Friday, March 2, 2018

Developing new biomarkers for liver cancer with RNA splicing techniques

Researchers at Cold Spring Harbor Laboratory (CSHL), led by Professor Adrian Krainer, have developed a method for identifying splicing-based biomarkers for hepatocellular carcinoma (HCC). They have published their findings in journal Genome Research.

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
"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," Krainer says.

Splicing refers to a process in which an RNA message copied from information encoded in a gene is edited before it can serve as a blueprint for the manufacture of a specific protein. A gene can give rise to multiple RNA messages, each resulting in a different protein variant, or "isoform." Variation and errors in RNA splicing cause the production of nonfunctional proteins or proteins with aberrant function, and it is associated with many diseases.

Recent studies have identified splicing irregularities in liver cancer cells. Led by Cold Spring Harbor Laboratory postdoctoral researcher Kuan-Ting Lin, Krainer's team developed a method that comprehensively analyzes all RNA messages made from a given gene. The team tested their splicing-variant detection method in HCC, by examining RNA messages in hepatocellular carcinoma cells sampled from hundreds of patients.

Researchers found that specific splicing isoforms of gene AFMID is associated poor survival.  These variant isoforms lead cells to manufacture truncated versions of the AFMID protein. These unusual versions of the protein are associated with adult liver cancer cells with mutations in tumor-suppressor genes called TP53 and ARID1A.

Researchers hypothesize that these mutations are associated with low levels of a molecule called NAD+ that is involved in repairing damaged DNA. Restoring missing portions, called exons, to AFMID's usual RNA message, they propose, might raise NAD+ to normal levels, avoiding mutations in TP53 and ARID1A. The team hopes to use small molecules called antisense oligonucleotides (ASOs) that can bind to RNA, to change the way AFMID's RNA messages are spliced. Krainer's team previously used this technique to correct errors in the splicing of the gene SMN2 as a way to treat spinal muscular atrophy (SMA).

Citation: Lin, Kuan-Ting, Wai Kit Ma, Juergen Scharner, Yun-Ru Liu, and Adrian R. Krainer. "A human-specific switch of alternatively splicedAFMIDisoforms contributes toTP53mutations and tumor recurrence in hepatocellular carcinoma." Genome Research 28, no. 3 (2018): 275-84. doi:10.1101/gr.227181.117.

Research funding: National Institutes of Health

Adapted from press release by Cold Spring Harbor Laboratory (CSHL).
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