Background: The somatic mutation theory as the origin of cancer (carcinogenesis) was born some 100 years ago, when Theodor Boveri 1914 suggested that a combination of chromosomal defects may result in cancer. This was followed by Karl-Heinrich Bauer in 1928 suggesting that mutations could cause cancer. Subsequently, in 1953 Carl Nordling proposed that a number of mutated genes could cause cancer. Alfred Knudson in 1971 proposed that one hit (one mutation) would result in a clone of cancerous cells. This was modified to a 2-hit-theory later and it seems that cancer biology has continued to try to bolster the somatic mutation theory by recently suggesting that ‘driver’ and ‘passenger’ mutations were necessary and when this proved insufficient, others proposed the hyper-mutation theory in 2014. In the attempt to clothe the Emperor, it was forgotten that mutations found in advanced cancers are either late events or epiphenomena that occur after carcinogenesis (cancer development) and especially after the appearance of a pre-cancerous niche. Reality: Fewer than 10% of cancers are proven to be hereditary (i.e., causally related to germline mutations) and this ratio is even lower in cancers of the stomach (<1%), the colorectum (3-8%) and breast (8%). Infection-triggered cancers constitute some 15% of all cancers and the remaining about some 80% cancers are sporadic, meaning their cause is unknown. New cancer paradigm: Findings from the plant and animal kingdoms, molecular and clinical data over the last 250 years were critically reviewed and gave rise to a new cancer hypothesis containing a multi-step process of 6 sequences. These include, (1) a pathogenic biological or chemical stimulus is followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. These remodeling changes result in a (4) pre-cancerous niche, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. Consequences: This recently proposed cancer model explains the origins of the vast majority of cancers which are until now were referred to as ‘sporadic’ cancers. Furthermore, this theory points out the need to establish preventive measures long before a cancer becomes clinically apparent. The epistemology of the origin of cancer is reviewed and presented.
One hundred years of somatic mutation theory of carcinogenesis: Is it time to switch?
