Invasive breast carcinoma - IARC

ATM protein is detected and missense
substitutions where mutant protein of
variable stability is observed, have suggested
that this mutant protein could produce
a dominant negative effect in heterozygotes,
resulting in an altered phenotype
and an increased breast cancer
susceptibility. The expected phenotypes
that might arise from having two types of
A-T carriers in the general population are
shown in Table 8.12.
The genotype ATM trun/trun with two truncating
mutations causes the classical A-T
disorder. The genotype ATM mis/mis with two
missense mutations is also found in
some children with the classical form of
the disease, in particular when these are
located within the ATM kinase domain
(for instance Belzen et al. {2987}, Angele
et al. {101}) but may also be associated
with a variant A-T phenotype with some
neurological features and cancer susceptibility.
Two types of ATM heterozygotes
exist and the phenotypes differ, i.e.
those with truncating mutations that
make no protein and those with missense
mutations that make reduced amount or
p a rtly defective protein {115,462,971,
1825,2331,2592,2775,2809,3088}, and
these two groups may have different
b reast cancer risks. If this pro p o s e d
model is correct it necessitates a reanalyses
of the epidemiological data
stratifying for the two types of heterozygotes.
The literature to date suggests
that germline ATM missense mutations
are more frequent than the 0.2-1% frequency
of A-T causing mutations and
hence contribute to a larger fraction of
breast cancer patients {351,462,2592}.
Ataxia telangiectasia syndrome 363