Nailing down neoplasms

RUTHERFORD, N.J.—Cancer Genetics, Inc. (CGI), a developer of DNA-based cancer diagnostics, has announced the launch of a genetic diagnostic test capable to detecting mutations in the calreticulin (CALR) gene to aid in the identification of patients with certain types of myeloproliferative neoplasms (MPN).

The National Center for Biotechnology Information, part of the U.S. National Library of Medicine of the National Institutes of Health, describes CALR as “a multifunctional protein that acts as a major Ca(2+)-binding (storage) protein in the lumen of the endoplasmic reticulum,” adding that “It is also found in the nucleus, suggesting that it may have a role in transcription regulation.” CALR “can inhibit the binding of androgen receptor to its hormone-responsive DNA element and can inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.”

MPN are a range of blood cancer types, and some 3 million patients in the United States are diagnosed as having MPN. According to the Leukaemia Foundation, MPN “are a group of diseases that affect normal blood cell production in the bone marrow. In this case, the bone marrow causes an overproduction of one or more blood cell types (red cells, white cells or platelets). Complications arise over time due to the abnormally high number of blood cells that accumulate in the bone marrow and in the circulating blood.” There are six types of MPN, including polycythemia vera, essential thrombocythemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia and idiopathic myelofibrosis. All types of these blood cancers have the potential to evolve into acute leukemia.

“CALR mutation analysis allows for a more comprehensive diagnosis of patients with myeloproliferative neoplasms,” Dr. Lan Wang, medical director at Cancer Genetics, said in a press release. “This test can help simplify the diagnosis of MPN and may be helpful in stratifying patients according to whether they should receive aggressive or conservative disease management. We see CALR mutation testing becoming one of the routine genomic tests provided to MPN patients.”

In addition to its potential as a diagnostic, looking at the CALR mutation could also potentially aid in prognosis as well. Patients who present with the CALR mutation generally have a more favorable disease outcome, including a lower risk of thrombosis, and longer overall survival when compared to patients with other biomarkers such as the Janus kinase 2 (JAK2) mutation. The JAK2 mutation appears in roughly 50 to 60 percent of patients with essential thrombocythemia or primary myelofibrosis, while “an additional 5 to 10 percent have activating mutations in the thrombopoietin receptor gene (MMPL),” according to the paper “Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms,” which appeared in the New England Journal of Medicine in December 2013.

“The CALR mutation analysis is a valuable addition to our test menu. The availability of this test positions CGI as one of the most comprehensive laboratories in the U.S. for MPN and acute leukemia. In launching this test, we responded quickly to demand from the clinical community, demonstrating our ability to rapidly adapt in a fast-paced, evolving environment,” Panna Sharma, CEO of Cancer Genetics, commented in a statement.

CALR mutations and JAK2 and MPL mutations were found to be mutually exclusive, according to the New England Journal of Medicine paper, and of patients with essential thrombocythemia or primary myelofibrosis who lacked JAK2 or MPL mutations, CALR mutations were found in 67 percent of those with essential thrombocythemia and 88 percent of those with primary myelofibrosis.