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CALR Gene Mutation

Calreticulin is a calcium-binding chaperone protein, located in the endoplasmic reticulum that is believed to be involved in clearing misfolded proteins. Mutations in the CALR gene create translation frameshifts in exon 9 which result in synthesis of a peptide with a truncated C-terminal calcium binding domain. These mutant peptides appear to promote abnormal expansion of the megakaryocytic cell line. Detection of a CALR gene mutation aids in the specific diagnosis of a myeloproliferative neoplasm (MPN), and helps to distinguish MPN from a benign reactive disease.

CALR mutations are mutually exclusive with JAK2 or MPL mutations. CALR mutations occur inapproximately 25% of essential thrombocythemia (ET) cases overall and in 70% of cases that are negative for JAK2- and MPL. Less than 10% of patients with myelodysplasia have mutations in the CALR gene. CALR mutations are rarely detected in patients with de novo acute myeloid leukemia, chronic myelogenous leukemia, lymphoid leukemia, or solid tumors.

Patients with CALR mutations tend to be younger and have higher platelet counts and lower hemoglobin than those with JAK2 mutations. Survival is longer and risk of thrombosis is lower in patients with CALR mutations compared to patients with JAK2 or MPL mutation.

CALR mutations are present in 88% of patients with primary myelofibrosis without JAK2 and MPL mutations. Patients with CALR mutations have longer overall survival than those with JAK2 and MPL mutations. Mutations have been reported in 8% of patients with MDS.

CALR mutations have not been detected in patients with polycythemia vera . Therefore, CALR mutation testing can be used to distinguish polycythemia vera from essential thrombocytosis or primary myelofibrosis

The majority of mutational changes involve a variety of insertion or deletion mutations in exon 9 of the calreticulin gene. Approximately 50% of all CALR mutations involve a 52 bp deletion, while approximately 30% have a 5 bp insertion. The remaining mutations consist of mostly deletions ranging from 1 bp to 52 bp and 1 or 2 insertion mutations.

Testing can be performed by bi-directional sequencing of exon 9 of the CALR gene and fragment length analysis or by a combination of polymerase chain reaction and capillary electrophoresis. Results positive for insertions/deletions are reported as a percentage mutant peak relative to wild-type peak.The PCR assay is capable of detecting a mutant cell population with a sensitivity of 5 mutant cells per 100 normal cells. A negative result does not exclude the presence of a myeloproliferative disorder or other neoplastic process.

Specimen requirement is 3 to 5 mL of whole blood or 1 to 2 mL bone marrow collected in a lavender-top (EDTA) tube or green-top (sodium heparin) tube.

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