@entity1412 mutations in sporadic XXXX from The Netherlands Cohort Study.

@entity1 @entity6344 @entity5 @entity14 @entity1412 @entity420
The @entity1412 ( @entity1412 ) gene is considered to be a gatekeeper in colorectal tumourigenesis. Inactivating mutations in @entity1412 have been reported in 34-70% of sporadic @entity14 @entity1 , the majority of which occur in the mutation cluster region (MCR). In this study, @entity5 tissue from 665 incident @entity14 @entity1 , who originate from 120 852 @entity1 and @entity1 (55-69 years of age at baseline) participating in The Netherlands Cohort Study, was evaluated for the occurrence and type of @entity1412 mutations with regard to age at diagnosis, gender, family history of @entity14 , Dukes' stage, @entity5 differentiation and sub-localization. Mutation analysis of the MCR, which spans codons 1286-1513, was performed on archival @entity420 samples using macrodissection, nested PCR and direct sequencing of purified PCR fragments. A large number of genetic aberrations (n = 978), including point mutations (n = 833), deletions (n = 126) and insertions (n = 19) was detected in the MCR in 72% of @entity1 (479/665). In particular, we observed a large number of missense mutations, more than reported previously. This may indicate involvement in colorectal carcinogenesis, although their significance for @entity1412 functions is unclear. Truncating mutations were found in 37% of @entity1 (248/665). @entity1 with @entity5 relatively more frequently harboured @entity6344 nonsense mutations and truncating frameshift mutations as compared with @entity1 with proximal and distal @entity5 (P = 0.009 and P = 0.045, respectively). Differences in occurrence of truncating mutations with regard to @entity5 sub-localization suggest a different aetiology of tumourigenesis in colon and rectum.
