Page 76 - Haematologica3

V.B. Pastor et al.
months to 3 years, and spontaneous remission was achieved within 1-20 months from diagnosis. It seems that the -7 clones in our patients either vanished spontaneously or were outcompeted by “fitter” UPD7q-corrected clones with a diploid copy of the wild-type SAMD9L allele. Based on these observations, a watch-and-wait strategy might be proposed for younger patients with RCC/-7 who have no additional somatic driver mutations and are clinically sta- ble. However, prolonged “watchful waiting” poses the risk of progression as witnessed in P1, who developed CMML and acquired oncogenic mutations 3.6 years after he was diagnosed with RCC.
In conclusion, our observations establish the molecular basis of a distinct subtype of familial MDS and point to the notion that MDS with chromosome 7 loss can be the sole and common manifestation of SAMD9L-related dis- ease. The negative mutational effect leads to escape and outgrowth of clones carrying -7/del(7q) with only wild- type SAMD9L allele, which might spontaneously dissa- pear or persist and provide the first step towards disease progression. Finally, this is the first description of long- term revertant mosaicism due to non-random UPD7q in SAMD9L disease, and a plausible explanation for transient monosomy 7 syndrome.
Acknowledgments
We are grateful to Sophia Hollander, Christina Jäger, Yahaira Pastor, Alexandra Fischer, Wilfried Truckenmüller (Freiburg),
Tamara Szattler (Stockholm) and Bart Przychodzien (USA) for their excellent laboratory assistance and data management, and to Dr. Anett Schmidt, Dr. Dagmar Möbius, and Dr. Elisabeth Holfeld (Cottbus) for clinical care. The authors are grateful to the Genomics Core Facility at the German Cancer Research Center/DKFZ, Heidelberg, Germany for performing whole exome sequencing and Claritas Genomics (Cambridge, MA, USA) for targeted sequencing in P4.
Funding
Deutsche Krebshilfe (Max Eder grant #109005) to MWW, BMBF (DKTK German Cancer Consortium, topic molecular diagnostics of pediatric malignancies) to CMN and MWW, BMBF (e:Med FKZ 01ZX1409B) to MB, the German Science Foundation (DFG, SFB 850, to MB and EXE306 to HB), the Research Council, Swedish Cancer Society, and Foundation for Strategic Research to YTB. MWW and ME are past trainees of EHA-ASH translational research training in hematology. MV is an EMBO Long-term Fellow (ALTF 206-2015 co-funded by the European Commission (LTFCOFUND2013, GA-2013- 609409). JCA is a Wellcome Trust Senior Research Fellow in Clinical Science (grant 098513/Z/12/Z) with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children, NHS Foundation Trust and UCL, and Great Ormond Street Children's Charity. This study was supported in part by the Excellence Initiative of the German Research Foundation (GSC- 4, Spemann Graduate School).
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