Study Finds GATA2 Deficiency Predisposes Children to MDS

Germline GATA2 mutations account for 15 percent of advanced and 7 percent of primary cases of myelodysplastic syndromes (MDS) in pediatric patients, but their presence does not affect rates of overall survival, according to research recently published in Blood.1 In this study of children and adolescents with MDS, the authors, led by Marcin W. Wlodarski, MD, also found that the majority of adolescent patients (72%) who had the cytogenetic aberration monosomy 7 carried an underlying GATA2 deficiency.

“Significant differences between primary MDS in children and adults are evident for morphology, cytogenetics, therapeutic approaches, and the somatic mutation landscape,” Dr. Wlodarski, from the Department of Pediatrics and Adolescent Medicine in the Division of Pediatric Hematology and Oncology at the University of Freiburg in Germany, and colleagues wrote. The role of GATA2 mutations in this disease is not well understood, limiting clinicians’ ability to predict outcomes and make recommendations for evidence-based clinical care.

“In this study, we aimed to assess the frequency of germline GATA2 mutations that underlie pediatric MDS, and to define clinical characteristics, therapeutic response, and prognostic consequences of this predisposition syndrome.”

Dr. Wlodarski and colleagues analyzed bone marrow and peripheral blood samples from 508 children and adolescents with primary or secondary MDS who were enrolled in two prospective studies of the European Working Group MDS in Childhood (EWOG-MDS). Patients were excluded from the study if they had known inherited bone marrow failure disorders.

Of the 508 patients, 426 had been diagnosed with primary MDS (including familial MDS, defined as at least one first-degree relative suffering from hematologic neoplasia) and 82 with MDS secondary to chemo- or radiation therapy or to acquired severe aplastic anemia.

Patients were followed for 15 years (from July 1, 1998, through June 30, 2013).

The researchers identified 24 distinct GATA2 mutations in 28 patients (7%) with primary MDS, while no mutations were found among the 82 patients with secondary MDS (TABLE).

Taking into account the MDS subtype, GATA2 mutations were more prevalent in patients with advanced disease than in those with refractory cytopenia of childhood (RCC; 15% vs. 4%; p<0.01).

Patients with the GATA2 mutatation (GATA2mut) also tended to be older at the time of diagnosis and, the authors noted, advanced MDS and monosomy 7 were “highly overrepresented” in these patients, compared with those with wild-type GATA2 (GATA2WT). “Surprisingly, in the majority (71%) of the GATA2mut group, MDS occurred sporadically without family history of hematologic malignancy,” they added.

MDS subtype, rather than GATA2 mutation status, was a significant prognostic factor for overall survival (OS), Dr. Wlodarski and colleagues found. Among the 426 children with primary MDS, five-year OS was 91 percent in patients with advanced MDS, versus 57 percent in the RCC group (p<0.01). When OS was evaluated according to mutational status alone, the GATA2WT cohort had better OS than the GATA2mut  cohort (84% vs. 73%; p<0.05).

Among the 57 children with MDS and GATA2 deficiency, 50 received hematopoietic cell transplantation (HCT), the only curative option available for GATA2-related MDS. The outcome of HCT was not influenced by GATA2 mutational status, the authors noted; the five-year OS and event-free survival rates were comparable between GATA2mut and GATA2WT groups (66% vs. 69% and 60% vs. 60%, respectively).

“Interestingly, we observed a slightly higher proportion of relapse after HCT within the GATA2mut group with monosomy 7 (21% vs. 13%; p = not significant), an observation deserving further validation in larger cohorts,” they reported.

The authors discussed limitations of the study, including that children with MDS and advanced disease are subjected to HCT in a timely manner. In addition, the finding that GATA2mut and GATA2WT survival is comparable in children with MDS suggests that the study’s findings may not be generalizable to the adult MDS population.

According to the authors, these results should “redefine the paradigm of MDS in children and adolescents,” suggesting that GATA2 analysis should be included in the work-up of all children and young adults presenting with MDS and monosomy 7 – regardless of family history or accessory GATA2 disease phenotype.

The findings echo the results of an earlier study published in The New England Journal of Medicine, which looked at the prevalence of germline mutations across several types of pediatric cancer.2 Using next-generation DNA sequencing, researchers found that 8.5 percent of patients had pathogenic or likely pathogenic genetic mutations predisposing them to developing cancer, again, irrespective of family history. Armed with this evidence that germline mutations contribute to pediatric cancer risk, the authors suggest that next-generation sequencing and genetic counseling can help guide clinical management.

“Ideally, the implementation of early diagnosis of GATA2 deficiency can avoid unnecessary diagnostic procedures, enable tailored surveillance strategy, and limit the use of non-curative therapies specifically avoiding immunosuppression,” Dr. Wlodarski and colleagues concluded.


  1. Wlodarski MC, Hirabayashi S, Pastor V, et al. Prevalence, clinical characteristics and prognosis of GATA2-related myelodysplastic syndromes (MDS) in children and adolescents. Blood. 2015 December 23. [Epub ahead of print]
  2. Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373:2336-46.

TABLE. Characteristics of Primary MDS with GATA2 Deficiency
GATA2mut GATA2WT p Value
Mutations Total/Distinct 28/24 0
Age Median (range) 12.3 years (5.2-17.4) 10.3 years (0.2-18.1) <0.05
Sex Male (n=248) 15 (54%) 233 (58%) Not significant
Female (n=178) 13 (46%) 165 (42%)
Subtype RCC (n-341) 15 (54%) 326 (82%) <0.01
RAEB/RAEB-t (n=85) 13 (46%) 72 (18%)
Karyotype Monosomy 7 (n=54) 19 (70%) 35 (11%) <0.01
Structural complex (n=9) 0 (0%) 9 (3%)
Other (n=30) 1 (4%) 29 (9%)
Normal (n=253) 7 (26%) 246 (77%)
RAEB = refractory anemia with excess blasts; RCC = refractory cytopenia of childhood