Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma （HCC）. Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway （BN） rats. Unrestrained extracellular signal-regulated kinase （ERK） activity linked to proteasomal degradation of dual-specificity phosphatase 1 （DUSP1）, a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-KB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-α transgenic mice. iNOS, IKK/NF-κB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.

Advances in clinical genetics and genomics

Developments in genetics and genomics are progressing at an unprecedented speed.Twenty years ago,the human genome project provided the first glimpses into the human genome sequence and launched a new era of human genetics.The emerging of next-generation sequencing(NGS)in 2005 then made possible comprehensive genetic testing such as exome sequencing and genome sequencing.Meanwhile,great efforts have been put into the optimization of bioinformatic pipelines to make increasingly speedy and accurate variant analyses based on NGS data.These advances in sequencing technologies and analytical methods have revolutionized the diagnostic odyssey of suspected hereditary diseases.More recently,the genotype-phenotype relationship and polygenic risk scores(PRSs)generated from genome-wide association studies have expanded our horizon from rare genetic mutations to a genomic landscape implicated by the combined effect of both rare variants and polymorphisms.At the same time,clinicians and genetic counselors are facing huge challenges conferred by overwhelming genomic knowledge and long sheets of testing reports for comprehensive genomic sequencing.The path toward the“next-generation”clinical genetics and genomics may underlie semiautomatic pipelines assisted by artificial intelligence techniques.