Seol So-Young, Yang Gi-Eun, Cho Yoon, Kim Min Chan, Choi Hong-Jo, Choi Yung Hyun, Leem Sun-Hee
Department of Biomedical Science, Dong-A University, Busan, 49315, Korea.
Department of Medical Oncology, Gangnam Severance Cancer Hospital, Yonsei University College of Medicine, Seoul, Korea.
Genes Genomics. 2021 Dec;43(12):1381-1388. doi: 10.1007/s13258-021-01158-0. Epub 2021 Aug 26.
Previously, we identified eight novel minisatellites in the MUC2, of which allelic variants in MUC2-MS6 were examined to influence susceptibility to gastric cancer. However, studies on the susceptibility to gastrointestinal cancer of other minisatellites in the MUC2 region still remain unprogressive.
In this study, we investigated whether polymorphic variations in the MUC2-MS8 region are related to susceptibility to gastrointestinal cancer.
We assessed the association between MUC2-MS8 and gastrointestinal cancers by a case-control study with 1229 controls, 486 gastric cancer cases, 220 colon cancer cases and 278 rectal cancer cases. To investigate whether intronic minisatellites affect gene expression, various minisatellites were inserted into the luciferase-reporter vector and their expression levels were examined. We also examined the length of MUC2-MS8 alleles in blood and cancer tissue matching samples of 107 gastric cancer patients, 125 colon cancer patients, and 85 rectal cancer patients, and investigated whether the repeat sequence affects genome instability.
A statistically significant association was identified between rare MUC2-MS8 alleles and the occurrence of rectal cancer: odds ratio (OR), 6.66; 95% confidence interval (CI), 1.11-39.96; and P = 0.0165. In the younger group (age, < 55), rare alleles were significant associated with an increased risk of rectal cancer (odds ratio, 24.93 and P = 0.0001). Suppression of expression was found in the reporter vector inserted with minisatellites, and loss of heterozygosity (LOH) of the MUC2-MS8 region was confirmed in cancer tissues of gastrointestinal cancer patients (0.8-5.9%).
Our results suggest that the rare alleles of MUC2-MS8 could be used to identify the risk of rectal cancer and that this repeat region is related to genomic instability.
此前，我们在MUC2中鉴定出8个新的微卫星，其中对MUC2-MS6的等位基因变异进行了研究，以探讨其对胃癌易感性的影响。然而，关于MUC2区域其他微卫星对胃肠道癌易感性的研究仍无进展。
在本研究中，我们调查了MUC2-MS8区域的多态性变异是否与胃肠道癌易感性相关。
我们通过病例对照研究评估了MUC2-MS8与胃肠道癌之间的关联，该研究纳入了1229名对照、486例胃癌病例、220例结肠癌病例和278例直肠癌病例。为了研究内含子微卫星是否影响基因表达，将各种微卫星插入荧光素酶报告载体并检测其表达水平。我们还检测了107例胃癌患者、125例结肠癌患者和85例直肠癌患者的血液和癌组织匹配样本中MUC2-MS8等位基因的长度，并研究了重复序列是否影响基因组稳定性。
发现罕见的MUC2-MS8等位基因与直肠癌的发生之间存在统计学显著关联：比值比（OR）为6.66；95%置信区间（CI）为1.11 - 39.96；P = 0.0165。在较年轻组（年龄<55岁）中，罕见等位基因与直肠癌风险增加显著相关（比值比为24.93，P = 0.0001）。在插入微卫星的报告载体中发现了表达抑制，并且在胃肠道癌患者的癌组织中证实了MUC2-MS8区域的杂合性缺失（LOH）（0.8 - 5.9%）。
我们的结果表明，MUC2-MS8的罕见等位基因可用于识别直肠癌风险，并且该重复区域与基因组不稳定有关。
