Precancer: sequentially acquired or predetermined?

Recognition of focal morphological intraepithelial lesions associated with the eventual development of invasive cancer has long been the sine qua non of precancer. Empirically, precancers are associated with a morphological continuum from atypia to dysplasia and invasive neoplasia. Such lesions are used as early indicators of cancers and have dramatically reduced mortality from cancers of the colon, uterine cervix, and breast. Progression has been modeled as a linear, stepwise process. Some molecular evidence supports a linear model. However, clinical studies now suggest that preexisting cofactors such as human papilloma virus (HPV) in cervical cancer determines the cell fate. Other clinical studies such as bladder, prostate, and breast suggest that many intraepithelial lesions do not progress to malignancy. The more recent experimental analyses reveal that the key molecular and genetic events even predate the emergence of visible lesions. Thus, a new nonlinear, parallel model is proposed. The parallel model suggests an origin in a putative progenitor cell that expands and invades. The clinical outcome is thus predetermined. If correct, this model suggests that "progression" to malignancy is epigenetic. Further, future assessment of biological potential will involve identification and genetic analysis of the progenitor cell populations.