Metabolism Based Molecular Classification Of Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is increasing in incidence and has a very high fatality rate It is the second leading cause of cancer-related death in the world,which accounts for an estimated 745,500 deaths occurred during 2012.Including curative resection,liver transplantation and radiofrequency ablation,multiple treatment options are available for HCC,but the prognosis for HCC patients is still poor.The 5-year survival rate for localized HCC patients is 30.5%,which drops below 5%for those with distant metastases.It underlines the urgent need for more effective biomarkers to improve clinical outcome through early detection and prognostic assessment.However,none of proteins or genes is considered a reliable clinically biomarker to accurately diagnosis or predict the recurrence and metastasis of HCC.On the other hand,the therapy for HCC patients has developed markedly in the past ten years,while the 5-year survival rate of HCC patients has just improved slightly.This is mainly due to the difficulty of reaching a consensus in the classification of HCC.There are more than 15 staging system available,which developed in different patient populations by measuring a range of different factors.Therefore,physicians are confused with the options.Fortunately,molecular classification based on tumor molecular pathology is expected to change this situation,which can provide a framework of HCC in biological mechanism,act as a supplement for the clinical staging system and improve clinical management of HCC.Although attempts have been undertaken in the field of HCC,these studies often based on the nonspecific genome-wide expression patterns,which included both HCC-specific and non-HCC-specific signatures,and led to the subtypes without common molecular characteristics.This highlights the fact that only on the basis of HCC-specific characteristics can we get consistent results of HCC molecular classification.As a hallmark of cancer,metabolic reprogramming plays an irreplaceable role in the molecular pathology of HCC.The metabolic status of liver can affect the occurrence of HCC,while the proliferation,invasion and metastasis of HCC are influenced by metabolism.Therefore,molecular classification based on HCC metabolism is of great significance in understanding the comprehensive molecular pathology of HCC,developing reliable markers for early diagnosis and prognosis prediction of HCC and improving HCC staging system as well as patients' outcome.Based on these rationales and for the first time,this study investigated the molecular pathologic features of metabolic disregulation in HCC at 4 levels:genes,pathways,metabolic patterns and overall characteristics of metabolism.At gene level,We developed a 2-metabolic-gene signature consisting of GOT2 and UPB1,which is closely associated with the prognosis of HCC patients,and verified its performance in predicting HCC patients' outcome by external dataset.Besides,we further validated the downregulation of GOT2 and UPB1 expression in clinical HCC samples,and their relationships between clinicopathological features.At pathway level,we demonstrated that the activity of bile acid synthesis pathway was an independent risk factor for overall survival and recurrence free survival of HCC patients by univariate and multivariate regression analysis,and confirmed its predictive values in several independent datasets.Furthermore,within the bile acid synthesis pathway we confirmed that ALDH2 gene plays the key role and is closely related to the prognosis of patients.Based on the study of metabolic pathways,we divided HCC into 3 metabolic subtypes according to the activation pattern of pathways.These 3 subtypes of HCC are significantly different in metabolism,clinical and molecular pathology.From the subtype I to the subtype?,the overall metabolic activity gradually decreased,while the volume,histologic grade,pathologic stage and invasion ability of tumors increased.Meanwhile,the onset age,recurrence free survival and overall survival of patients decreased from subtype ? to subtype?.What is more,the molecular pathologic features of the three subtypes were also significantly different from each other.CTNNB1 and ALB mutations were more common in metabolic subtype ?,while metabolic subtype ? mainly mutated in TP53.From metabolic subtype ? to subtype ?,the genomic instability and the methylation level of the genome increased gradually.Besides,3 metabolic subtypes exhibited unique cell phenotypes and activated signaling pathways of their own.After summarizing the results of the first three parts,we further explored the overall characteristics of HCC metabolism.We found that,the difference degree of HCC metabolism relative to normal liver is closely related to the recurrence and overall survival of HCC patients.The greater degree of metabolic dysregulation,the greater risk of recurrence,and the higher mortality of the patients.In summary,this study systematically demonstrated the key role of the metabolic dysregulation playing in the prognosis of HCC patients at 4 levels:gene,pathway,metabolic subtype and overall metabolic characteristic.We identified a series of metabolic gene signature,metabolic pathway,metabolic subtypes and metabolic characteristic as independent prognostic factors of HCC patients,which can measure the prognosis risk of HCC patients.After a comprehensive and systematic investigation,for the first time,we displayed a stereo landscape of metabolic dysregulation in HCC,which could help to elucidate the important role of metabolism playing in the carcinogenesis,development,invasion and metastasis of HCC,and support the diagnosis,staging,treatment and prognosis prediction in clinical practice.