The role of somatic mutations in cancer was debated for many years. Witkowski (1990) puts that historical debate in context with a comprehensive time line of developments in cancer research interleaved with developments in basic genetics and molecular biology.
Boveri (1914, 1929) often gets credit for the first comprehensive theory of somatic genetic changes in cancer progression (Wunderlich 2002). Tyzzer (1916) used the term “somatic mutation” to describe events in cancer progression. In the 1950s, Armitage and Doll (1954, 1957) cautiously described the stages of multistage progression as possibly resulting from somatic mutations but perhaps arising from other causes. Burdette (1955), in a comprehensive review of the role of genetic mutations in carcinogenesis, tended to oppose the central role of mutations in progression. In (1969), Fould’s extensive summary of cancer progression also downplayed the role of mutation.
The first steps in the modern molecular era began in the late 1970s, with the cloning of the first oncogenes that stimulate cellular proliferation. In the 1980s, several groups cloned the Rb (retinoblastoma) gene and other tumor suppressor genes. The tumor suppressors stop the cell cycle in response to various checkpoints (see review by Witkowski 1990). From these molecular studies arose the concept that oncogene loci require mutation to only one allele to stimulate proliferation, because the mutant allele provides an aberrant positive control, whereas tumor suppressor loci require mutations to both alleles to abrogate the negative control on the cell cycle: one hit for oncogenes, two hits for tumor suppressor genes.
The initial studies of cancer genes focused on changes in progress through the cell cycle: mutations to oncogenes typically accelerated the cycle, and mutations to tumor suppressor genes typically released blocks to cell-cycle progress. Further studies showed that many cancerrelated genes influence DNA repair and chromosomal homeostasis.
In summary, the dominant view at present focuses on accumulation of genomic changes in one or perhaps a few cell lineages. Tissue interactions, such as angiogenesis and signals from the stromal environment, clearly influence tumorigenesis, but their relative importance compared to genetic change in limiting the quantitative rate of progression remains unknown. Finally, other types of genomic changes that regulate gene expression may be important, such as methylation of DNA promoter regions and modification of histones.