**1. Introduction**

Chronic infection of hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Although the strong etiologic relationship between HBV infection and HCC has been supported by substantial evidence, the underlying mechanism is still elusive. There are more than nine thousand studies investigating HBV-induced hepatocarcinogenesis, which yield 143 genes function in 137 pathways [1]. Most of the studies are one-sided investigations, only a few trying to provide a theoretical hypothesis and to promote the system-level understanding of HBV-induced HCC (HBV-HCC). In past decades, continuous attempts have been made to investigate carcinogenesis from an evolutionary point of view. In 1976, Dr. Nowell first proposed that most neoplasms originate from a single cell. Malignant cells are more genetically unstable than normal cells [2]. In 2006, it was pointed out

that cancer clone genetic diversification and sub-clonal selection occurs within the microenvironment, which is similar to the process of Darwinian natural selection [3]. This viewpoint was put forward mainly based on morphological evidence and only a limited number of gene mutations and related signaling pathways were discussed. The widespread application of new generation sequencing promotes the investigation of genetic diversification and clonal selection within tissue ecosystems. It was found that the number of mutations in cancer range from 10 to hundreds of thousands. The majority of mutations are "passengers" and a small part are "drivers" [4]. Cancer cells acquire a variety of critical phenotypes via driver mutations, which compound to enhance the capabilities of self-renewal, migration, and invasion. The mutational spectra in cancers can reflect the characteristics of the mutational process, including the error-prone repair and genotoxic exposure [5]. Interestingly, the cytidine deaminase induced mutation is dominant in most cancers [6]. Cytidine deaminase is upregulated during inflammation and defense against many viruses, including HBV. Epidemiological and experimental evidence identified the co-evolution of HBV and cancer cells during chronic inflammation. In turn, the mutant cells and viruses also affect the inflammatory microenvironment [7]. Thus, there is a similarity between the process of carcinogenesis and Darwinian evolution. Furthermore, the investigation of cancer evolution can draw upon the understanding of developmental processes. Development is referred to the process that a fertilized egg develops into an individual. In humans, the fertilized diploid cell differentiates into various functional and/or structural cells to form different organs and tissues within 40 weeks. This process resembles the process of long-term organic evolution morphologically, from single cell creatures to multicellular creatures, and from aquatic creatures to terrestrial mammals. Some evolutionarily conserved molecules, like Hedgehog, HOX, and Myc are essential for the developmental process, suggesting evolution and development have similar inherent mechanisms [8–11]. The integration of evolution and developmental biology was termed *Evo-Devo* [12, 13]. In this chapter, we present a scientific theory of Cancer Evolution-Development (*Cancer Evo-Dev*) based on the current understanding of HBV-HCC [14]. This theoretical hypothesis can provide an evolutionary insight of profiling HCC risk and developing more reasonable predictive and prognostic strategies.
