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Constitutional genetic association with CALR mutations?

Leukemia volume 29, pages 2410–2411 (2015)Cite this article

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Myeloproliferative neoplasms (MPN) are driven primarily by somatically acquired mutations in JAK2, CALR or MPL.1 In addition, evidence from epidemiological and family studies indicates that common, low-penetrance genetic variants present in the general population contribute to the risk of developing MPN.2 Some of these variants have been identified, for example, the JAK2 46/1 haplotype is strongly associated with the acquisition of JAK2 mutations3, 4, 5 and also predisposes to JAK2-unmutated disease, along with variation at TERT, MECOM and HBS1L/MYB.6 Furthermore, variation at HBS1L/MYB contributes to MPN phenotype, specifically the A allele of rs9376092 is associated with essential thrombocythemia (ET) as opposed to polycythemia vera in JAK2 V617F-positive MPN, whereas in JAK2 V617F-negative ET and primary myelofibrosis it has a stronger effect in cases with somatic CALR or MPL mutations compared with those that are triple negative.6

All CALR mutations are indels located in the last exon of the gene that generate a +1 frameshift and encode a protein with an aberrant carboxyl terminus.7, 8 The great majority (80–85%) are classed as either type 1 (52 bp deletion) or type 2 (5 bp insertion) and emerging evidence suggests that these subtypes have different biological features9 associated with distinct clinical outcomes.10, 11 Recently it has been suggested that there is a constitutional allelic imbalance at the CALR locus associated with somatic CALR mutations, which may indicate a genetic influence on the probability of acquiring a CALR mutation and/or the probability of such a mutation leading to the development of an MPN.12 Harutyunyan and colleagues analysed 162 CALR-mutated cases that were heterozygous (T/G) for rs1049481, a common SNP located 54 bp downstream of the CALR stop codon. If there was no allelic imbalance, CALR mutations would be expected to be distributed 50:50 between the G and T alleles, but Harutyunyan et al. observed that CALR mutations occurred more frequently on the T allele (100 on the T allele versus 62 on the G allele; P=0.0028). Furthermore, they found that the effect was most pronounced for cases with type 2 CALR mutations (5 bp insertion) but was also discernible for cases with type 1 mutations (52 bp deletion). No difference in rs1049481 genotype was seen for cases with other CALR frameshift mutations and no difference in rs1049481 genotype was seen on comparison of cases and controls, suggesting that the association is much weaker than that between JAK2 V617F and the 46/1 haplotype.

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Acknowledgements

This study was supported by a grant from the Research Plan of the University of Navarra (PIUNA Projects), as well as Leukaemia and Lymphoma Specialist Programme Grant Number 13002. Some of the samples used in this study were gratefully received from the Central England Haemato-oncology and Oncology Research.

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Authors and Affiliations

  1. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK

    L Eder-Azanza, A Chase & N C P Cross

  2. Department of Biochemistry & Genetics, School of Science, University of Navarra, Pamplona, Spain

    L Eder-Azanza & J L Vizmanos

  3. Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital, Leeds, UK

    P Evans

  4. Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

    C Wickham

  5. West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK

    S Akiki

  6. Faculty of Medicine, University of Southampton, Southampton, UK

    A Chase & N C P Cross

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  1. L Eder-Azanza
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Correspondence to N C P Cross.

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Eder-Azanza, L., Evans, P., Wickham, C. et al. Constitutional genetic association with CALR mutations?. Leukemia 29, 2410–2411 (2015). https://doi.org/10.1038/leu.2015.186

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