# The dual impact of GBA1 in disease: from germline mutations in neurological disorders to alterations in cancer

## TL;DR

This paper explores how mutations or amplifications in the GBA1 gene are linked to both neurological diseases and cancer, suggesting a dual role in disease development.

## Contribution

The paper provides a narrative review and analysis of GBA1's role in cancer, highlighting its potential impact on tumorigenesis and treatment response.

## Key findings

- GBA1 mutations are linked to Gaucher disease and Parkinson’s disease, and may also influence cancer development.
- GBA1 amplification and elevated expression are observed in various cancer types, potentially affecting patient outcomes.
- GBA1 alterations may impact cancer pathogenesis and therapy response through context-dependent mechanisms.

## Abstract

The GBA1 gene encodes the enzyme glucocerebrosidase, which is responsible for lysosomal degradation of the glycosphingolipid glucosylceramide. Biallelic mutations in GBA1 are causative for Gaucher disease, whereas either monoallelic or biallelic mutations are a risk factor for Parkinson’s disease. GBA1 mutations, beside reducing enzymatic activity and leading to substrate accumulation, influence a number of molecular and cellular pathways, including lipid homeostasis, endosome-lysosome pathway, endoplasmic reticulum to Golgi protein trafficking, autophagy and mitophagy. Given the critical role of GBA1 in these key pathways for cellular homeostasis, it can be expected that alterations in this enzyme may influence also cancer development and/or pathology, keeping in mind that Gaucher disease is associated with an increased risk of cancer development. Notably, a large fraction of patients affected by different cancer types carry an amplification of the long arm of chromosome 1, that includes the GBA1 gene. Furthermore, GBA1 expression is elevated in different cancer tissues, compared with healthy counterparts and associated with outcome in some cases. In this perspective, we narratively review the main evidence supporting a role for GBA1 in influencing tumorigenesis and we present our analyses on GBA1 amplification and expression throughout different cancer types. Taken together, these data suggest that the presence of a GBA1 germline mutation or a somatic amplification may influence cancer pathogenesis and/or response to therapies through context-dependent mechanisms that are still to be characterized.