Biology subjects

Koh, Y.

Publications and source records attributed to Koh, Y..

3 recordsLinked to original sources

bioRxiv2018

Oncogenic effects of germline mutations in lysosomal storage disease genes

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.

genetics↗

bioRxiv2018

Immuno-genomic PanCancer Landscape Reveals Diverse Immune Escape Mechanisms and Immuno-Editing Histories

Immune reactions in the tumor micro-environment are one of the cancer hallmarks and emerging immune therapies have been proven effective in many types of cancer. To investigate cancer genome-immune interactions and the role of immuno-editing or immune escape mechanisms in cancer development, we analyzed 2,834 whole genomes and RNA-seq datasets across 31 distinct tumor types from the PanCancer Analysis of Whole Genomes (PCAWG) project with respect to key immuno-genomic aspects. We show that selective copy number changes in immune-related genes could contribute to immune escape. Furthermore, we developed an index of the immuno-editing history of each tumor sample based on the information of mutations in exonic regions and pseudogenes. Our immuno-genomic analyses of pan-cancer analyses have the potential to identify a subset of tumors with immunogenicity and diverse background or intrinsic pathways associated with their immune status and immuno-editing history.

genomics↗

bioRxiv2017

LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells

Melanoma cells steer out of tumours using self-generated lysophosphatidic acid (LPA) gradients. The cells break down LPA, which is present at high levels around the tumours, creating a dynamic gradient that is low in the tumour and high outside. They then also migrate up this gradient, creating a complex and evolving outward chemotactic stimulus. Here we introduce a new assay for self-generated chemotaxis, and show that raising LPA levels causes a delay in migration rather than loss of chemotactic efficiency. Knockdown of the lipid phosphatase LPP3 - but not its homologues LPP1 or LPP2 - diminishes the cells ability to break down LPA. This is specific for chemotactically active LPAs, such as the 18:1 and 20:4 species. Inhibition of autotaxin-mediated LPA production does not diminish outward chemotaxis, but loss of LPP3-mediated LPA breakdown blocks it. Similarly, in both 2D and 3D invasion assays, knockdown of LPP3 diminishes melanoma cells ability to invade. Our results demonstrate that LPP3 is the key enzyme in melanoma cells breakdown of LPA, and confirm the importance of attractant breakdown in LPAmediated cell steering.

cancer biology↗