Somatic Hits in Polycystic Liver Diseases

Polycystic Liver Disease (PLD) encompasses a number of disorders with the development of multiple cysts distributed throughout the liver either focally or equally. Hepatic cysts are fluid-filled cavities lined by benign epithelium. PLD is the major phenotype of isolated Polycystic Liver Disease (PCLD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD). The molecular principles in carcinogenesis indicate that there is an accumulation of multiple (somatic) mutations. This concept assumes that presence of a germline mutation (‘first hit’) in an inherited disorder requires a ‘second hit’ at the somatic level for cyst development to occur. The second hit is the rate-limiting step and results in somatic inactivation of the normal allele. Studies have identified secondary, somatic hits in human liver cyst tissues in PCLD and ADPKD. Inactivation of both copies in PLD is demonstrated through somatic mutations or loss of heterozygosity (LOH). The frequency of somatic mutations varies between genes and genomic disorders. Genetic studies detected LOH in 9% and somatic mutations in 8-29% in ADPKD derived hepatic cysts. In PCLD, almost ~80% of hepatic cysts from PRKCSH carriers had completely lost the PRKCSH gene. There is important clinical heterogeneity among PLD patients. Differences in phenotypical expression may be explained by age, gender and environment, but also modifier genes or inactivating somatic events may play key roles. This review will give an overview of the data gained from genetic studies in liver cyst tissues from PCLD and ADPKD patients in relation to the clinical manifestations.