Molecular markers

CALR


Editorial Board Member: Mario L. Marques-Piubelli, M.D.
Megan Parilla, M.D.

Last staff update: 7 May 2024 (update in progress)

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PubMed Search: CALR

Megan Parilla, M.D.
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Cite this page: Parilla M. CALR. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/molecularcalr.html. Accessed May 19th, 2024.
Definition / general
  • CALR is an oncogene that is mutated in hematologic disorders, especially myeloproliferative neoplasms
  • CALR is located on the short arm of chromosome 19 (19p13) and encodes the protein calreticulin, a calcium binding protein that is located primarily in the endoplasmic reticulum
  • The 2 most common mutations in the CALR gene are a type 1, 52 base pair (bp) deletion mutation (L367fs*46) and a type 2, 5 bp insertion (K385fs*47)
Essential features
  • Mutations in CALR are found in a substantial proportion of myeloproliferative neoplasms when the genes JAK2 and MPL are nonmutated (N Engl J Med 2013;369:2379)
  • Oncogenic CALR mutations occur in exon 9 and are (3n+1) bp for deletions and (3n+2) bp for insertions, all resulting in a 1 base pair frameshift
  • The 2 most common oncogenic CALR mutations are a 52 base pair deletion (CALR type 1 mutation) and a 5 base pair insertion (CALR type 2 mutation)
Terminology
  • CALR (approved HUGO nomenclature)
  • Calreticulin
  • Historical terms that are no longer approved
    • CALR1
    • Calregulin
    • Autoantigen Ro
    • Sicca syndrome antigen A
    • Endoplasmic reticulum resident protein 60
Pathophysiology
  • CALR encodes a protein folding molecular chaperone in the cisternae of the endoplasmic reticulum (ER), which assists other proteins during their synthesis (Biochem J 1999;344:281)
  • Calreticulin also acts as a calcium binding protein with a role in cellular calcium regulation
    • Calcium levels in the ER are higher than in the surrounding cytosol; influx or efflux of calcium into the cytosol can trigger various cellular processes (Biochem J 1999;344:281)
  • Mutations in CALR are found in a substantial proportion of myeloproliferative neoplasms when the genes JAK2 and MPL are nonmutated (N Engl J Med 2013;369:2379)
  • Oncogenic CALR mutations all occur in exon 9 and shift the reading frame by 1 base pair, resulting in a neoterminus and presumably a novel function for the protein (N Engl J Med 2013;369:2391)
Diagrams / tables

Images hosted on other servers:

Oncogenic CALR mutations

Frequency of MPL,
JAK2 and CALR
mutations in
myeloid neoplasms

Clinical features
Interpretation
  • Mutant calreticulin protein does not localize to the endoplasmic reticulum as wild type protein does (N Engl J Med 2013;369:2379)
Uses by pathologists
  • Presence of an oncogenic CALR mutation may assist in the diagnosis of myeloproliferative neoplasms
  • CALR mutations without the 1 base pair frameshift or mutations outside of exon 9 should not be used as supportive evidence for the diagnosis of a myeloproliferative neoplasm
Prognostic factors
Microscopic (histologic) images

Contributed by Megan Parilla, M.D.

Essential thrombocythemia bone marrow biopsy

Essential thrombocythemia reticulin stain

Primary myelofibrosis bone marrow biopsy

Primary myelofibrosis reticulin stain

Peripheral smear images

Contributed by Megan Parilla, M.D.

Essential thrombocythemia with CALR type 2 mutation

Primary myelofibrosis with CALR type 1 mutation

Molecular / cytogenetics description
  • The 2 most common CALR mutations are CALR type 1 and CALR type 2
    • CALR type 1 mutations are more frequent in primary myelofibrosis and CALR type 2 mutations are more common in essential thrombocythemia
    • CALR type 1 mutations are 52 base pair deletions (see Molecular / cytogenetics image #1)
    • CALR type 2 mutations are 5 base pair insertions (see Molecular / cytogenetics image #2)
    • Other less common CALR mutations occur in exon 9 and are (3n+1) bp for deletions and (3n+2) bp for insertions, all resulting in a 1 base pair frameshift (see Molecular / cytogenetics image #3)
Molecular / cytogenetics images

Contributed by Megan Parilla, M.D.

CALR type 1 mutation

CALR type 2 mutation

Uncommon 46 base pair deletion in CALR

Example NGS report

Sample pathology report
  • Bone marrow, right posterior iliac crest, biopsy:
    • Hypercellular marrow with increased reticulin fibrosis consistent with involvement by a myeloproliferative neoplasm, favor primary myelofibrosis (see comment)
    • Comment: The aspirate smears are aspicular and consist of an admixture of peripheral blood elements. The bone marrow biopsy is hypercellular for age (~90% cellularity) with an increase in granulocytic elements. Megakaryocytes are increased in number and are found in small aggregates. The megakaryocytes are enlarged with atypical nuclear features. Nuclear streaming and dilated lymphatics are noted. There is no increase in blasts. NGS testing identified a pathogenic CALR mutation consistent with the diagnosis of a myeloproliferative neoplasm.
Board review style question #1


Which of the following CALR mutations supports the diagnosis of a myeloproliferative neoplasm?

  1. 3 base pair insertion mutation in exon 3, CALR c.252_253insAGG / p.F84_S85insR
  2. 30 base pair deletion mutation in exon 9, CALR c.1099_1128del / p.L367_R376del
  3. 52 base pair deletion mutation in exon 9, CALR c.1099_1150del / p.L367Tfs*46
  4. Missense mutation in exon 1, CALR c.50C>G / p. A17G
Board review style answer #1
C. 52 base pair deletion mutation in exon 9, CALR c.1099_1150del / p.L367Tfs*46. This is a common oncogenic mutation seen in myeloproliferative disorders (type 1 CALR mutation). Oncogenic CALR mutations support a diagnosis of a myeloproliferative neoplasm. Answer B is incorrect because an in frame deletion in CALR would not create the oncogenic 1 base pair frameshift seen in myeloproliferative neoplasms. This variant is a variant of uncertain significance and should not be used as evidence of a myeloproliferative neoplasm. Answer D is incorrect because missense alterations in CALR would not create the oncogenic 1 base pair frameshift seen in myeloproliferative neoplasms. Additionally, oncogenic CALR mutations are in exon 9 of the CALR gene. This exon 1 variant is a variant of uncertain significance and should not be used as evidence of a myeloproliferative neoplasm. Answer A is incorrect because an in frame insertion in CALR would not create the oncogenic 1 base pair frameshift seen in myeloproliferative neoplasms. Additionally, oncogenic CALR mutations are in exon 9 of the CALR gene. This exon 3 variant is a variant of uncertain significance and should not be used as evidence of a myeloproliferative neoplasm.

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Reference: CALR
Board review style question #2
Which of the following statements regarding BCR::ABL negative myeloproliferative neoplasms (MPN) is true?

  1. Absence of a JAK2 V617F mutation precludes the diagnosis of a myeloproliferative neoplasm
  2. CALR is a tumor suppressor and thus any frameshift mutation in CALR can be considered oncogenic
  3. CALR is an oncogene and thus only select frameshift mutations resulting in a neoepitope in the carboxyl terminus can be considered oncogenic
  4. MPL mutations are exclusively seen in essential thrombocythemia and CALR mutations are unique to primary myelofibrosis
  5. MPL, CALR or JAK2 mutation is required for the diagnosis of a myeloproliferative neoplasm
Board review style answer #2
C. CALR is an oncogene and thus only select frameshift mutations resulting in a neoepitope in the carboxyl terminus can be considered oncogenic. Frameshift mutations in the last exon of CALR, which result in a 1 bp shift and a neoepitope in the carboxyl terminus, should be considered oncogenic. Answer A is incorrect because MPN can have alternate driver mutations other than JAK2, including CALR and MPL. Additionally, MPN can be driver negative / triple negative with no mutations identified in all 3 genes. Answer D is incorrect because activating mutations in MPL are reported in ~5 - 8% of all patients with myelofibrosis and 1 - 4% of all patients with essential thrombocythemia. Frameshift mutations in exon 9 of CALR are reported in ~20 - 35% of all patients with essential thrombocythemia and myelofibrosis. Answer E is incorrect because JAK2, CALR or MPL mutations can aid in the diagnosis of an MPN but are not required for such a diagnosis. Answer B is incorrect because CALR is not a tumor suppressor and frameshift mutations outside of exon 9 or alterations that do not result in a neoepitope in the carboxyl terminus are not considered oncogenic.

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Reference: CALR
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