Page 85 - 20dynamics of cancer

70 CHAPTER 4

Knudson’s (1971) study strongly supported mutation as the primary
cause of progression. But Knudson’s evidence for the role of mutation
came indirectly through quantitative analysis of incidence curves; I sus-
pect that Knudson’s study had only limited impact at the time with re-
gard to the debate about the importance 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 prolifera-
tion. 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, be-
cause 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.
Fearon and Vogelstein (1990) provided the next step with their ge-
netic analysis of colorectal tumor progression. They isolated tumors in
different morphological stages of progression. From genetic analysis of
those samples, they concluded that mutational activation of oncogenes
and mutational inactivation of tumor suppressor genes drive progres-
sion. Fewer genetic changes in key oncogenes and tumor suppressor
genes lead to benign tumors; more changes lead to aggressive cancers.
The mutations tend to happen in a certain order, but much variability
occurs. Five or so key mutations seem to be involved in progression. The
mutations accumulate in a cell lineage over time, leading to monoclonal
tumors. Together, these observations support multistage carcinogene-
sis by the accumulation of mutations in cell lineages.
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 cancer-
related genes influence DNA repair and chromosomal homeostasis. Mu-
tations in such genes increase the rate of point mutations, the loss of
chromosomes, the accumulation of duplicate chromosomes, and several
varieties of chromosomal instability. Most cancers appear to have some
sort of breakdown in DNA repair capacity or in chromosomal home-
ostasis. Kinzler and Vogelstein (1998) named those genes that regulate