Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
Present address: Department of General, Visceral and Transplantation Surgery, University Clinic Cologne, Cologne, Germany.
Ann Surg Oncol. 2022 Feb;29(2):1453-1462. doi: 10.1245/s10434-021-10771-y. Epub 2021 Sep 16.
Gastric and esophageal cancers are malignant diseases with rising importance in Western countries. To improve oncologic outcome after surgery, it is essential to understand the relevance of germline mutations. The aim of the study was to identify and distinguish clinically relevant single-nucleotide polymorphisms (SNPs).
In total, 190 patients with curative oncological resections of gastric and distal esophageal adenocarcinomas at Heidelberg University Hospital were eligible for this study. Outcome differences were determined for each SNP by analysis of clinical variables, survival, and mRNA expression levels.
Significant survival differences were found on univariate analysis for usual prognostic variables (such as pTNM) and for six SNPs. On multivariate survival analysis, the SNPs rs12268840 (intron variant of MGMT, p = 0.045) and rs9972882 (intron variant of STARD3 and eQTL of PGAP3, p = 0.030) were independent and significant survival predictors along with R status and pT/pN category. Group TT of rs12268840 had the highest rate of second primary carcinoma (30.4%, p = 0.0003), lowest expression of MGMT based on cis-eQTL analysis in normal gastroesophageal tissue (p = 1.99 × 10), and worst oncologic outcome. Group AA of rs9972882 had the highest rate of distant metastases pM1 (42.9%, p = 0.0117), highest expression of PGAP3 (p = 1.29 × 10), and worst oncologic outcome.
Two intron variant SNPs of MGMT and STARD3 were identified that were significant survival predictors and may influence tumor biology. The data indicate that DNA methylation (MGMT) and malfunction of GPI anchoring (PGAP3) are distinct mechanisms that are relevant for tumor progression and relapse.
胃癌和食管癌是西方国家发病率不断上升的恶性肿瘤。为了提高手术后的肿瘤学疗效，了解种系突变的相关性至关重要。本研究的目的是识别和区分具有临床意义的单核苷酸多态性（SNP）。
本研究共纳入了海德堡大学医院接受根治性胃和远端食管腺癌切除术的 190 名患者。通过分析临床变量、生存和 mRNA 表达水平，确定每个 SNP 的预后差异。
单因素分析显示，通常的预后变量（如 pTNM）和 6 个 SNP 存在显著的生存差异。多因素生存分析显示，rs12268840（MGMT 内含子变异，p=0.045）和 rs9972882（STARD3 内含子变异和 PGAP3 的顺式 eQTL，p=0.030）这两个 SNP 以及 R 状态和 pT/pN 分期是独立的显著生存预测因素。rs12268840 的 TT 组发生第二原发癌的比例最高（30.4%，p=0.0003），基于 cis-eQTL 分析，正常胃食管组织中 MGMT 的表达最低（p=1.99×10），肿瘤学预后最差。rs9972882 的 AA 组发生远处转移 pM1 的比例最高（42.9%，p=0.0117），PGAP3 的表达最高（p=1.29×10），肿瘤学预后最差。
本研究鉴定出两个与 MGMT 和 STARD3 相关的内含子变异 SNP，它们是显著的生存预测因子，可能影响肿瘤生物学。这些数据表明，DNA 甲基化（MGMT）和 GPI 锚定功能障碍（PGAP3）是与肿瘤进展和复发相关的不同机制。
