title: Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines.
abstract: Wnt signaling pathway activation via mutation of genetic components, commonly adenomatous polyposis coli (APC), has a major role in colorectal cancer (CRC). Most components have not been assessed for mutation in sporadic CRC. We have analyzed AXIN2, CK1alpha, DKK1, GSK-3beta, SOX17, LRP6 and PPP2R1B, beta-catenin and APC in a collection of sporadic CRCs (n = 47) and CRC cell lines (CLs; n = 26). The CRC set was enriched for microsatellite unstable cancers (MSI+, 30%, 14/47). Somatic mutation was not found in CK1alpha, DKK1, LRP6, beta-catenin or GSK-3beta; but heterozygous frame-shift mutations, and an in-frame deletion mutation were detected in exon 7 of AXIN2 (CRCs, 11%, 5/47; CLs, 8%, 2/26). Our data refute a previous suggestion that a CRC-related mutational hot-spot occurred in the Huntington elongation A subunit TOR (HEAT) repeat 2 of PPP2R1B; this "hotspot" is, more likely, a rare germline polymorphism. An early investigation proposing a high mutational frequency in HEAT repeat 13 was not substantiated. A heterozygous SOX17 mutation (L194P) was also found in a cell line. APC gene mutations were identified in 64% (30/47) of cancers and 7% of these (2/30) had an additional mutation in another Wnt gene. Overall, 70% (33/47) of CRCs had a somatic mutation in a Wnt pathway gene. The number of tumors containing such a mutation was not significantly higher in MSI+ (57%, 8/14) compared to MSI- (76%, 25/33) cancers (p = 0.3, Fisher's exact test); APC mutation was significantly increased in the MSI- subgroup (p = 0.02, Fisher's exact test). Further, mutational screening of other Wnt pathway genes is warranted.
authors.affiliation: Cancer Research UK Colorectal Cancer Unit, St Mark's Hospital, Harrow, Middlesex, United Kingdom.
authors.forename: Nirosha
authors.initials: N
authors.lastname: Suraweera
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.forename: Emmanuoil
authors.initials: E
authors.lastname: Volikos
authors.forename: Thomas
authors.initials: T
authors.lastname: Guenther
authors.forename: Ian
authors.initials: I
authors.lastname: Talbot
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: D051153:Wnt Proteins