Together, we anticipate that full coverage sequencing (coding and noncoding sequences) of all known components of the telomerase enzyme complex and the shelterin complex of telomere-binding proteins will reveal an increasing percentage of telomere-related mutations in human cirrhosis. It remains

to be analyzed whether TERT mutations influence the development of HCC. Cirrhosis represents one of the main risk factors for HCC formation. There is ample evidence that telomere shortening increases the risk of cancer formation in humans by inducing chromosomal instability. Therefore, TERT mutations that increase the risk of cirrhosis formation may increase the risk of HCC. In contrast, tumor cells need to activate telomere maintenance mechanisms in order to gain immortal growth capacity—a prerequisite for tumor formation. Thus, it is possible that TERT mutations could also protect individuals from cancer ALK mutation formation.

In the current cohort, 5/14 (36%) cirrhosis patients with telomerase mutations (including one patient with a homozygous p.G1109R TERT mutation) developed HCC, indicating that telomerase mutations did not prevent cancer formation. Together, the current findings represent the first evidence for telomerase mutations in cirrhosis induced see more by chronic liver disease. The results indicate that telomerase mutations represent confounding factors increasing the risk of cirrhosis formation in the context of chronic liver disease. The study results improve our understanding on the molecular causes of cirrhosis. These findings will influence the future development MCE of molecular therapies for cirrhosis patients and may also have an impact on future surveillance programs and decision making in treatment of patients with chronic liver disease and cirrhosis. Additional Supporting Information may be found in the online version of this article. “
“Sodium valproate (VPA) is widely used throughout the world to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy.

VPA toxicity is an uncommon but potentially fatal cause of idiosyncratic liver injury. Rare mutations in POLG, which codes for the mitochondrial DNA polymerase γ (polγ), cause Alpers-Huttenlocher syndrome (AHS). AHS is a neurometabolic disorder associated with an increased risk of developing fatal VPA hepatotoxicity. We therefore set out to determine whether common genetic variants in POLG explain why some otherwise healthy individuals develop VPA hepatotoxicity. We carried out a prospective study of subjects enrolled in the Drug Induced Liver Injury Network (DILIN) from 2004 to 2008 through five US centers. POLG was sequenced and the functional consequences of VPA and novel POLG variants were evaluated in primary human cell lines and the yeast model system Saccharomyces cerevisiae.