Sequencing of Candidate Chromosome Instability Genes in Endometrial Cancers Reveals Somatic Mutations in <i>ESCO1</i>, <i>CHTF18</i>, and <i>MRE11A</i>

<div><p>Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in <i>ESCO1</i>, <i>CHTF18,</i> and <i>MRE11A</i> in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in <i>ESCO1</i> and <i>CHTF18</i> was statistically significant (<i>P</i> = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within <i>ESCO1</i> and <i>CHTF18</i> in endometrial tumors and of <i>MRE11A</i> mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer.</p></div

Co-occurrence of <i>ESCO1</i> mutations with <i>CHTF18</i> or <i>ATAD5</i> mutations in EC.

§<p>Two-tailed Fisher's exact test.</p

Nonsynonymous, somatic mutations in <i>ESCO1</i>, <i>CHTF18</i> and <i>MRE11A</i>, in ECs.

†<p>Case no T3 is also known as OM-1323.</p><p>n/a Not applicable.</p>§<p>Transcript accession numbers: <i>ESCO1</i> (NM_052911.1), <i>CHTF18</i> (NM_022092.1), <i>MRE11A</i> (NM_005591).</p>¶<p>Protein accession numbers: ESCO1 (NP_443143.2), CHTF18 (NP_071375.1), MRE11A (NP_005582.1).</p

Genes resequenced in the mutation discovery screen.

1<p>Gene analyzed because it is somatically mutated in colorectal cancer.</p>2<p>Implicated in meiotic specific cohesion.</p

Oncoprint displaying nonsynonymous somatic mutations in <i>ESCO1</i>, <i>CHTF18</i>, <i>MRE11A</i>, and <i>ATAD5</i> in eight primary endometrial cancers.

<p>Individual tumors (T) are indicated by vertical gray bars. Tumors consist of NEECs (T3, T51, T62, T68, T77, T79, T113) and an EEC (T88). Genes (left) and nonsynonymous somatic mutations (orange boxes) are indicated. <i>ESCO1</i>, <i>CHTF18</i>, and <i>MRE11A</i> were analyzed in this study; *<i>ATAD5</i> mutations, <i>MSH6</i> mutations, and microsatellite instability (MSI) have previously been described elsewhere <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063313#pone.0063313-Bell1" target="_blank">[44]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063313#pone.0063313-LeGallo1" target="_blank">[52]</a>.</p