Page 231 - 20dynamics of cancer

216 CHAPTER 11

6
1
5 4 8
Incidence 3 2 R X 10 -5 4 $LLA

1
2
0
0 (a) (b) (c)
1.25 2.25 3.25 1.25 2.25 3.25 1.25 2.25 3.25
Age from conception

Figure 11.1 Age-specific incidence of bilateral and unilateral retinoblastoma.
Bilateral cases are mostly inherited, and unilateral cases are mostly sporadic.
(a) Bilateral (solid line) and unilateral (dashed line) incidence of retinoblastoma
6
per 10 population, shown on a log 10 scale. (b) Ratio, R, of unilateral to bilateral
incidence at each age multiplied by 10 −5 , using the fitted lines in the previous
panel. (c) Difference in log-log acceleration between unilateral and bilateral
cases, which is the log-log slope of R versus age in Eq. (8.2). Ages measured in
years. I presented this figure earlier as Figure 8.3; see my earlier presentation
for more details.
Figure 11.2 compares incidence rates between inherited and sporadic
cases of colon cancer. In the inherited cases, individuals carry one mu-
tated allele at the APC locus. Again, the multistage framework predicts
that an inherited mutation in a key rate-limiting process advances pro-
gression by one stage and therefore reduces the log-log acceleration of
incidence by one. Figure 11.2c shows a difference in LLA of about 1.5, a
reasonable match to the theory’s prediction given the sample sizes and
complexities of progression.

COMMON VARIANTS AT A SINGLE SITE
The previous section described studies that aggregated variants into
wild-type and mutant classes. This section presents two cases in which
mutations at specific sites define the variants.

BRCA MUTATIONS AND BREAST CANCER
Struewing et al. (1997) screened Ashkenazi Jewish females for two
specific mutations in BRCA1 and one specific mutation in BRCA2. They
obtained age of breast cancer onset among the 89 carriers and 3653
noncarriers. They used a statistical procedure that accounted for relat-
edness between certain sample members to obtain estimates for the risk
of breast cancer, measured as the expected fraction of women at each