Data from Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and <i>MUTYH</i>-associated Polyposis

Abstract

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

Hierarchical determinants of the oxidation-induced mutational landscape in human cells

“…Due to their direct role in removing 8-oxoG or Hoogsteen paired adenines, loss of OGG1 and MUTYH results in increased mutation rates and an altered mutation spectrum consisting of higher numbers of G to T (and complementary C to A) substitutions [15][16][17] . This elevated mutation rate is believed to cause MUTYH-associated polyposis syndrome 16 , where individuals inheriting germline MUTYH mutations develop higher incidences of gastro-intestinal cancers throughout life [18][19][20][21] . Accordingly, human cells or cancer genomes with bi-allelic OGG1 or MUTYH mutations display respective SBS18 16,17,22 and SBS36 23 mutation signatures, both of which are dominated by C to A substitutions.…”