The primary filter identifies enrichment of cancer mutations in
CATH functional families (CATH-FunFams) – structurally
and functionally coherent sets of evolutionary related domains.
Using structural representatives from CATH-FunFams, we
subsequently seek enrichment of mutations in 3D and show that these
mutation clusters have a very significant tendency to lie close to known
functional sites or conserved sites predicted using CATH-FunFams.
Our third filter identifies enrichment of putative driver genes in
functionally coherent protein network modules confirmed by literature
analysis to be cancer associated.
Our approach is complementary to other domain enrichment approaches
exploiting Pfam families, but benefits from more functionally coherent
groupings of domains. Using a set of mutations from 22 cancers we detect
151 putative cancer drivers, of which 79 are not listed in cancer resources
and include recently validated cancer associated genes EPHA7, DCC netrin-1
receptor and zinc-finger protein ZNF479.