Page 238 - 20dynamics of cancer

INHERITANCE 223

100
(a)
80 G/G
Percent with cancer 100 (b) 25 33 41 49 57 65 G/T
60
40
20
T/T
0
17
73 81
80
60
40
20
0
0 20 40 60 80
Age of onset

Figure 11.4 Onset of soft tissue sarcoma for individuals classified by genotype
at a single nucleotide polymorphism in the promoter region of MDM2. At the
polymorphic site, individuals are wild type (T/T), heterozygote for the variant
allele (T/G), or homozygote for the variant (G/G). The y axis shows the per-
centage of individuals of a particular genotype who have suffered cancer by a
particular age. (a) The homozygote variant has earlier age of onset than the wild
type. (b) Pattern for those soft tissue sarcomas classified as liposarcoma, the
most common form of soft tissue sarcoma in the sample. Redrawn from Figure
7C,E of Bond et al. (2004).

(2004) discussed in the previous section provides a glimpse of the sort
of study that will become common in the future.
In the previous section, I described how MDM2 acts as a negative reg-
ulator of p53. Bond et al. (2004) showed that a nucleotide variant in the
promoter of MDM2 enhances expression of the MDM2 protein and thus
negatively influences the p53 regulatory system. In individuals with a
normal p53 locus, the MDM2 promoter variant enhances progression of
soft tissue sarcomas, the same type of cancer often found in individuals
who inherit p53 defects.
Bond et al. (2004) extended their study to samples that included indi-
viduals who carry both the MDM2 promoter variant and a mutation in
p53. Those double mutant individuals suffered faster progression than
individuals who inherited only one of the two mutations. If we use +