Hepatocellular Carcinoma's Molecular Markers: The New Trend as Diagnostic/Prognostic Markers!

The current emerging molecular markers of hepatocellular carcinoma including molecular, immune-histochemical IHC and serological markers, and their potential role as diagnostic/prognostic markers from a pathogenic perspective have shown researchers great interest. HCC is considered the most common primary liver malignancy; Risk factors for HCC vary from region to region. HBV and HCV represent the most common ones. Furthermore, ALD, obesity, and NAFLD are important risk factors and are increasing in incidence. As known that hepatocarcinogenesis mainly converges on the vicious circle of inflammation and regeneration processes increasing the risk of genomic instability and carcinogenesis; These pathogenic mechanisms represent 80–90% of HCC, that arises in a cirrhotic and non-cirrhotic liver (HBV or NAFLD cases)^,. It's well known that the serum AFP, AFP-L3 and DCP are the most used non-invasive circulating biomarkers for HCC diagnosis in clinical practice; however, they are not included in the diagnostic criteria for HCC in the American or European guidelines owing to their low sensitivity and specificity. Hence, the idea of using molecular markers as diagnostic/prognostic tools for HCC detection was proposed focusing on the following: The molecular markers that have been strongly related to high-grade dysplasia include telomere shortening, telomerase reverse transcriptase TERT activation, and cell-cycle checkpoint inactivation owing to the detection of CTNNB1 related mutations, TP53 mutations, altered methylations and DNA amplification earlier in HCC that end with aggressive behaviour. Regarding this, the IHC markers that support HCC diagnosis include polyclonal CEA, CD10, HepPar, arginase-1 and albumin ISH; moreover, glypican-3, glutamine synthetase GS, HSP70, CD34, alpha-fetoprotein AFP and clusterin have been recommended in identifying hepatocellular malignancy in several international guidelines, so far, several HCC genetic studies are evaluating various molecular markers particularly autophagy-related genes and their regulatory proteins^,. On the other hand, the molecular markers of prognostic value include cytokeratin 19 CK19 positivity and increased miR-1180-3p expression that have been associated with aggressive behaviour with a tendency to metastasize, poor overall survival and resistance to locoregional therapies^,. Also, Immune checkpoint proteins drive signalling pathways including PD-1, PD-L1 and CTLA4 can be used as therapeutic targets; Tumor mutation burden and microsatellite instability MSI/mismatch repair MMR have been evaluated to assess the response to HCC immunotherapy^,. In conclusion, the molecular markers have shown promising results as diagnostic/prognostic tools in hepatocellular carcinoma opening the gate for the idea of developing novel therapies targeting these markers, however further studies on a larger scale are needed with a comparative analysis to strengthen their efficacy (Table 1).