evolution in diffuse large B-cell lymphoma with central nervous system recurrence

• Published in: ESMO open 2021-02, Vol.6 (1), p.100012-100012, Article 100012
• Main Authors: Magnes, T., Wagner, S., Thorner, A.R., Neureiter, D., Klieser, E., Rinnerthaler, G., Weiss, L., Huemer, F., Zaborsky, N., Steiner, M., Weis, S., Greil, R., Egle, A., Melchardt, T.
• Format: Article
• Language: English
• Subjects: clonal evolution; diffuse large B-cell lymphoma; massively parallel sequencing; Original Research; secondary central nervous system lymphoma
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2020.100012

The prognosis of patients with secondary central nervous system lymphoma (SCNSL) is poor and despite massive advances in understanding the mutational landscape of primary diffuse large B-cell lymphoma (DLBCL), the genetic comparison to SCNSL is still lacking. We therefore collected paired samples from six patients with DLBCL with available biopsies from a lymph node (LN) at primary diagnosis and the central nervous system (CNS) at recurrence. A targeted, massively parallel sequencing approach was used to analyze 216 genes recurrently mutated in DLBCL. Healthy tissue from each patient was also sequenced in order to exclude germline mutations. The results of the primary biopsies were compared with those of the CNS recurrences to depict the genetic background of SCNSL and evaluate clonal evolution. Sequencing was successful in five patients, all of whom had at least one discordant mutation that was not detected in one of their samples. Four patients had mutations that were found in the CNS but not in the primary LN. Discordant mutations were found in genes known to be important in lymphoma biology such as MYC, CARD11, EP300 and CCND3. Two patients had a Jaccard similarity coefficient below 0.5 indicating substantial genetic differences between the primary LN and the CNS recurrence. This analysis gives an insight into the genetic landscape of SCNSL and confirms the results of our previous study on patients with systemic recurrence of DLBCL with evidence of substantial clonal diversification at relapse in some patients, which might be one of the mechanisms of treatment resistance. •We sequenced paired samples of five patients with DLBCL and available biopsies at primary diagnosis and CNS recurrence.•This is one of the first descriptions of the genetic landscape of secondary CNS lymphoma.•All patients had at least one mutation that was discordant and therefore not found in one of their biopsies.•Two patients showed substantial clonal diversification between the primary diagnosis and CNS recurrence.•Some mutations detected in SCNSL involve genes known to influence the response to small molecules in DLBCL.