Cancer predisposition syndromes: lessons for truly precision medicine - Glaire - 2016 - The Journal of Pathology (open access/pdf)
Table 1. Germline cancer predisposition variants
Cancer
predisposition syndromes are typically uncommon, monogenic,
high-penetrance disorders. Despite their rarity, they have proven to be
highly clinically relevant in directing cancer prevention strategies. As
such, they share notable similarities with an expanding class of
low-frequency somatic mutations that are associated with a
striking
prognostic or predictive effect in the tumours in which they occur. In
this review, we highlight these commonalities, with particular reference
to mutations in the proofreading domain of replicative DNA polymerases.
These molecular phenotypes may occur as either germline or somatic
events, and in the latter case, have been shown to confer a favourable
prognosis and potential increased benefit from immune checkpoint
inhibition. We note that incorporation of these variants into clinical
management algorithms will help refine patient management, and that this
will be further improved by the inclusion of other germline variants,
such as those that determine the likelihood of benefit or toxicity from
anti-neoplastic therapy. Finally, we propose that such integrated
patient and tumour profiling will be essential if we are to deliver
truly precision medicine for cancer patients, but in a similar way to
rare germline mutations, we must ensure that we identify and utilize
rare somatic mutations with strong predictive and prognostic effects.
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