Hematologic indices in individuals with pathogenic germline DICER1 variants

Abstract

Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder. Murine models with the loss of DICER1 in hematopoietic stem cell progenitors demonstrate hematologic aberrations that include reductions in red and white blood cell counts, hemoglobin volume, and impaired maturation resulting in dysplasia. We investigated whether hematologic abnormalities such as those observed in DICER1-deficient mice were observed in humans with a pathogenic germline variant in DICER1. A natural history study of individuals with germline pathogenic DICER1 variants and family controls conducted through the National Cancer Institute (NCI) evaluated enrollees at the National Institutes of Health Clinical Center during a comprehensive clinical outpatient visit that included collecting routine clinical laboratory studies. These were compared against normative laboratory values and compared between the DICER1 carriers and controls. There were no statistical differences in routine clinical hematology laboratory studies observed in DICER1 carriers and family controls. A review of the medical history of DICER1 carriers showed that none of the individuals in the NCI cohort developed myelodysplastic syndrome or leukemia. Query of the International Pleuropulmonary Blastoma/DICER1 Registry revealed 1 DICER1 carrier who developed a secondary leukemia after treatment of pleuropulmonary blastoma. We found limited evidence that the hematologic abnormalities observed in murine DICER1 models developed in our cohort of DICER1 carriers. In addition, no cases of myelodysplastic syndrome were observed in either the NCI cohort or the International Pleuropulmonary Blastoma/DICER1 Registry; 1 case of presumed secondary leukemia was reported. Abnormalities in hematologic indices should not be solely attributed to DICER1. This trial was registered at www.clinicaltrials.gov as #NCT01247597.

Conflict of interest statement

Conflict-of-interest disclosure: D.R.S. provided contract clinical telegenetics services to Genome Medical Inc. in accordance with relevant NCI ethics policies. The remaining authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

Scatter plot comparing WBC number in DICER1 carriers and controls in total and stratified by sex. Red triangles represent DICER1 carriers; blue circles represent controls. H, high; L, low. Vertical line associated with H or L is drawn from the upper limit or the lower limit, respectively, of that individual’s normal range.

Figure 2.

Scatter plot comparing RBC number in DICER1 carriers and controls in total and stratified by sex. Red triangles represent DICER1 carriers; blue circles represent controls. H, high; L, low. Vertical line associated with H or L is drawn from the upper limit or the lower limit, respectively, of that individual’s normal range.

Figure 3.

Scatter plot comparing ANC in DICER1 carriers and controls in total and stratified by sex. Red triangles represent DICER1 carriers; blue circles represent controls. H, high; L, low. Vertical line associated with H or L is drawn from the upper limit or the lower limit, respectively, of that individual’s normal range.