Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps

<b>Objective:</b> A subgroup of patients with hamartomatous polyps in the GI tract has a hereditary Hamartomatous Polyposis Syndrome with an increased risk of cancer. The distinction between patients with one or few polyps and patients with a syndrome can be difficult. A pathogenic germline mutation can be detected in a majority of HPS patients. This study investigates whether patients with one or few hamartomatous polyps could have a syndrome based on genetic screening of relevant genes. <b>Methods:</b> We designed a gene panel including 26 hamartomatous polyposis-associated genes. Using targeted Next Generation Sequencing, DNA samples from 77 patients with 84 hamartomatous polyps were sequenced. The detected germline variants were classified into pathogenicity classes. <b>Results:</b> We detected several germline variants, among them three in <i>ENG</i>, two in <i>BMPR1A</i>, one in <i>PTEN</i>, and one in <i>SMAD4.</i> Although some of the detected variants have been reported previously none could be definitely pathogenic or likely pathogenic. <b>Conclusions:</b> Our study points towards that genetic testing for the Hamartomatous Polyposis Syndromes in patients with one or few polyps does not improve diagnostics, however we illustrate that the clinical significance of genetic variants can be difficult to interpret. A family history of polyps, cancer, or extraintestinal findings or a minimum of 3–5 polyps seems to be relevant information to include before genetic testing.

研究目的：胃肠道错构瘤性息肉患者中存在一类群体罹患遗传性错构瘤性息肉病综合征（Hamartomatous Polyposis Syndrome, HPS），此类患者的癌症发病风险显著升高。区分单发或少数错构瘤性息肉患者与该综合征患者存在一定难度，而多数HPS患者可检出致病性生殖系突变。本研究旨在通过对相关基因开展遗传筛查，探究单发或少数错构瘤性息肉患者是否可能罹患该综合征。
研究方法：本研究设计了包含26个错构瘤性息肉病相关基因的基因检测组合（gene panel）。采用靶向下一代测序（Next Generation Sequencing）技术，对77例共携带84个错构瘤性息肉患者的DNA样本进行测序，并将检测到的生殖系变异划分为不同致病性等级。
研究结果：本研究共检测到多种生殖系变异，其中ENG基因3个、BMPR1A基因2个、PTEN基因1个、SMAD4基因1个。尽管部分检测到的变异此前已有文献报道，但均无法明确界定为致病性或可能致病性变异。
研究结论：本研究提示，对单发或少数错构瘤性息肉患者开展遗传性错构瘤性息肉病综合征基因检测并不能提升诊断效能，但本研究也凸显出遗传变异的临床意义难以精准解读这一问题。在开展基因检测前，应将息肉家族史、癌症家族史、肠外表现或至少3~5个错构瘤性息肉等相关信息纳入评估参考。