Page 234 - 20dynamics of cancer

INHERITANCE 219

panel (h). I work through the steps that lead to panel (h). As I men-
tioned, I do not regard these manipulations as tests of any hypothesis,
but rather as ways to generate new hypotheses.
Panel (e) shows the direct estimate of carrier incidence using the orig-
inal values of Struewing et al. (1997) and the standard smoothing pa-
rameter of 0.5 for fitting the curves in panel (a). In (e), carrier incidence
declines strongly and steadily after about age 55. In (f), I considered
the possibility that only a fraction of carriers have highly elevated risk.
The division of carriers into very high risk and moderate risk categories
may arise from genetic predisposition caused by other loci. I discuss
evidence for this idea in following sections; here I just look at the con-
sequences.
The estimated fraction of carriers who develop cancer by age 80 is
about 0.66. What if nearly all carriers with highly elevated risk de-
velop cancer? Suppose, for example, that only a fraction max = 0.7
of carriers have elevated risk, and nearly all of them develop cancer.
Then the fraction tumorless among the class with highly elevated risk is
S = (max − f)/max, where f is the fraction tumorless among all carri-
ers. Panels (b) and (d) show the fraction tumorless among carriers with
highly elevated risk, using max = 0.7. Panel (f), derived from (b), has a
carrier incidence curve that drops later in life, but less strongly than in
(e).
Panel (h), derived from (d), has what I consider to be the right shape
for the carrier incidence curve. The difference between (h) and (f) comes
only from the smoothing parameter used to fit the curves in the top
row. Whenever a key match to expectations arises only from a moderate
change in the smoothing parameter, one clearly does not have enough
data to draw any conclusions. Normally, after seeing such a pattern,
I would suggest not presenting such an analysis. I present it here to
warn about the importance of sample size and sensitivity to smoothing
procedures, and because I think the alternative biological interpretations
are sufficiently interesting to stimulate further work.
In summary, I suggest that the estimated incidence curve in (h), based
on the stiffer smoothing method, comes closer to the actual incidence
pattern. More importantly, I propose that, among carriers, only a frac-
tion have highly elevated risk. I will discuss below two ways in which
background genotype may elevate risk in some BRCA mutant carriers.