Myeloproliferative Neoplasms in Danish Twins

Andersen, Michael Asger; Bjerrum, Ole Weis; Ranjan, Ajenthen; Skov, Vibe; Kruse, Torben A.; Thomassen, Mads; Skytthe, Axel; Hasselbalch, Hans Carl; Christensen, Kaare

doi:10.1159/000488384

Cited by 9 publications

(4 citation statements)

References 18 publications

(20 reference statements)

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“…Twin studies from the Scandinavia have shown an increased familial risk of cancer, and in chronic myeloid neoplasms, Andersen et al 16 demonstrated a casewise concordance (cc) rate of 15% among monozygotic (MZ) twins compared to 0% among dizygotic (DZ) twins p = 0.016, suggesting a genetic predisposition. In addition, it has been known for decades that some germline aberrancies predispose to hematological cancer such as AML and MDS.…”

Section: Introductionmentioning

confidence: 99%

Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality

Hansen

Pedersen

Larsen

et al. 2020

Blood

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Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is defined by mutations in myeloid cancer–associated genes with a variant allele frequency of at least 2%. Recent studies have suggested a possible genetic predisposition to CH. To further explore this phenomenon, we conducted a population-based study of 594 twins from 299 pairs aged 73 to 94 years, all with >20 years’ follow-up. We sequenced DNA from peripheral blood with a customized 21-gene panel at a median coverage of 6179X. The casewise concordance rates for mutations were calculated to assess genetic predisposition. Mutations were identified in 214 (36%) of the twins. Whereas 20 twin pairs had mutations within the same genes, the exact same mutation was only observed in 2 twin pairs. No significant difference in casewise concordance between monozygotic and dizygotic twins was found for any specific gene, subgroup, or CHIP mutations overall, and no significant heritability could be detected. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the association of having CH when controlling for familial factors. A total of 127 twin pairs were discordant for carrying a mutation, and in 61 (48%) cases, the affected twin died first (P = .72). Overall, we did not find a genetic predisposition to CHIP mutations in this twin study. The previously described negative association of CHIP mutations on survival could not be confirmed in a direct comparison among twin pairs that were discordant for CHIP mutations.

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Section: Introductionmentioning

confidence: 99%

Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality

Hansen

Pedersen

Larsen

et al. 2020

Blood

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“…A Danish cohort study previously reported concordance for MPN in 15% of monozygotic twins; 29 although the authors concluded that this might reflect genetic predisposition to MPN, it may be that these cases were due to an in utero origin and transplacental transmission, as concordant cases were not observed in dizygotic twins. Furthermore, concordance of clonal hematopoiesis with identical somatic mutations in elderly twins has also been reported, suggesting that clones that arise in utero might even persist lifelong until old age without causing disease 30 , 31 .…”

Section: Discussionmentioning

confidence: 95%

In utero origin of myelofibrosis presenting in adult monozygotic twins

Sousos

Leathlobhair

Karali

et al. 2022

Nat Med

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The latency between acquisition of an initiating somatic driver mutation by a single-cell and clinical presentation with cancer is largely unknown. We describe a remarkable case of monozygotic twins presenting with CALR mutation-positive myeloproliferative neoplasms (MPNs) (aged 37 and 38 years), with a clinical phenotype of primary myelofibrosis. The CALR mutation was absent in T cells and dermal fibroblasts, confirming somatic acquisition. Whole-genome sequencing lineage tracing revealed a common clonal origin of the CALR-mutant MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. Index sorting and single-colony genotyping revealed phenotypic hematopoietic stem cells (HSCs) as the likely MPN-propagating cell. Furthermore, neonatal blood spot analysis confirmed in utero origin of the JAK2V617F mutation in a patient presenting with polycythemia vera (aged 34 years). These findings provide a unique window into the prolonged evolutionary dynamics of MPNs and fitness advantage exerted by MPN-associated driver mutations in HSCs.

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“…The role of genetic predisposition and landscape in the development of MPN have been quite extensively elucidated [13]. The discovery of driver genes JAK2, CALR, and MPL is an important milestone in unrevealing the myths of MPN, hence the World Health Organization has included mutations in all three genes as the hallmark of MPN [1].…”

Section: Hypercellularity With Clusteredmentioning

confidence: 99%

Molecular Genetics of Thrombotic Myeloproliferative Neoplasms: Implications in Precision Oncology

et al. 2023

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Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis. Unlike monogenic disorders, a more complicated series of genetic mutations are believed to be responsible for MPN with various degrees of thromboembolic and bleeding complications. Thrombosis is one of the early manifestations in patients with MPN. To date, the driver genes responsible for MPN include JAK2, CALR, MPL, TET2, ASXL1, and MTHFR. Affords have been done to elucidate these mutations and the incidence of thromboembolic events. Several lines of evidence indicate that mutations in JAK2, MPL, TET2 and ASXL1 gene and polymorphisms in several clotting factors (GPIa, GPIIa, and GPIIIa) are associated with the occurrence and prevalence of thrombosis in MPN patients. Some polymorphisms within XRCC1, FBG, F2, F5, F7, F12, MMP9, HPA5, MTHFR, SDF-1, FAS, FASL, TERT, ACE, and TLR4 genes may also play a role in MPN manifestation. This review aims to provide an insightful overview on the genetic perspective of thrombotic complications in patients with MPN.

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Myeloproliferative Neoplasms in Danish Twins

Cited by 9 publications

References 18 publications

Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality

Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality

In utero origin of myelofibrosis presenting in adult monozygotic twins

Molecular Genetics of Thrombotic Myeloproliferative Neoplasms: Implications in Precision Oncology

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