The t(X;20)(q13;q13) translocation is a good prognostic factor in myeloid neoplasms: A report of 25 cases from the <i>Groupe Francophone de Cytogénétique Hématologique</i>
Authors: Florence Nguyen‐Khac, Marc Muller, Elise Chapiro, Nassera Abermil, Marie‐Agnes Collonge‐Rame, Agnes Daudignon, Baptiste Gaillard, Doina Guzun, Antoine Ittel, Christine Lefebvre, Jean‐Francois Lesesve, Marie‐Joelle Mozziconacci, Dominique Penther, Julie Quessada, Catherine Settegrana, Luce Smagghe, Christine Terre, Lauren Veronese, Pierre Hirsch, Marie‐Bérengère Troadec
Journal: American Journal of Hematology (2024)

t(X;20)(q13;q13) is a very rare but recurrent translocation observed in myeloid neoplasms such as myelodysplastic neoplasm (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML). While only nine cases have been reported previously,1-5 we have collected data (including gene sequencing data) on a large series of 25 cases of myeloid neoplasms with t(X;20). By retrospectively screening databases at 13 French cytogenetic laboratories, we identified 25 cases of t(X;20)(q13;q13) (Figure 1A,B; Table S1). The study was approved by the local institutional review board (AP-HP (Paris, France); reference: BPD2018DIA008) and complied with the tenets of the Declaration of Helsinki. All the patients provided their written, informed consent to participation. Bone marrow smears (available for 16 of the 25 patients) were blind-reviewed by two independent expert cytologists (J-FL and CS). To obtain R- or G-banded chromosomes, cells were prepared from bone marrow using standard techniques. All the karyotypes were reviewed by the members of the Groupe Francophone de Cytogénétique Hématologique and classified according to the International System for Human Cytogenetic Nomenclature (ISCN 2020). A complex karyotype was defined as the presence of three or more clonal chromosomal abnormalities (CAs). Standard fluorescence in situ hybridization was performed on metaphase and interphase nuclei, using the commercial probes XIST (Xq13.2)/CCPX (CytoTest, Rockville, MD, USA), 20q12 (PTPRT)/20q13 (MYBL2) (Cytocell, Cambridge, UK), WCP20 and WCPX (Metasystems, Altlußheim, Germany). Fourteen patient samples were sequenced with a next-generation sequencing myeloid panel (Supplemental Information). For one center (Pitié-Salpêtrière, between 2015 and 2022), we were able to calculate the exact prevalence of t(X;20) in MDS (0.4%; 2 out of 421) and in MDS or unexplained cytopenia (0.1%; 2 out of 1283). All 25 patients were female. The median age was 78 (range: 60–91). Five of the 23 patients with available clinical data had received chemotherapy for follicular lymphoma (case #1), multiple myeloma (case #16), breast cancer (case #19), ovarian cancer (case #14) or AML (case #24) before the t(X;20) was detected. The initial diagnoses were MDS (n = 12, including ring sideroblasts in cases #2, #8, and #18), cytopenia (n = 6), AML (n = 3), and MPN with eosinophilia (n = 1). Three myelograms were hemodiluted so a morphologic diagnosis could not be made. The morphologic review of 16 samples confirmed the diagnoses for 11 cases of MDS and one case of AML and led to the reclassification of two out of four cases of cytopenia as unclassifiable MDS (MDS-U, cases #6 and #21) (Figure S1). The two reviewers observed an abnormal chromatin clumping in 6/16 (37%) cases, but no specific feature of the t(X;20). Finally, the four remaining cases of cytopenia were considered to be clonal cytopenia of undetermined significance (CCUS). In the 14 cases of MDS and 4 cases of CCUS, the karyotype was never complex; the t(X;20) was the only CA in 12 of the 18 cases (67%). In the other 6 cases, the additional CAs were del(5q) (3 out of 18, 17%; none in CCUS), del(20q) (2 out of 18, 11%; none in CCUS), and trisomy (tri) 8 (1 out of 18, 5%). The t(X;20) was subclonal in only one of the 18 cases (5%). In cases presenting with both t(X;20) and del(20q), the two CAs were always in independent clones. All the cases of AML had complex karyotypes with 3 to 7 CAs. The t(X;20) was present in the major clone in all three patients (Tables S1 and S2). In the cohort as a whole, the most common associated CA was del(5q) (6 out of 25, 24%)—which was variously clonal, subclonal, or present in independent clones—and followed by del(20q) (3 out of 25, 12%) or tri8 (2/25, 8%). It is noteworthy that in one patient (case #24), tri8 was present in 24 of the 25 (96%) mitoses observed at the time of AML diagnosis. Four months later (during the first-line treatment), tri8 was still observed in three mitoses independently of t(X;20); this might correspond to residual AML blasts. At relapse 2 years later, tri8 reappeared (additionally with tetrasomy 8), whereas t(X;20) was no longer observed (Figure S2). In all 14 tested cases, the breakpoint on the X chromosome was proximal to XIST (Xq13.2), and the breakpoint on chromosome 20 was distal to MYBL2 on 20q13 (Figure 1C,D). Molecular data revealed mutations in TET2 (n = 7 out of 14, 50%), SF3B1 (n = 3, 21%), DNMT3A (n = 3, 21%), RUNX1 (n = 2, 14%), and U2AF1 (n = 2, 14%) (Table S1). Of note, the 3 patients with SF3B1mut also had a del(5q); and the only CCUS case tested by NGS had mutations in TET2 and DNMT3A. No TP53 mutations were observed. We also detected mutations in SRSF2, BCOR, BCORL1, IDH1, EP300, NRAS, and ETV6 (n = 1 each). Regarding MDS and CCUS, the cytogenetic category for the Revised International Prognostic Scoring System (IPSS-R) score was intermediate in all but the three cases of MDS with t(X;20) and del(5q) (with a favorable score).6 The median MDS IPSS-R score was 2.25 (range, 1–4). Of the 18 scores, 15 (83%) were classified as low risk, one was classified as very low risk, and two were classified as intermediate risk (Table S1 and Figure 1E). With a median follow-up time of 17 months (95% CI: 10–37), the median overall survival was not reached, and 69% of the patients were alive at 5 years. To the best of our knowledge, the present series of t(X;20) cases is the largest yet. As previously described, all patients were female, and the median age was 78. The majority (64%) of t(X;20) cases corresponded to MDS. The morphological evidence for MDS was not always easy to interpret: two of the four morphologically reviewed cases of cytopenia were reclassified as MDS. However, four cases of cytopenia had no morphological evidence of MDS. According to the fourth edition of the World Health Organization's classification of hematolymphoid tumors, t(X;20)(q13;q13) is not one of the CAs that defines MDS-U. In the fifth edition, patients with isolated t(X;20)(q13;q13) are classified as having CCUS. In our series of MDS/CCUS cases, t(X;20) was frequently isolated (in 67% of cases) and was associated with a low-risk MDS IPSS-R in 83% of cases. Overall, t(X;20) was associated with cases of MDS/CCUS (82%) with a favorable prognosis. In a few cases, t(X;20) was observed in AML but only included in a complex karyotype. Our series included a case of MPN with hypereosinophilia. t(X;20) was frequently isolated or present in the major clone, and may be an early event. The most frequent associated CA was del(5q) (24%). Interestingly, when associated with del(20q) (12%), t(X;20) was always present in an independent clone. This is in line with the possible silencing of 20q genes by a position effect of the XIST gene on der(20).2 The spreading of X inactivation to the 20q region provides an alternate mechanism for del(20q).4 Indeed, in all the tested cases, XIST gene was translocated on the der(20), and all 20q genes stayed on the long arm of der(20). In conclusion, t(X;20)(q13;q13) is a rare translocation observed in older women. It may be an early event. t(X;20)(q13;q13) is often isolated and is mostly associated with MDS/CCUS with a favorable prognosis. It is found less frequently in cases of AML and MPN. The most commonly associated CAs are del(5q) and del(20q), and the latter is always in an independent clone. We therefore suggest that isolated t(X;20) should be classified in a good cytogenetic IPSS-R category (score = 1), rather than in an intermediate cytogenetic category (score = 2). F.N-K. and M.M. designed the study. N.A., E.C., M-A.C-R., A.D., V.E., B.G., A.I., C.L., M-J.M., D.P., J.Q., C.T., and L.V. provided samples and clinical data. J-F.L and C.S performed the morphological review. L.S. performed additional FISH analysis. P.H. performed NGS sequencing. E.C. performed statistical analysis. F.N-K., M.M., D.G., and M-B.T. analyzed data. F.N-K. wrote the manuscript. M.M. and M-B.T. reviewed the manuscript. All co-authors approved the manuscript. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting information. 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