Page 239 - 20dynamics of cancer

224 CHAPTER 11

and − superscripts to label the wild type and variant, then the order-
ing of the median age of onset was MDM2 /p53 − < MDM2 /p53 − <
+
−
−
MDM2 /p53 + < MDM2 /p53 , with values for the medians of 2 <
+
+
14 < 38 < 57.
The MDM2 variant alone shifts the median from 57 in the wild type
to 38; the p53 variant alone shifts the median from 57 in the wild type
to 14. In this case, either variant by itself causes significantly enhanced
progression. In other cases, a variant by itself may have little effect in
the absence of a synergistic variant at another site.

COMPARISON BETWEEN RARE VARIANTS AT SINGLE SITES

Technical advances in DNA sequencing efficiency provide an oppor-
tunity to study individual nucleotide variants. Ideally, one would like
to associate nucleotide variants to their consequences for cancer, mea-
sured by the age of cancer onset. However, each particular variant often
occurs only rarely in natural populations, so it may be difficult to com-
pare the age of onset between those individuals with and without the
variant. In addition, many amino acid substitutions may have a weak
effect on biochemical function, whereas a few substitutions may have
a strong effect. Some a priori way of weighting the expected effects of
particular substitutions would greatly enhance the association between
DNA sequence variants and their consequences for cancer onset.
The association between the nucleotide sequence of DNA mismatch
repair genes and colorectal cancer has been the focus of many recent
studies. In those studies, each observed human subject provides an
age of cancer onset and information about variant nucleotide sites or
amino acid substitutions in the mismatch repair genes. The two prob-
lems mentioned above arise when analyzing the data from those studies:
each particular variant occurs rarely, and some method must be used to
weight the expected consequences of a substitution.
To solve these problems, various computational methods predict the
expected functional consequences of amino acid substitutions. One
method examines the evolutionary history of a gene, and weights more
heavily those substitutions that occur rarely across different species (Ng
and Henikoff 2003). The idea is that relatively rare changes must of-
ten be more constrained by functional consequences of substitutions,