Somatically acquired mutations in primary myelofibrosis: A case report and meta-analysis

Abstract

Familial myeloproliferative disease (MPD) cases account for 7.6% of the global MPD cases. The present study reported 2 cases of primary myelofibrosis (PMF). The patients were two sisters; the older sister succumbed to the disease at the age of 37, whereas the younger sister maintained a stable disease status and gave birth to a son through in vitro fertilization. Genetic analysis of bone marrow DNA samples showed that both sisters carried a Janus kinase 2 (JAK2) V617F mutation, and the older sister also had a trisomy 8 chromosomal abnormality (47, XX, +8). A systematic literature search was also performed using PubMed, CNKI and Wanfang databases, to determine the association between JAK2 and PMF. Following comprehensive screening of the published literature, 19 studies were found to be eligible for the current meta-analysis. The results showed that JAK2 V617F was a risk factor of PMF, and no sex dimorphism was observed in JAK2 V617F mutation prevalence amongst all PMF cases. In addition, there was a lack of association between the JAK2 V617F mutation and PMF-related mortality.

Keywords: Janus kinase 2 V617F; familial; primary myelofibrosis; somatic mutation.

Figure 1

Karyotypes and bone marrow biopsy of the sisters. (A) Karyotype of the younger sister was 46, XX (Giemsa stain; magnification, x1,000). (B) Karyotype of the older sister was 47, XX, +8 (Giemsa stain; magnification, x1,000). (C) Bone marrow hematopoietic tissue biopsy of the younger sister (H&E staining; magnification, x100). (D) Bone marrow hematopoietic tissue biopsy of the older sister (H&E staining; magnification, x100). Atypical nuclear morphology was identified and staining of the reticular protein from a bone marrow biopsy suggested that there was increased collagen compared to levels typically seen in individuals without myelofibrosis. H&E, hematoxylin and eosin.

Figure 2

Flow diagram of the selection process for the meta-analysis; CALR, calreticulin.

Figure 3

Funnel plots for the meta-analysis exploring the association between JAK2 V617F mutation and PMF. (A) No bias was observed in the funnel plots between the case and control, (B) between males and females, and (C) between PMF-related mortality with the JAK2 V617F mutation in the meta-analysis. PMF, primary myelofibrosis; SE, standard error; RR, risk ratio; M-H, Mantel-Haenszel; IMF idiopathic myelofibrosis.

Figure 4

Forest plot of the meta-analysis exploring the association between the JAK2 V617F mutation and PMF. Total ORs and 95% CIs were estimated to assess the association between JAK2 V617F mutation and PMF risk. Minimal heterogeneity was found in the meta-analysis; I²=0%. The results indicated that JAK2 V617F was a risk factor for PMF. OR=17.12, 95% CI=11.32-25.89, P<0.00001. OR, odds ratio; CI, confidence interval; PMF, primary myelofibrosis; IMF idiopathic myelofibrosis.

Figure 5

Forest plot of the meta-analysis exploring the association between the JAK2 V617F mutation and sex of IMF patients. Total OR and 95% CIs were estimated to assess the association between the JAK2 V617F mutation and the sex of patients. Z-test with a two-sided P<0.05 was used to determine the significance of the total OR. No association was observed between the sex of patients and the JAK2 V617F mutation; OR=0.98, 95% CI=0.89-1.08, P=0.69. OR, odds ratio; CI, confidence interval; PMF, primary myelofibrosis; M-H, Mantel-Haenszel.

Figure 6

Forest plots of the meta-analysis exploring the association between the JAK2 V617F mutation and PMF-related mortality. Total OR and 95% CIs were estimated to assess the association between the JAK2 V617F mutation and PMF-related mortality. Z-test with a two-sided P<0.05 was used to determine the significance of the total ORs. No association was observed between PMF-related mortality and the JAK2 V617F mutation; OR=1.43, 95% CI=0.94-2.18, P=0.09). OR, odds ratio; CI, confidence interval; PMF, primary myelofibrosis; M-H, Mantel-Haenszel; IMF, idiopathic myelofibrosis.