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Genomic landscape of B-other ALL
further specify the prognostic impact of IKZF1plus and explain its absence in standard risk patients.17
One of the most striking findings of our study is the low frequency of kinase/cytokine receptor gene fusions other than those involving CRLF2. Except for CRLF2 fusions and a single case with ABL-class fusion, no other kinase-acti- vating fusions were detected among all B-other patients diagnosed in the Czech Republic over a 7-year period. The low frequency of non-CRLF2 fusions, supported also by the result of the Swedish study,2 seems to contrast with some American genomic studies;21,30 however, a direct comparison of frequencies between the European and American populations is not possible at the moment, as only the two European studies refer to consecutive, unselected cohorts. Considering the low costs and the excellent performance of flow cytometry in detecting CRLF2r-positive patients, it remains questionable whether any benefit can be gained from testing the BCR-ABL1-like signature in all B-other ALL patients (irrespective of their treatment response) in order to identify patients with a higher probability of having druggable kinase/cytokine receptor gene fusions. Instead, identification of targetable lesions (guiding the choice of appropriate drug) can be per- formed in patients with poor response to treatment upfront and irrespective of potential presence/absence of BCR-ABL1-like phenotype.
In our study, we also aimed to assess the feasibility and benefit of incorporating genome-wide technologies into routine diagnostics. Thanks to centralization in a single laboratory, we successfully standardized all processes and minimized the time to integrate results of all analyses. Although we see some benefit in performing all three genome-wide analyses (SNPa, RNA-sequencing, WES) to obtain the most complex genomic profile, considering the cost-benefit ratio, we found the combination of SNPa and RNA-sequencing to be the most efficient. This combina- tion enables the therapeutically most relevant aberrations
Moreover, RNA-sequencing enables patients to be classi- fied into novel subtypes; this would not be possible with targeted approaches, which are methodologically and ana- lytically less demanding and possibly cheaper. However, these advantages fade with the increasing number of aber- rations that need to be tested and, in addition, unde- scribed/private, but druggable aberrations, cannot always be detected. Furthermore, the complex data gained through genome-wide methods are extremely valuable for retrospective discovery/validation analyses. Nevertheless, it should be noted that genome-wide methods also have additional limitations (e.g. lower sensitivity in fusion tran- script detection than PCR), and these need to be consid- ered and tested during the implementation process.
In conclusion, our study shows unbiased European pop- ulation-based frequency of novel B-other ALL subtypes, recurrent (cyto)genetic aberrations as well as their mutual associations, some of which have not yet been reported. We believe that these findings not only help to strengthen and deepen the current knowledge of B-other ALL, but also provide an objective basis on which other groups/countries can decide how to optimize their current diagnostic routine.
Acknowledgments
We would like to thank to all centers of the Czech Paediatric Haematology Working Group (CPH).
Funding
This study was supported by the “Kapka nadeje” foundation, grants from the Czech Health Research Council (NV15- 30626A), Czech Science Foundation (GJ15-06049Y) and Charles University (Primus/MED/28, UNCE 204012) and by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic). Research infrastruc- ture was supported by the Ministry of Education, Youth and Sports (NPU I no. LO1604 and LM2015091).
(IKZF1plus and kinase-activating lesions)
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