Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines

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 , CK1 α, DKK1 , GSK‐3 β, SOX17, LRP6 and PPP2R1B , β‐ 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 CK1 α, DKK1 , LRP6 , β‐ catenin or GSK‐3 β; 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. © 2006 Wiley‐Liss, Inc.