Unraveling the genetics of transformed splenic marginal zone lymphoma

Abstract

Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Mutation

Leucemia linfocítica crónica de células B; Linfoma de células B grandes difuso; Mutación

Leucèmia limfocítica crònica de cèl·lules B; Limfoma de cèl·lules B grans difús; Mutació

The genetic mechanisms associated with splenic marginal zone lymphoma (SMZL) transformation are not well defined. We studied 41 patients with SMZL that eventually underwent large B-cell lymphoma transformation. Tumor material was obtained either only at diagnosis (9 patients), at diagnosis and transformation (18 patients), and only at transformation (14 patients). Samples were categorized in 2 groups: (1) at diagnosis (SMZL, n = 27 samples), and (2) at transformation (SMZL-T, n = 32 samples). Using copy number arrays and a next-generation sequencing custom panel, we identified that the main genomic alterations in SMZL-T involved TNFAIP3, KMT2D, TP53, ARID1A, KLF2, 1q gains, and losses of 9p21.3 (CDKN2A/B) and 7q31-q32. Compared with SMZL, SMZL-T had higher genomic complexity, and higher incidence of TNFAIP3 and TP53 alterations, 9p21.3 (CDKN2A/B) losses, and 6p gains. SMZL and SMZL-T clones arose by divergent evolution from a common altered precursor cell that acquired different genetic alterations in virtually all evaluable cases (92%, 12 of 13 cases). Using whole-genome sequencing of diagnostic and transformation samples in 1 patient, we observed that the SMZL-T sample carried more genomic aberrations than the diagnostic sample, identified a translocation t(14;19)(q32;q13) present in both samples, and detected a focal B2M deletion due to chromothripsis acquired at transformation. Survival analysis showed that KLF2 mutations, complex karyotype, and International Prognostic Index score at transformation were predictive of a shorter survival from transformation (P = .001; P = .042; and P = .007; respectively). In summary, SMZL-T are characterized by higher genomic complexity than SMZL, and characteristic genomic alterations that could represent key players in the transformation event.

This study was supported by Fundacion Asociación Española Contra el Cancer (AECC)/Centro de Investigación Biomédica en Red de Cancer (CIBERONC): PROYE18020BEA (S.B.), fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III “Cofinanciado por la Union Europea ´ and Fondos FEDER: European Regional Development Fund “Una manera de hacer Europa”: PI17/ 01061 (S.B.), PI19/00887 (A.L.-G. and E.G.), INT20/00050 (A.L.- G.), MaratO TV3-Cancer/201904-30 (S.B.), Generalitat de Catalunya Suport Grups de Recerca AGAUR (2021-SGR-01293 [S.B.] and 2021-SGR-01172 [E.C.]), and Ministerio de Ciencia e Innovacion (PID2021-123054OB-I00 [E.C.]). C.L. is supported by postdoctoral Beatriu de Pinos grant, Secretaria d´Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and by Marie Sklodowska-Curie COFUND program from H2020 (2018-BP-00055). E.C. is an Academia Researcher of the "Institucio Catalana de Recerca i Estudis Avançats" of the Generalitat de Catalunya. This work was mainly developed at the Centre Esther Koplowitz (CEK), Barcelona, Spain.