Page 235 - 20dynamics of cancer

220 CHAPTER 11

Hypothesis 2: BRCA mutations abrogate a rate-limiting step.—An inher-
ited mutation may increase incidence in at least two different ways.
First, an inherited mutation may raise the rate of somatic mutations,
including epigenetic and chromosomal changes. In this case, the inher-
ited mutation may not abrogate a rate-limiting step, but instead increase
the transition rates between the normal rate-limiting steps that charac-
terize carcinogenesis in the absence of the mutation. If so, then the the-
ory predicts a rise with age in the difference between the log-log slopes
of incidence (ΔLLA) for sporadic versus inherited cases. (See Eq. (7.6)
and Figures 7.5 and 7.6.)
Second, an inherited mutation may directly or indirectly abrogate a
single rate-limiting step. In this case, the theory in Eq. (7.5) predicts that
ΔLLA ≈ 1 and does not change much with age.
The bottom row of Figure 11.3 shows a range of patterns for ΔLLA. In
panel (i), the value rises strongly with age; in panel (l), the value remains
mostly flat and near one. The two middle panels follow intermediate
trends. We do not know enough yet to assign significantly higher likeli-
hood to one pattern over the others because of: the limited sample size
for inherited cases; the fluctuations in the fraction tumorless caused by
the estimation procedure in the original paper; and the uncertainty with
regard to the fraction of carriers who have elevated risk.
I favor the right column of panels in Figure 11.3, because the incidence
pattern for carriers has the common shape for breast cancer, in which
incidence plateaus later in life but does not decline significantly before
age 80. The right column matches the prediction for a BRCA mutation
to knock out one rate-limiting step. To test that hypothesis, we need
more data on incidence in carriers and on the fraction of carriers who
have highly elevated risk.

MDM2 VARIANT AND THE P53 PATHWAY
p53 is the most commonly mutated gene in tumors. In some tumors,
mutations arise in those genes that regulate p53 rather than in p53 itself.
To search for new inherited variants that affect the p53 system and
cancer, Bond et al. (2004) focused on MDM2, a direct negative regulator
of p53. They found a single nucleotide polymorphism in the MDM2 pro-
moter that enhanced MDM2 expression and attenuated the p53 pathway.
In particular, the variant had a T → G change at the 309th nucleotide of
the first intron (SNP309). This SNP occurred at high frequency in a sam-