Cancer risk and gammopathies in 2123 adults with Gaucher disease type 1 in the International Gaucher Group Gaucher Registry

Abstract

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single‐center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non‐Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age‐specific incidence rates of MGUS were unexpectedly high among younger patients. The 10‐year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology.

Gaucher disease prevalence in 600 patients affected by monoclonal gammopathy of undetermined significance

“…Patients with GD had a four times higher risk of developing hematological malignancies than the general population, with MM onset being approximately nine times higher. Furthermore, the incidence of MGUS was higher among younger patients, although this did not lead to the more rapid development of MM after 10 years compared to the general population 16 …”

“…Furthermore, the incidence of MGUS was higher among younger patients, although this did not lead to the more rapid development of MM after 10 years compared to the general population. 16 The increased risk of malignancies, particularly MM, might be explained by the direct oncogenic effect of the accumulated glycosphingolipids and the immune dysregulation in the bone marrow microenvironment. Gaucher cells secrete chemokines and cytokines (such as IL-6) that can create an inflammatory environment, thus triggering first B-lymphocyte polyclonal immunoglobulin secretion and, finally, clonal evolution of plasma cells leading to MGUS and eventually MM.…”

“…The prevalence of polyclonal gammopathies and monoclonal gammopathy ranged from 25% to 91% and from 0% to 35%, respectively (Table 1). [6][7][8][9][10][11][12][13][14][15][16][17][18] Interestingly. In contrast, some patients were severely affected with massive hepatosplenomegaly, lung involvement, and avascular necrosis of the hip joint, in others, both polyclonal and monoclonal gammopathy were frequently associated with patients older than 50 years with only a mild clinical presentation of Gaucher disease.…”

A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach

“…Apart from its primary manifestations, GD is associated with the increased risk and incidence of other health issues. These conditions include PD 86 , 87 , bone complications 46 , 60 , blood disorders 88 , and multiple myeloma 89 . Additionally, individuals with GD may experience increased susceptibility to infections and cancer.…”

“…Noteworthily, gammopathies which imply conditions with abnormal antibodies in the blood are also associated with GD 88 . Multiple myeloma is associated with the wide occurrence of monoclonal gammopathy of undetermined significance (MGUS) which is a condition characterized by the presence of monoclonal gammopathy with uncertain implications 109 .…”