Page 241 - 20dynamics of cancer

226 CHAPTER 11

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Age of onset (a) 1.2 1.4 1.6 1.8 2.0 2.2 2.4

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(b)
0.02 0.04 0.06 0.08
Polyphen

Figure 11.5 Association between cancer onset and the predicted functional
consequences of amino acid substitution in DNA repair genes measured by the
PolyPhen score. (a) A data set of 78 individuals culled from the literature, in
which each paper reported the age of onset and the associated amino acid sub-
stitution. The PolyPhen score was calculated for the single amino acid replace-
ment. Each observation provided a PolyPhen score and an age of onset. I first
sorted the observations by PolyPhen score. I then calculated a sliding window
of average values with a window size of 35. Each point in the figure shows the
average value of age and PolyPhen score in the window. (b) Individuals who
come from families with a tendency for early-onset colorectal cancer. For each
individual, DNA sequences were obtained from parts of the mismatch repair
genes Mlh1, Mlh2, and Mlh6. I used a window size of 25 for this analysis of
the 62 individuals with nonzero PolyPhen scores. I obtained these data and all
calculations of PolyPhen scores from the laboratory of Steven M. Lipkin at the
University of California, Irvine.

one or a few variant sites. The sliding window analysis in Figure 11.5b
demonstrates the predictive power of the PolyPhen scoring for age of
onset. In this case, the variants were collected blindly with regard to