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Crit Rev Oncog. 2013;18(3):235-46.

Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism.

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Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06520-8064, USA.


Clinical observations spanning almost half a century have demonstrated a consistent association of type 1 Gaucher disease (GD1) and cancers. However, the cellular and molecular bases of the association are not understood. Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency of acid β-glucosidase that underlies the accumulation of glucosylceramide in lysosomes of mononuclear phagocytes and immune dysregulation. The overall cancer risk is markedly increased in GD, and the determinants of malignancy in a subset of patients with GD1 are not known. The association of GD and cancer is most striking for hematological malignancies, with the risk for multiple myeloma estimated at almost 37-fold compared to the general population; some studies have also suggested increased cancer risk for non-hematological malignancies. There is no association of overall severity of GD to risk of cancer, although there is an increased prevalence of splenectomy among patients exhibiting the GD/cancer phenotype. Moreover, there appears to be an increased incidence of multiple consecutive cancers in individual patients. Several factors could contribute to cancer development in GD, including polarization of macrophages to the alternatively activated phenotype, chronic inflammation, chronic B-cell stimulation, splenectomy, hyperferritinemia, lysosomal dysfunction, and endoplasmic reticulum stress. Recent studies have highlighted T-cell dysfunction and modifier genes contributing to an increased cancer risk in GD. Macrophage-targeted enzyme replacement therapy (ERT) reverses systemic features of GD1; while cancer risk appears to be reduced in the era of ERT, it is not known whether this is a direct effect of therapy. Delineation of the mechanisms underlying the increased cancer risk in GD will provide additional novel insights into the role of lipids and macrophages in cancer pathogenesis and, moreover, have the potential to reveal novel therapeutic targets.

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