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Calreticulin is a multifunctional soluble protein that plays a role in calcium homeostasis, it also binds to misfolded proteins and prevents their exit from the endoplasmic reticulum to the Golgi apparatus. The CALR mutation is acquired after birth and is not an inherited mutation.
This disease is caused by the addition or deletion of small amounts of genetic material to a region of the gene called exon 9. This leads to the abnormal protein calreticulin. Calreticulin (CALR) mutations are the second most common genetic abnormality (after JAK2 mutations).
Somatic insertion/deletion mutations in exon 9 of the CALR gene are associated with several chronic myeloproliferative disorders, including essential thrombocythemia (ET) and primary myelofibrosis (PMF), and rarely other Myeloid stem cell disorders are associated. In studies published to date, CALR mutations have been found in approximately 20-25% of ET patients and 30-35% of PMF patients.
Although this mutation is rare and well known in children However, 50% of pediatric PMF patients had a CALR mutation. This mutation may occur with low probability in some low-grade myelodysplastic syndromes and other myeloid stem cell disorders such as chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML).
myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). In 2016, the World Health Organization (WHO) revised its diagnostic criteria for MPNs. The presence of CALR exon 9 mutation is one of the three main criteria listed. To detect ET and PMF.
CARL overexpression has been reported in a variety of solid tumors and is also associated with more aggressive and advanced malignant processes. It is not yet clear how the mutated protein leads to the signs and symptoms of MPN. While more than 50 CALR mutations have been found, only the two most common variants associated with MPNs are included in routine PCR testing.
The most common reported subtypes of CALR mutations include type 1 mutation (52 bp deletion) and type 2 mutation (5 bp insertion). Additional trench sequencing will not be performed for these mutation subtypes. For other mutation subtypes, particularly non-type 1 and non-type 2, sequencing is performed to confirm the size of the deletion/insertion. Next-generation sequencing (NGS)-based analysis should identify all mutational variants but is not widely available. In addition to helping diagnose MPNs, CALR mutation testing can provide information about a person’s prognosis.
Most patients with sporadic ET or PMF not associated with JAK2 or MPL alterations have been shown to carry somatic CALR mutations. Compared to those with JAK2 mutations, those with CALR mutations had a milder disease course, fewer signs and symptoms of blood clots (thrombotic episodes), and better survival.
Application of CALR mutation test
The CALR mutation test is used to help diagnose and classify bone marrow disorders that result in an overproduction of blood cells. These disorders are known as myeloproliferative neoplasms (MPN). As noted, CALR mutations are the second most common genetic abnormality associated with two types of MPN: essential thrombocythemia (ET) and primary myelofibrosis (PMF). Testing for genetic abnormalities associated with MPNs is usually done as a follow-up if a person has markedly elevated hemoglobin, hematocrit, red blood cell and/or platelet count, or blood smear findings suggestive of myelofibrosis. along with clinical signs and symptoms suggestive of MPN.
CALR mutation testing is usually done along with testing for other mutations associated with MPNs, such as BCR-ABL1 and JAK2 mutation testing.
CALR mutation test results
A positive CALR mutation test means that the person probably has a myeloproliferative neoplasm (MPN), specifically essential thrombocythemia (ET) or primary myelofibrosis (PMF). Other tests, such as a bone marrow biopsy, may be needed to determine the MPN and assess its severity. A negative result usually means that the tested CALR mutation was not detected. You may have a negative result and still have an unusual CALR mutation that the test cannot detect. It is also possible, although unlikely, that the test failed to detect a CALR exon 9 mutation. Note that next-generation sequencing (NGS)-based analysis should detect all types of mutations in the CALR gene, but this test is not widely available. A negative result does not rule out the possibility of MPN. 10-15% of cases of essential thrombocythemia and primary myelofibrosis have no common genetic abnormality associated with them, that is, they are negative for JAK2, CALR, and MPL mutations known as “triple-negative” MPN.
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