Prevalence, distribution and predictive value of <i>XPO1</i> mutation in a real‐life chronic lymphocytic leukaemia cohort

Tueur, Giulia; Lazarian, Grégory; Éclache, Virginie; Fleury, Carole; Letestu, Rémi; Lévy, Vincent; Lefebvre, Valérie; Collon, Jean-François; Zini, Jean‐Marc; Thiéblemont, Catherine; Soussi, Thierry; Cymbalista, Florence; Baran‐Marszak, Fanny

doi:10.1111/bjh.17046

Cited by 2 publications

(2 citation statements)

References 18 publications

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“…Among these genes JAK2 , RUNX1 , and ASXL1 primarily preceded myeloid malignancies (20 out of 26 total cases), XPO1 and KMT2D exclusively preceded lymphoid malignancies (7 out of 7 total cases), and TP53 and TET2 preceded disease from both lineages relatively equally (17 total myeloid and 25 total lymphoid cases), consistent with what is known about the pathobiology associated with these variants. 29 , 30 , 31 , 32 , 33 Mutations in SUZ12 and ERBB4 are less well described in the context of CH and warrant further study. Notably, DNMT3A and PPM1D were not associated with increased rate of hematologic malignancy despite being highly prevalent.…”

Section: Resultsmentioning

confidence: 95%

High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer

Stonestrom,

Menghrajani,

Devlin

et al. 2024

Blood Advances

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Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) >= 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy we analyzed data from 42,714 patients who underwent blood sequencing as a normal comparator for non-hematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and non-coding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset while DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of non-hematologic cancer.

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Section: Resultsmentioning

confidence: 95%

High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer

Stonestrom,

Menghrajani,

Devlin

et al. 2024

Blood Advances

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“…indicated the involvement of aberrant expression of FBXW7 for tumorigenesis [29]. An XPO1 mutation is a driving event in B cell malignancies through alteration of the nuclear trafficking of proteins involved in inflammatory signalling, DNA repair, RNA export and chromatin remodelling pathways [30]. Thus these three gene mutations may each be involved in CLL pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial

et al. 2021

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Causes of death, in particular deaths due to infection, have not been widely studied in randomised trials in chronic lymphocytic leukaemia. With long-term follow-up (median 13 years) we examined the cause of death in 600/777 patients in the LRF CLL4 trial. Blood samples, taken at randomisation from 499 patients, were available for identifying gene mutations. Infection was a cause of death in 258 patients (43%). Patients dying of infection were more likely than those who died of other causes to have received ≥2 lines of treatment (194/258 [75%] versus 231/342 [68%], P = 0.04) and to have died in the winter months (149/258 [58%] versus 166/342 [49%], P = 0.03), respectively. In patients with mutation data, the factors significantly associated with death from infection versus all other deaths were 11q deletion (47/162 [29%] versus 40/209 [19%], P = 0.03) and mutations of the BRAF, FBXW7, NRAS and XPO1 genes. Death was caused by an infection in 46/67 assessable patients (69%) who had a mutation of one or more of these four genes versus only 129/333 patients (39%) without any of these mutations (odds ratio: 3.46 [95% CI 1.98–6.07] P < 0.0001). Careful management of infection risk, including prophylaxis against infection, may be important in patients who carry these mutations.

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Prevalence, distribution and predictive value of XPO1 mutation in a real‐life chronic lymphocytic leukaemia cohort

Cited by 2 publications

References 18 publications

High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer

High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer

The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial

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