Increased incidence of cancer in adult Gaucher disease in Western Europe

Fost, Maaike de; Dahl, Stephan Vom; Weverling, Gerrit Jan; Brill, Nicole; Brett, Sarah; Häussinger, Dieter; Hollak, Carla E. M.

doi:10.1016/j.bcmd.2005.08.004

Cited by 162 publications

(174 citation statements)

References 33 publications

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“…However, several clinical manifestations, such as gammopathies (15,16), predisposition to infections (10,11), and lymphoid malignancies (15)(16)(17)(18), suggest a more diverse dysregulation of the immune system, surely beyond the macrophage. Notably, we have shown that the immune cell composition of the thymus is significantly altered in GBA KO mice (3).…”

Section: Discussionmentioning

confidence: 99%

“…The involvement of immune cells has been implicated, but the underlying molecular defect is poorly understood (6)(7)(8)(9). For example, GD has been associated with impaired host-defense against microbial infections (10,11), up-regulation of T-helper (Th)1 and Th2 cytokines (6,12,13), dysfunction of monocytes (14), and an increased risk for lymphoid malignancies, most strikingly for multiple myeloma (15)(16)(17)(18).…”

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confidence: 99%

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Gaucher disease geneGBAfunctions in immune regulation

Liu

Halene

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Inherited deficiency of acid β-glucosidase (GCase) due to biallelic mutations in the GBA (glucosidase, β, acid) gene causes the classic manifestations of Gaucher disease (GD) involving the viscera, the skeleton, and the lungs. Clinical observations point to immune defects in GD beyond the accumulation of activated macrophages engorged with lysosomal glucosylceramide. Here, we show a plethora of immune cell aberrations in mice in which the GBA gene is deleted conditionally in hematopoietic stem cells (HSCs). The thymus exhibited the earliest and most striking alterations reminiscent of impaired T-cell maturation, aberrant B-cell recruitment, enhanced antigen presentation, and impaired egress of mature thymocytes. These changes correlated strongly with disease severity. In contrast to the profound defects in the thymus, there were only limited cellular defects in peripheral lymphoid organs, mainly restricted to mice with severe disease. The cellular changes in GCase deficiency were accompanied by elevated T-helper (Th)1 and Th2 cytokines that also tracked with disease severity. Finally, the proliferation of GCase-deficient HSCs was inhibited significantly by both GL1 and Lyso-GL1, suggesting that the “supply” of early thymic progenitors from bone marrow may, in fact, be reduced in GBA deficiency. The results not only point to a fundamental role for GBA in immune regulation but also suggest that GBA mutations in GD may cause widespread immune dysregulation through the accumulation of substrates.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Gaucher disease geneGBAfunctions in immune regulation

Liu

Halene

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The benefit of reversing symptomatic hepatomegaly and splenomegaly also seems evident. Failure to treat persistent, asymptomatic hepatomegaly may result in hepatic fibrosis, cirrhosis, and portal hypertension [26], and persistent, asymptomatic splenomegaly can leave a reservoir of Gaucher cells that eventually provokes immunoproliferative disorders [27][28][29]. An improved platelet count may also be an important outcome measure, as severe thrombocytopenia correlates with bleeding tendency and the risk of spontaneous, post-traumatic, surgical or obstetrical bleeding [30], particularly in conjunction with qualitative platelet defects or coagulation factor abnormalities that occur concurrently in some patients with GD1 [31,32].…”

Section: Discussionmentioning

confidence: 99%

A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase

Weinreb¹,

Taylor²,

Cox

et al. 2008

American J Hematol

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To assess the extent to which patients with type 1 Gaucher disease (GD1) receiving individualized enzyme replacement therapy with imiglucerase attain six defined therapeutic goals. One hundred and ninety-five GD1 patients enrolled in the ICGG Gaucher Registry, all of whom had data available for hemoglobin, platelet count, liver volume, spleen volume, bone pain, and bone crises at first infusion and after 4 years of therapy with imiglucerase, were evaluated for achievement of published therapeutic goals. The proportion of patients who met all six therapeutic goals increased from 2.1% at first infusion to 41.5% at 4 years; ‡5 goals from 12.8% to 76.9%; ‡4 goals from 37.4% to 92.8%; ‡3 goals from 70.8% to 99.0%; and ‡2 goals from 95.4% to 99.5%. All patients met at least one goal at first infusion and after 4 years of treatment. The proportion of patients meeting specific therapeutic goals increased for all parameters between first infusion and 4 years of therapy: platelet count (24.6%-79.5%), spleen volume (25.6%-78.5%), liver volume (45.6%-90.8%), bone pain (62.6-70.3%), hemoglobin (68.2-91.8%), and bone crises (91.8-99.0%). On average, patients who received higher doses of imiglucerase achieved a greater number of therapeutic goals. This analysis provides a benchmark for evaluating the utility of a disease management approach for GD1 based on monitoring achievement of therapeutic goals after treatment with imiglucerase. Am. J. Hematol. 83:890-895, 2008. V

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“…45 A single-centre cohort study of 131 patients with Gaucher disease of mixed ancestry in Western Europe investigated cancer incidence and mortality compared with controls. 46 A 2.5-fold (95 % confidence interval [CI] 1.1-4.7) increased incidence of cancer was reported and a 12.7-fold (95 % CI 2.6-37.0) increased risk of haematological cancers.…”

Section: Gaucher Disease and Haematological Malignanciesmentioning

confidence: 99%

A Rare Condition in Haematological Practice – Gaucher Disease

Cappellini

2015

European Oncology &Amp; Haematology

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Gaucher disease, which is caused by an inherited glucocerebrosidase deficiency, is the most prevalent lysosomal storage disease worldwide. Estimated prevalence of Gaucher disease is 1:50,000 in most countries and the disease has its highest incidence in the Ashkenazi Jewish population. Type 1 (non-neuropathic) Gaucher disease is by far the most common form. Gaucher disease type 1 should be considered in cases of unexplained splenomegaly with or without bleeding diathesis, skeletal manifestations or hepatomegaly. Diagnosis is made by demonstrating decreased glucocerebrosidase activity in peripheral blood leucocytes. Dried blood spots can be used for screening but conventional enzyme assay on heparinised blood is essential. Patients with Gaucher disease may have extensive organ involvement despite relatively minor overt symptomatology. Evidence suggests that Gaucher disease may remain undiagnosed for years, leading to severe complications that are preventable or reversible with enzyme replacement therapy. These complications include avascular necrosis, severe bleeding, chronic bone pain, pathological fractures, growth failure, liver pathology and life-threatening sepsis. Most patients with Gaucher disease are initially evaluated by a haematologist–oncologist. Improved education is needed to enable prompt detection of Gaucher disease. An increased risk of multiple myeloma and haematological and non-haematological malignancies has been reported in type 1 Gaucher disease. This review aims to offer familiarisation with a rare disorder in haematological practice, focusing on adult patient management.

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Increased incidence of cancer in adult Gaucher disease in Western Europe

Cited by 162 publications

References 33 publications

Gaucher disease geneGBAfunctions in immune regulation

Gaucher disease geneGBAfunctions in immune regulation

A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase

A Rare Condition in Haematological Practice – Gaucher Disease

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