ABSTRACT
Studies of the role of germline or inherited genetic variation
on cancer outcome can fall into three distinct categories.
First,
the impact of highly penetrant but lowly prevalent mutations
of germline DNA on cancer prognosis has been studied extensively
for
BRCA1 and
BRCA2 mutations as well as mutations related to
hereditary nonpolyposis colorectal cancer syndrome (
Lynch Syndrome). These mainly
modest-sized analyses have produced conflicting results. Although
some associations have been observed, they may not be independent
of other known clinical or molecular prognostic factors.
Second,
the impact of germline polymorphisms on cancer prognosis is
a burgeoning field of research. However, a deeper understanding
of potentially confounding somatic changes and larger multi-institutional,
multistage studies may be needed before consistent results are
seen.
Third, research examining the impact of germline genetic
variation on differential treatment response or toxicity (pharmacogenetics)
has produced some proof-of-principle results. Putative germline
pharmacogenetic predictors of outcome include
DPYD polymorphisms
and fluorouracil toxicity,
UGT1A1 variation and irinotecan toxicity,
and
CYP2D6 polymorphisms and tamoxifen efficacy, with emerging
data on predictors of molecularly targeted or biologic drugs.
Here we review data pertaining to these germline outcome and
germline toxicity relationships.
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