The epigenetic progenitor origin of human cancer

Abstract

Cancer is fundamentally a disease of stem cells; we argue that the epigenome is a logical target for early events in carcinogenesis, given that stem cells are defined epigenetically and that epigenetic alterations in cancer modify stem/progenitor cell properties. An epigenetic disruption of progenitor cells might be a common early event in human cancer. Epigenetic alterations include global hypomethylation, site-specific hypomethylation and hypermethylation, and chromatin modification that is linked to tumour-suppressor-gene silencing and oncogene activation. Epigenetic changes also promote chromosomal instability. Cancer is proposed to involve three steps: an epigenetic alteration of stem cells, a gatekeeper mutation, and genetic instability during tumour progression. Epigenetic changes, including loss of imprinting, are found in normal cells of patients with cancer and are associated with cancer risk. We propose that cancer stem cells arise from misregulation of 'tumour-progenitor genes', which can include stem cell regulatory genes, imprinted genes, DNA deaminases and chromatin modifying genes. The epigenetic progenitor model can help to explain tumour latency, progression, heterogeneity and environmental effects in cancer. The model suggests that greater attention be paid to the apparently normal cells of patients with cancer or who are at risk of cancer, as they might be crucial targets for epigenetic alteration, and might be an important target for chemoprevention and screening.