New Method Identifies Splicing Biomarkers For Liver Cancer

Source: Cold Spring Harbor Laboratory

Summary: Researchers reported that they have developed a method for identifying splicing-based biomarkers for the most common form of liver cancer, hepatocellular carcinoma (HCC).

Hepatocellular carcinoma (HCC) is a liver cancer with symptoms including jaundice, weight loss, stomach pain, vomiting and yellowed skin. Because liver cancer is particularly diverse, genetically, and prone to relapse, identifying biomarkers that can predict disease progression is a critical goal in the fight against it. Researchers from the Cold Spring Harbor Laboratory reported that they have developed a method for identifying splicing-based biomarkers for the liver cancer, hepatocellular carcinoma. Splicing refers to a process in which an RNA message copied from information encoded in a gene is edited before it is able to serve as a blueprint for the manufacture of a specific protein. Many diseases have been associated with errors or variations in the way that RNA is spliced. Errors or variations in splicing can lead to non-functional proteins or proteins with distinct or aberrant functions. The study findings were published in the journal Genome Research.

Hepatocellular carcinoma

Different versions, or isoforms, of messenger RNAs generated by the human AFMID gene, are represented, showing their relative prevalence in cancerous (top) and non-cancerous tissue (bottom), sampled from throughout the body. Black peaks, representing the normal variant found in adult cells, are much lower in cancerous tissue than in normal tissue. The reverse is true of variants color-coded orange and red, which serve as biomarkers in liver cancer. Credit: Krainer Lab, CSHL

A gene can give rise to multiple RNA messages, each resulting in a different protein variant, or “isoform.” The team developed a method that comprehensively analyzes all RNA messages made from a given gene and tested their splicing-variant detection method in HCC, by analyzing RNA messages in HCC cells sampled from hundreds of patients. They found that particular splicing isoforms of the gene AFMID correlated with very poor patient survival. These variants lead cells to manufacture truncated versions of the AFMID protein. These unusual versions of the protein are associated in adult liver cancer cells with mutations in tumor-suppressor genes called TP53 and ARID1A. Fixing AFMID splicing could lead to enhanced production of NAD+ and an increase in DNA repair. They demonstrated that coaxing cells to over-express AFMID spliced in the normal manner led to higher NAD+ levels and slower growth of liver cancer cells.

Prof. Adrian Krainer said, “This study underscores the potential for learning how RNA splicing variants can contribute to cancer and points to these variants as potential biomarkers for cancer progression.”

More Information: Kuan-Ting Lin et al, “A human-specific switch of alternatively spliced AFMID isoforms contributes to TP53 mutations and tumor recurrence in hepatocellular carcinoma”, Genome Research (2017). DOI: 10.1101/169029

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