As explained above, genetic alterations in HCC are found in a variety of cancer driver pathways with a highly heterogeneous pattern of alteration among patients [
60,
73,
88]. The main challenge is to classify the different molecular profiles of HCC, in order to stratify the patients and more accurately define the treatment options and prognosis. However, subclassifications based only on genomic profiling do not encompass all the factors that contribute to the phenotypic heterogeneity observed in tumors, either because they do not integrate other factors, such as tumor-extrinsic factors, or due to the complexity and contribution of the possible combinations of mutations found in this cancer. There are 2 major subgroups of HCC tumors accurately defined by different biological processes: the proliferation and non-proliferation subclasses [
89]. Although this classification is mainly based on the gene expression profile of the tumors, it is strongly associated with clinical and pathological features of the patients and their surrounding etiology, thus integrating different sources of information to define clinical outcomes [
22]. On one hand, the proliferation subclass accounting for around 50% of patients is enriched in signals related to cell proliferation and cell cycle progression and is generally associated with a more aggressive phenotype and poor outcome. The activated signaling cascades found in this group and related to proliferation and cell survival include MET or hepatocyte growth factor receptor (HGFR) pathway [
90], TGFβ signaling, insulin-like factor I (IGF) pathway [
91], RAS/mitogen-activated protein kinase pathways [
92], and AKT/MTOR signaling pathway [
93], among others. Enrichment in the expression patterns associated with stem cell features (e.g., NOTCH) [
94] and markers of progenitor cells (e.g., epithelial cell adhesion molecule) [
95], also found in this subclass, indicate a moderate/poor cell differentiation state that correlates with more aggressive clinical behavior [
96,
97]. Another characteristic aspect of this subgroup is that tumors present higher rates of chromosomal instability due to aberrant epigenetic changes. In fact, there is a defined DNA methylation-based prognostic signature [
77] that correlates with signatures of progenitor cells and poor survival. On the other hand, the non-proliferation subclass is characterized by a well-differentiated phenotype, with normal hepatocyte-like features. This subgroup of HCC is less aggressive and correlates with low levels of a-fetoprotein (AFP), the most widely used biomarker to detect HCC, contrary to the high levels found in the proliferation subclassified patients [
22]. One subset of this group is characterized by the liver-specific activation of WNT signaling pathway (about 25%), mainly by mutations in CTNNB1 [
98], while the other main subgroup is associated with immune response [
99]. Overexpression of the epidermal growth factor receptor (EGFR) is also observed in the non-proliferation group and plays a critical role in the maintenance of the transformed phenotype of HCC cells [
100]. Regarding etiologic factors, HBV-related HCC tumors are predominantly classified in the proliferation subclass, whereas HCV and alcohol-related HCC are more prevalent in the non-proliferation subclass.