The role of APCin WNT pathway activation in serrated neoplasia

Conventional adenomas are initiated by APCgene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAFor KRASmutation. WNT pathway activation may also occur, however, to what extent this is owing to APCmutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APCgene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APCmutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAFwild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APCmutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAFmutant cancers with microsatellite instability that arise from them (8%). In contrast, APCmissense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAFwild-type cancers) were more frequent in BRAFmutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APCmutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APCmutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APCmutations common in conventional adenomas.