Abstract: The occurrence and development of malignant tumors follow an evolutionary trajectory of "mutation⁃selection⁃adaption". External and internal carcinogenic factors promote alterations in chromosomes and mutations in the major functional genes of affected cells directly or indirectly via arousing chronic non⁃resolving inflammation. At the stage of precancerous lesion, chronic inflammation facilitates the accumulation of mutation⁃driving forces, of which the transcription and translation of an important tumor suppressor, the fragile histidine triad (FHIT), are seriously inhibited in more than 50% precancerous lesions. External carcinogenic factors induces the promoter CpG methylation and replication stress leads to loss of heterozygosity, both of which result in the defect of FHIT expression. The defect of FHIT expression leads to aneuploidy, resulting in macroevolution characterized by chromosome instability; while the defect of FHIT expression promotes the formation of single⁃stranded DNA, which facilitates the mutagenic effect of APOBEC3B, resulting in microevolution characterized by single base substitutions. Inflammatory factors such as interleukin⁃6 trans⁃activates the expression of APOBEC3B and trans⁃inactivates the expression of uracil glycosylase (UNG), thus dis⁃balancing APOBEC3B and UNG. This promotes somatic mutations and viral mutations, facilitating cancer evolution. The mutated cells actively transform surrounding fibroblasts into cancer⁃associated fibroblasts that recruit suppressive immune cells to establish tumor microenvironment under hypoxia conditions. The mutated cells are selected and adapted to tumor microenvironment and then retro⁃differentiated into cancer initiation cells, thus facilitating retro⁃development of cancer cells. Based on this theory, FHIT and APOBEC3B/UNG should be novel targets for the prophylaxis and control of malignancies. It will develop a novel avenue for the specific prophylaxis and control of cancers to remove external and internal factors that inhibit the function of FHIT and/or upregulate the expression of AID/APOBEC3s, rectify tumor microenvironment that facilitates cancer retro⁃differentiation via aerobic exercise and immunotherapy, and interrupt the retro⁃development of cancer via targeted therapy.

Key words: Cancer Evo?Dev, Functional molecule, Prophylaxis and treatment