Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Int J Mol Sci. 2021 Jan 28;22(3):1310. doi: 10.3390/ijms22031310.
The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, , , and seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.
一些具有胃癌（GC）聚集家族的遗传原因尚不清楚，在早发患者中具有明显的相关性。我们旨在确定涉及 GC 种系易感性的新候选基因。对 20 名无先前种系突变的早发性 GC 患者的种系样本进行了全外显子组测序（WES）。还对 9 个肿瘤样本进行了 WES，使用 SigProfilerExtractor 工具分析体细胞图谱。对种系数据进行过滤，以选择具有合理致病性、罕见频率和先前涉及癌症的变异。然后，根据当前知识和功能对基因进行手动过滤以进行优先级排序。使用 Integrative Genomics Viewer 2.8.2（IGV）对这些遗传变异进行了预验证。随后，根据肿瘤样本获得的功能和信息进行了进一步的选择步骤。在 IGV 和选择步骤之后，通过 Sanger 测序验证了 52 个不同候选基因中的 58 个遗传变异。其中， 、 、 和 似乎是最有前途的基因，因为它们分别在遗传性癌症综合征、肿瘤抑制、细胞粘附和 识别中发挥作用。这些令人鼓舞的结果为鉴定参与 GC 种系易感性的新基因开辟了道路。
