Relevant gene mutations in MPN and their prognostic significance for primary myelofibrosis (PMF).
Myeloproliferative neoplasms (MPN) are a group of blood cancers characterized by significant symptoms and a high risk of transformation into acute leukemia. MPN include (primary) myelofibrosis (PMF), essential thrombocythemia (ET) and polycythemia vera (PV), and affect around 13,000, 134,000 and 148,000 patients in the US, respectively (1). The rarity of MPNs is further reflected in a 2014 global random effects meta-analysis study which reported combined annual incidence rates for PMF, ET and PV of 0.47, 1.03 and 0.84 per 100,000, respectively (2). Myelofibrosis is a type of MPN that is usually caused by one of three genetic mutations within the JAK2 signaling pathway (3). Earlier this year, updated clinical guidelines for MPN were included in the update to the WHO guidelines for the classification of myeloid neoplasms and acute leukemia (4; see related post here). In addition, new guidelines for MPN were recently published, which focus on diagnosis, treatment and supportive care strategies for myelofibrosis (16). Below is a summary of relevant gene mutations in MPN and their prognostic significance for PMF.
JAK2 V617F is an indicator of intermediate prognosis and higher risk of thrombosis compared to patients with CALR mutations (5).
CALR mutations indicate improved survival (5–8) compared to patients with JAK2 mutation and ‘triple-negative’ PMF, and lower risk of thrombosis compared to patients with JAK2 mutation (5).
CALR Type 1/Type 1-like mutations indicate improved overall survival compared to CALR Type 2/Type2-like and the JAK2 V617F mutation (9–12).
MPLW515L/K mutations indicate higher risk of thrombosis and intermediate prognosis compared to patients with CALR mutations (5).
“Triple-negative” (non-mutated JAK2, MPL and CALR) indicate inferior leukemia-free survival compared to patients with JAK2- and/or CALR-mutated PMF (5–7), and inferior overall survival compared to patients with CALR-mutated PMF (6).
Combined CALR and ASXL1 mutation status: Survival is expected to be the longest for CALR(+)ASXL1(-) patients (median 10.4 years) and the shortest in CALR(-)ASXL1(+) patients (median 2.3 years) (14), while intermediate survival (median 5.8 years) is expected for CALR(+)ASXL1(+) or CALR(-)ASXL1(-) patients (14).
EZH2 mutations are independently associated with inferior overall survival (13).
TP53 mutations are associated with leukemic transformation (15).
QIAGEN’s ipsogen portfolio offers an expanding menu of reliable solutions for improved translational research and molecular diagnostics for hematological cancers such as MPN. For specific diagnosis of myeloproliferative neoplasms (MPN) the ipsogen_JAK2_RGQ_PCR_Kit* can be used for quick and precise quantification of the JAK2 V617F mutation. For CALR testing, the ipsogen CALR RGQ PCR Kit will soon be available in CE-IVD and can be used in the same workflow as the CE-IVD ipsogen JAK2 RGQ PCR kit for detection of both JAK2 V617F and CALR exon 9 mutations from the same blood sample. The CALR_RGQ_PCR_Kit** will soon be available in the US for research use only. For sensitive, qualitative detection of MPLW515L/K mutations for hematological cancer research, the ipsogen_MPL_W515L/K_MutaScreen_Kit ** offers an easy workflow and reliable, reproducible results.
QIAGEN also offers the next-generation sequencing (NGS) QIAseq_Targeted_Panel† solution, which is NGS platform-agnostic for digital DNA sequencing, and utilizes molecular barcodes to detect variants with high confidence. The Human Myeloid Neoplasms QIASeq DNA Panel† enables NGS analysis of the 141 genes most commonly mutated in myeloid neoplasm samples and involved in development and progression of these cancers, including those summarized above. For a complete gene list, see here.
* Available for in vitro diagnostic (IVD) use in Europe; available in a research use only version in the US.
** For research use only. Not for use in diagnostics procedures. No claim or representation is intended to provide information for the diagnosis, prevention, or treatment of a disease.
† QIAseq Targeted DNA Panels are intended for molecular biology applications. These products are not intended for the diagnosis, prevention, or treatment of a disease.
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- 16. Press Release, Posted on September 27, 2016 by MPN Advocacy & Education. Link