Klin Padiatr 2017; 229(06): 329-334
DOI: 10.1055/s-0043-117046
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms

Mutations-Spektrum der Fanconi-Anämie assoziierten myeloischen Neoplasien
Mwe Mwe Chao*
1   Pediatric Hematology/Oncology, Hannover Medical School, Hannover
,
Kathrin Thomay*
2   Department of Human Genetics, Hannover Medical School, Hannover
,
Gudrun Goehring
2   Department of Human Genetics, Hannover Medical School, Hannover
,
Marcin Wlodarski
3   Faculty of Medicine, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg
4   German Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany
,
Victor Pastor
3   Faculty of Medicine, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg
,
Brigitte Schlegelberger
2   Department of Human Genetics, Hannover Medical School, Hannover
,
Detlev Schindler
5   Institute for Human Genetics, University of Würzburg, Würzberg
,
Christian Peter Kratz
1   Pediatric Hematology/Oncology, Hannover Medical School, Hannover
,
Charlotte Niemeyer
3   Faculty of Medicine, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg
4   German Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
13 November 2017 (online)

Abstract

Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in RUNX1 and genes of the RAS pathway appeared more instrumental in the pathogenesis of FA myeloid malignancies. RUNX1 mutations were associated with more advanced disease. Interestingly, one patient with refractory anemia with ring sideroblasts harbored the SF3B1 p.K700E mutation highlighting the mutation’s causative role in MDS with ring sideroblasts even in the context of FA. On the whole, our findings implicate a different genetic architecture of FA MDS/AML from adult sporadic MDS. Notably, the genetic events resemble those described in pediatric MDS.

Zusammenfassung

Individuen mit Fanconi-Anämie (FA) haben ein hohes Risiko, ein myelodysplastisches Syndrom (MDS) oder eine akute myeloische Leukämie (AML) zu entwickeln, doch die sekundären somatischen Mutationen, die diesen Neoplasien zugrunde liegen, sind weitgehend unklar. Wir führten die Sequenzanalyse eines Multigen-Panels für myeloische Neoplasien durch, um das Mutationsspektrum von FA-assoziiertem MDS/AML zu untersuchen. Zehn von 16 FA/MDS bzw. FA/AML Patienten zeigten somatische Missense-, Nonsense-, Insertions- oder Duplikationsmutationen in 13 Genen. Im Gegensatz zum Mutationsspektrum beim sporadischen MDS waren Mutationen in Genen für RNA-Spleißen selten. Mutationen in RUNX1 und Genen des RAS-Signalweges waren in der Pathogenese von FA assoziierten myeloischen Neoplasien bedeutsamer. RUNX1-Mutationen waren mit fortgeschrittenem MDS assoziiert. Interessanterweise zeigte ein Patient mit refraktärer Anämie mit Ring-Sideroblasten eine SF3B1-Mutation, was die Bedeutung dieser Mutationen beim MDS mit Ring-Sideroblasten selbst im FA Kontext hervorhebt. Unsere Ergebnisse implizieren eine genetische Architektur des FA assoziierten MDS/AML, welches dem pädiatrischen MDS ähnelt und sich von adulten MDS unterscheidet.

*  Shared first authorship


Supplementary Material

 
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