Tight junction and gap junction are major cell junctions that play important roles in cellular communication and structural integrity. Alterations of these junctions are known to be involved in cancer pathogenesis. Claudins and connexins are major tight and gap junction proteins, but genetic alterations of these genes have not been reported in gastric (GC) and colorectal cancers (CRC) with microsatellite instability (MSI). Claudin genes CLDN5 and CKDN6, and connexin genes GJB6 and GJB7 have mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with MSI. We analyzed 79 GCs and 145 CRCs, and found CLDN5 frameshift mutations in 3 (3%) CRCs and 1 (2.9%) GC, CLDN6 frameshift mutations in 6 (6%) CRCs, GJB6 frameshift mutations in 5 (5%) CRCs and GJB7 frameshift mutation in one CRC (1%) with high MSI (MSI-H). We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutations in 16 CRCs and found that CLDN6 and GJB6 frameshift mutations showed regional ITH in 2 (12.5%) and 2 (12.5%) cases, respectively. Our results show that CLDN5, CLDN6, GJB6 and GJB7 genes harbor not only frameshift mutations but also mutational ITH, which together may be features of GC and CRC with MSI-H. Based on the roles of cellular junctions in cancers, frameshift mutations of tight junction and gap junction genes might contribute to tumorigenesis by altering their functions in GC and CRC.

紧密连接和间隙连接是主要的细胞连接，在细胞通讯和结构完整性中起重要作用。这些连接的改变已知与癌症发病机理有关。claudins和连接蛋白是主要的紧密和间隙连接蛋白，但是在具有微卫星不稳定性（MSI）的胃癌（GC）和结直肠癌（CRC）中尚未报道这些基因的遗传改变。克劳丁基因CLDN5和CKDN6，以及连接蛋白基因GJB6和GJB7在编码序列中均具有单核苷酸重复，这可能是MSI癌症的突变靶标。我们分析了79个GC和145个CRC，发现3个（3％）CRC和1个（2.9％）GC中的CLDN5移码突变，CLDN6移码突变在6（6％）的CRC，GJB6移码突变5（5％）CRC和GJB7在一个CRC（1％）具有高MSI（MSI-H）移码突变。我们还分析了16个CRC中移码突变的肿瘤内异质性（ITH），发现CLDN6和GJB6移码突变分别在2（12.5％）和2（12.5％）病例中显示区域ITH。我们的结果表明，CLDN5，CLDN6，GJB6和GJB7这些基因不仅包含移码突变，而且还包含ITH突变，这可能是GC和CRC与MSI-H的特征。根据细胞连接在癌症中的作用，紧密连接和间隙连接基因的移码突变可能会通过改变它们在GC和CRC中的功能来促进肿瘤发生。