Oncogenic effects of germline mutations in lysosomal storage disease genes

Abstract

Clinical observations have indicated that patients with Gaucher disease or Fabry disease are at increased risk of cancer. However, a systematic evaluation of the oncogenic effects of causal mutations of lysosomal storage diseases (LSDs) has been lacking. Here we report a comprehensive association analysis between potentially pathogenic germline mutations in LSD genes and cancer interrogating genomic (or exomic) variant datasets derived from the Pan-Cancer Analysis of Whole Genomes project (case cohort), the 1000 Genomes project (primary control cohort), and the Exome Aggregation Consortium that does not include The Cancer Genome Atlas subset (validation control cohort). We show that potentially pathogenic variants (PPVs) in 42 LSD genes are significantly enriched in cancer patients in a histology-dependent manner, cancer risk is higher in individuals with a greater number of PPVs, and cancer develops earlier in PPV carriers. Analysis of tumor genomic and transcriptomic data from the pancreatic adenocarcinoma cohort revealed potential mechanisms that might be involved in the oncogenic contribution of PPVs. Our findings extend the mechanistic understanding of inherited cancer susceptibility and highlight the promise of harnessing available therapeutic strategies to restore lysosomal function for personalized cancer prevention.