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

AbstractWnt 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, CK1α, DKK1, GSK‐3β, 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 CK1α, DKK1, LRP6, β‐catenin or GSK‐3β; 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.