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Burden and profile of somatic mutation in duodenal adenomas from patients with familial adenomatous- and MUTYH-associated polyposis

Thomas, Laura Elizabeth, Hurley, Joanna J., Meuser, Elena, Jose, Sian, Ashelford, Kevin E., Mort, Matthew, Idziaszczyk, Shelley, Maynard, Julie, Leon Brito, Helena, Harry, Manon, Walters, Angharad, Raja, Meera, Walton, Sarah Jane, Dolwani, Sunil, Williams, Geraint T., Morgan, Meleri, Moorghen, Morgan, Clark, Susan K. and Sampson, Julian R. 2017. Burden and profile of somatic mutation in duodenal adenomas from patients with familial adenomatous- and MUTYH-associated polyposis. Clinical Cancer Research 23 (21) , pp. 6721-6732. 10.1158/1078-0432.CCR-17-1269

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Abstract

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders. Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas. Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017). Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Advanced Research Computing @ Cardiff (ARCCA)
Publisher: American Association for Cancer Research
ISSN: 1078-0432
Funders: Health and Care Research Wales
Date of First Compliant Deposit: 22 August 2017
Date of Acceptance: 25 July 2017
Last Modified: 23 Aug 2019 12:17
URI: http://orca-mwe.cf.ac.uk/id/eprint/103525

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