Background: The key to interpreting the
contribution of a disease-associated mutation in the development and
progression of cancer is an understanding of the consequences of that
mutation both on the function of the affected protein and on the pathways in
which that protein is involved. Protein domains encapsulate function and
position-specific domain based analysis of mutations have been shown to help
elucidate their phenotypes.
Results: In this paper we examine the
domain biases in oncogenes and tumour suppressors, and find that their domain
compositions substantially differ. Using data from over 30 different cancers
from whole-exome sequencing cancer genomic projects we mapped over one million
mutations to their respective Pfam domains to identify which domains are
enriched in any of three different classes of mutation; missense, indels or
truncations. Next, we identified the mutational hotspots within domain
families by mapping small mutations to equivalent positions in multiple
sequence alignments of protein domains
We find that gain of function mutations
from oncogenes and loss of function mutations from tumour suppressors are
normally found in different domain families and when observed in the same
domain families, hotspot mutations are located at different positions within
the multiple sequence alignment of the domain.
Conclusions: By considering hotspots in tumour
suppressors and oncogenes independently, we find that there are different
specific positions within domain families that are particularly suited to
accommodate either a loss or a gain of function mutation. The position is
also dependent on the class of mutation.
We find rare mutations co-located with
well-known functional mutation hotspots, in members of homologous domain
superfamilies, and we detect novel mutation hotspots in domain families
previously unconnected with cancer. The results of this analysis can be
accessed through the MOKCa database (Click Here).