Oncogenic potential of germline mutations in lysosomal storage disease-associated genes

Lysosomal storage disease;germline mutations;rare variant;cancer;association;transcriptome;gene expression;610

의과대학 의학과 ;

University:서울대학교 대학원

关键词: Lysosomal storage disease;    germline mutations;    rare variant;    cancer;    association;    transcriptome;    gene expression;    610;   

Others  :  http://s-space.snu.ac.kr/bitstream/10371/142344/1/000000149982.pdf

美国|英语

来源: Seoul National University Open Repository

【 摘 要 】

Introduction: Lysosomal storage diseases (LSDs) comprise inborn metabolic disorders caused by mutations in genes related to lysosomal function. As already observed in certain LSDs, the accumulation of macromolecules caused by LSDs may facilitate carcinogenesis. Methods: Using whole genome sequence data from the International Cancer Genome Consortium (ICGC) PanCancer Analysis of Whole Genomes (PCAWG) and the 1000 Genomes projects, we analyzed the relationship between potentially pathogenic variants (PPVs) in 42 LSD genes and cancer. We evaluated age of cancer onset and patterns of somatic mutation and gene expression according to PPV carrier status (wild type versus mutant).Results: PPV prevalence in the ICGC-PCAWG cohort was significantly higher than that of the 1000 Genomes cohort (20.7% versus 13.5%, P=8.7×10-12). Cancer risk was increased in individuals with a greater number of PPVs. Population structure-adjusted SKAT-O analysis revealed 37 significantly associated cancer type-LSD gene pairs. These results were validated using ExAC cohort as a control population. Cancer developed earlier in carriers of PPVs in LSD genes in pancreatic adenocarcinoma (MAN2B1, GALNS, and GUSB), skin cancer (NPC2), and chronic myeloid disorder (SGSH). Analysis of transcriptome data from the pancreatic cancer project revealed 508 genes that were differentially expressed according to PPV carrier status, which were highly relevant for pancreatic cancer-related signaling pathways.Conclusion: Carriers of germline PPVs in LSD-related genes have an increased incidence of cancer. The available therapeutic options to restore lysosomal function suggest the potential of personalized cancer prevention for these patients.