Expanding spectrum of the association between Type 1 Gaucher disease and cancers: A series of patients with up to 3 sequential cancers of multiple types—Correlation with genotype and phenotype

Abstract

In Gaucher disease (GD), inherited deficiency of lysosomal glucocerebrosidase due to mutations in GBA1 gene results in accumulation of glucosylceramide in tissue macrophages, systemic macrophage activation, and a complex multisystemic phenotype. We and others have reported an increased risk of multiple myeloma and other malignancies in non-neuronopathic Type 1 GD (GD1). Here, we describe a subset of GD1 patients with multiple malignancies. In our cohort of 403 patients with GD1, nine patients (2.2%) developed two or three different types of cancers either consecutively or simultaneously. Patients were characterized by age at diagnosis of GD1, GBA1 genotype, disease severity, age at cancer diagnosis, enzyme replacement therapy (ERT) status, and splenectomy status. Of the nine patients, six developed two types of malignancies and three had three cancers each. Overall, the hematologic malignancies comprised lymphoma/leukemia (4) and multiple myeloma (4). Nonhematologic malignancies included colon (2), lung (2), thyroid (2), and prostate cancer (1). Of the seven patients who received ERT, the first cancer was diagnosed before initiation of ERT in all but one. Asplenic patients were more likely to have single or multiple cancers compared with patients with intact spleens (P < 0.0072 and P < 0.0203, respectively). Our data strengthen the association of GD1 and cancer and suggest that patients may be at risk of developing multiple malignancies. We found an association between splenectomy and multiple cancers in GD1. It will be of interest to determine whether timely ERT and declining rates of splenectomy will translate into declining rates of multiple and single cancers. Am. J. Hematol. 85:340-345, 2010. V

Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

“…Stem cell transplantation cured her lymphoma (as well as her GD); nevertheless, on a background of DNA instability, she is now at greater risk for second cancers, including CNS-and LS-associated malignancies, because of alkylating agents and total body irradiation administered during her treatment and conditioning regimens. It should be noted that GD patients are at higher risk of developing multiple malignancies 12 and therefore the above considerations may be of general applicability to patients exhibiting a GD/cancer phenotype. Finally, the parents in this pedigree are obligate carriers of heterozygous MMR mutations and therefore have the genotype for LS.…”

“…4,5 Phenotype diversity manifests as variations in the overall severity of the disease, as well as in the pattern of organ involvement (eg, visceral/hematologic vs skeletal vs pulmonary involvement). 2,[6][7][8] Another category of phenotype variation in GD1 is exemplified by the occurrence of unusual manifestations such as Parkinson disease, 9 pulmonary hypertension, 10 and cancers, [11][12][13][14][15][16] which, despite their potentially life-threatening nature, appear to show imperfect correlation with the overall severity of the classic manifestations. 11,12 These observations are consistent with the notion that modifier genes may underlie these phenotypes.…”

“…[11][12][13][14][15][16] However, the pathophysiologic basis of increased cancer risk is not known. Several mechanisms have been proposed to be involved in the pathogenesis of malignancy in GD1, including alternatively activated macrophages, 17 immune dysregulation, [18][19][20] splenectomy, 12 hyperferritinemia, 21 lysosomal dysfunction, and endoplasmic reticulum stress. 22 Moreover, in vitro studies have suggested that the cellular accumulation of glucocerebroside itself is conducive to cancer progression.…”

Splenomegaly, hypersplenism, and hereditary disorders with splenomegaly

“…Subject to any other inborn or acquired risk factors, such individuals should have normal life expectancy although they presumably at share the increased risk for Parkinsonism that is now known to be associated with even a single Gaucher GBA mutation [113]. Because most such individuals are unidentified, save for sporadic cases that are increasingly coming to light because of genetic screening programs and greater attention to family histories, it is currently unknown whether they, like symptomatic patients with GD1, also have an enhanced risk for developing MGUS, myeloma, other hematological malignancies and possibly other cancers [114][115][116][117]. Nevertheless, there is a general consensus that such minimally affected individuals, when discovered, do not require definitive treatment for GD1 but nonetheless, should have regular annual to biannual comprehensive evaluations.…”

Successful autologous stem cell transplantation in Gaucher disease patient with multiple myeloma

“…This case also suggests that prognosis of MM may not be worse for patients with GD, as regards to the evolution of MM or GD following usual treatments, including HSCT. However, it seems to remain a risk of recurrent malignancies justifying a close monitoring of these patients [12].…”