Myeloid malignancies with translocation t(4;12)(q11-13;p13): molecular landscape, clonal hierarchy and clinical outcomes

Abstract

Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.

Keywords: CHIC2; ETV6; acute myeloid leukaemia; myelodysplastic syndrome; prognosis; t(4;12).

FIGURE 1

Mutational and cytogenetic analyses of t(4;12) patients. Targeted sequencing data were available for 16 of 21 patients (complete list of targeted genes and mutations available in Tables S1 and S3). Each column represents a patient sample and each row a mutated gene. Mutated genes have been grouped by different functional categories. The percentage of each mutated gene in the whole cohort is indicated on the right of the grid, the number (nb) of mutations per sample on the top, and the complete karyotype by ISCN at the bottom. Coloured and dark grey box: presence; white box: absence; hatched boxes: not available. Abbreviations: I, initiating; S, secondary; K, karyotype, MRC‐AML, myelodysplastic‐related changes‐AML; NA, not available; *, not applicable (MDS with excess blasts)

FIGURE 2

Clonal architecture of t(4;12) samples. Panels A and B respectively represent initiating and secondary t(4;12). The order of cytogenetic and mutational events was inferred from variant cell fractions (VCF) of identified mutations and cytogenetic abnormalities frequencies (Table S5), as previously described. This analysis only included analysis of genomic lesions at the time of t(4;12) identification and did not represent follow‐up samples of the same patient. The precise clonal architecture was difficult to infer in samples #6 and #10 because chromosomal abnormalities were identified in independent clones by conventional karyotype: t(4;12) and monosomy 7 for sample #6; and t(4;12) and trisomy 21 for sample #10. This is thus not possible to infer if subclonal mutations (ie NRAS in #6 or FLT3 in #10) belong to the t(4;12) clone or another clone (monosomy 7 in #6, trisomy 21 in #10). ¶ Subclonality of t(4;12) in case #11 was inferred thanks to analysis of relapse sample in which the t(4;12) detected by interphase FISH was present in 2%, while VAFs of IDH2 and ASXL1 mutations were respectively 28 and 24%

FIGURE 3

Overall survival (OS) (red) and progression‐free survival (PFS) (blue) for the whole cohort of t(4;12) patients