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 ¼ 0.018), truncating mutations (P ¼ 0.006), and copy number variants (P ¼ 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 ¼ 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.

Sirenomelia is an uncommon complex congenital anomaly associated with fusion of the lower limbs and abnormalities of the urinary and gastrointestinal tract. Most cases of sirenomelia are not diagnosed in utero due to the complexity of the anomalies coupled with anhydramnios. With a male predominance of approximately 3:1, amniocentesis or noninvasive prenatal screening is the only way to confirm the chromosomes and gender of fetuses diagnosed with sirenomelia in utero. Few cases have been reported surviving past the neonatal period and a majority die in utero.

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> MAP duodenal adenomas had significantly more protein-changing somatic mutations (<i>P</i> = 0.018), truncating mutations (<i>P</i> = 0.006), and copy number variants (<i>P</i> = 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 <i>APC</i>, <i>KRAS</i>, <i>PTCHD2</i>, and <i>PLCL1</i> 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 <i>WTX</i> mutations (<i>P</i> = 0.0017).</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 23(21); 6721–32. ©2017 AACR</i>.</p></div>

<p>Histogram showing number of validated protein changing somatic variants identified per adenoma.</p>

<p>Summary of the 62 recurrently mutated genes in the exome dataset (supplementary table 2) and the number of mutations identified in each gene. Total numbers of variants in each gene take into account any mutations identified in duplicate adenomas.</p>