Page 230 - 20dynamics of cancer

INHERITANCE 215

been limited to indirect analysis of multiple sites by associations be-
tween familial relationships and incidence, the classical nonmolecular
approach to quantitative inheritance.

VARIANTS AT A SINGLE LOCUS

This section compares progression and incidence between individu-
als who carry, at a single locus, either the wild-type allele or a loss of
function mutation. In most cases, one compares homozygotes for the
wild type and heterozygotes that carry one wild-type and one loss of
function mutation. In practice, “wild type” means the class of all variant
alleles that do not have a large effect on incidence, and “loss of function”
means the class of all variant alleles that cause a large increase in the
rate of progression.
The comparison between individuals carrying wild-type and loss of
function genotypes played a key role in the history of multistage theo-
ries of carcinogenesis. The shift of the incidence curve to earlier ages
in the loss of function genotypes provided the first direct evidence that
mutations in cell lineages affect progression. The observed magnitude
of the shift in incidence curves matched the expected shift under multi-
stage theory. In that theory, progression follows the accumulation of
multiple genetic changes, and the inherited mutation provides the first
of two or more steps in carcinogenesis.
In earlier chapters, I described studies that compared age incidence
between genotypes that differed at a single locus, comparing the wild-
type with loss of function mutations. In this section, I copy the figures
from two earlier examples. The following sections provide new exam-
ples.
Figure 11.1 compares incidence rates between inherited and sporadic
cases of retinoblastoma. In the inherited cases, individuals carry one
mutated allele at the retinoblastoma locus. Within the multistage frame-
work, inheriting a key mutation means being born one stage advanced in
progression. The theory predicts that an advance by one stage reduces
the slope of the incidence curve by one. The difference in the log-log ac-
celeration (LLA) of the two incidence curves measures the difference in
the slopes of the incidence curves. Figure 11.1c shows that the observed
difference in slopes is close to one, matching the theory’s prediction.