Frequency of Non-Type I/II CALR Mutations in Patients Undergoing Molecular Diagnostics for Myeloproliferative...

Somatic CALR gene insertions/deletions in exon 9, causing frameshift, are a diagnostic sign of myeloproliferative neoplasms (MPNs). Besides the most common somatic mutations of type I (52 bp deletion) and type II (5 bp insertion), there are rare ones whose significance is not always clear. This study evaluates the frequency of rare mutations and demonstrates a germline rather than somatic nature for some of them.

A retrospective analysis of 8417 blood samples subjected to molecular diagnosis of myeloproliferative neoplasm (MPN) was performed. Cases suspected as germline variants were sequenced, and paired samples (when available) of buccal epithelium were analyzed.

We have identified 632 CALR gene mutation-positive cases. Most of the cases were typical insertions/deletions (5 bp/52 bp). Non-type I/II frameshift or nonframeshift mutations were observed in 68 cases (11%). The buccal swab samples obtained from 4 patients confirmed the germline nature of these variants. It is worth noting that the MPN diagnosis for three of these patients was made considering the presence of the JAK2 V617F mutation (two cases) or BCR::ABL1 translocation (one case). In one case, the diagnosis of MPN was reclassified to CML.

Non-type I/II CALR mutations, according to our data, could be found in 0.8% of MPN-suspected cases, and may not be associated with the diagnosis. The detection of a non-standard CALR mutation with an allelic frequency close to 50% should raise suspicion of the possibility of a germline CALR variant, and such cases should be investigated further.