The role of APC in WNT pathway activation in serrated neoplasia

Borowsky, Jennifer, Dumenil, Troy, Bettington, Mark, Pearson, Sally-Ann, Bond, Catherine, Fennell, Lochlan, Liu, Cheng, McKeone, Diane, Rosty, Christophe, Brown, Ian, Walker, Neal, Leggett, Barbara and Whitehall, Vicki (2017) The role of APC in WNT pathway activation in serrated neoplasia. Modern Pathology , 31 3: 495-504. doi:10.1038/modpathol.2017.150

Author Borowsky, Jennifer
Dumenil, Troy
Bettington, Mark
Pearson, Sally-Ann
Bond, Catherine
Fennell, Lochlan
Liu, Cheng
McKeone, Diane
Rosty, Christophe
Brown, Ian
Walker, Neal
Leggett, Barbara
Whitehall, Vicki
Title The role of APC in WNT pathway activation in serrated neoplasia
Journal name Modern Pathology    Check publisher's open access policy
ISSN 1530-0285
Publication date 2017-11-17
Year available 2017
Sub-type Article (original research)
DOI 10.1038/modpathol.2017.150
Open Access Status Not yet assessed
Volume 31
Issue 3
Start page 495
End page 504
Total pages 10
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 2734 Pathology and Forensic Medicine
Abstract Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene 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 APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-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 APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.Modern Pathology advance online publication, 17 November 2017; doi:10.1038/modpathol.2017.150.
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Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Wed, 29 Nov 2017, 12:03:17 EST