Department of General Surgery, College of Medicine, The Catholic University of Korea, Seoul, 137-701 Korea.
Hum Pathol. 2012 Jan;43(1):40-7. doi: 10.1016/j.humpath.2010.03.015. Epub 2011 Jul 5.
Vacuolar protein sorting plays crucial roles in the traffic of molecules between cellular organelles. Although involvement of vacuolar protein sorting proteins in cancer is known, genetic alterations of VPS genes have not been reported in cancers. We found that VPS4B, VPS13A, VPS13B, VPS13C, VPS33A, VPS35, VPS37B, VPS37D, VPS41, and VPS54 have mononucleotide repeats in their coding sequences. To see whether these genes are mutated in cancers with microsatellite instability, we analyzed the mononucleotide repeats in 30 gastric cancers with high microsatellite instability, 13 gastric cancers with low microsatellite instability, and 45 gastric cancers with stable microsatellites and 40 colorectal cancers with high microsatellite instability, 14 colorectal cancers with low microsatellite instability, and 45 colorectal cancers with stable microsatellites by single-strand conformation polymorphism. We found mutations of VPS13A, VPS13B, VPS13C, VPS33A, VPS35, VPS37B, VPS41, and VPS54 in 9, 3, 12, 3, 5, 9, 2, and 2 cancers, respectively, all in cancers with high microsatellite instability. The gastric cancers and colorectal cancers with high microsatellite instability harbored one or more mutations of the VPS genes in 53.3% and 50.0%, respectively. Loss of Vps13A expression was observed in 30% of the gastric cancers and 35% of the colorectal cancers, whereas loss of Vps35 was observed in 55% of the gastric cancers and 55% of the colorectal cancers. Our data indicate that frameshift mutations of VPS genes and losses of expression of Vps13A and Vps35 proteins are common in gastric cancers and colorectal cancers with high microsatellite instability and suggest that these alterations might contribute to development of cancers with high microsatellite instability by deregulating vacuolar protein sorting proteins.
液泡分选蛋白在分子在细胞器官间的运输中起着至关重要的作用。尽管已经知道液泡分选蛋白参与了癌症的发生，但是在癌症中尚未报道 VPS 基因的遗传改变。我们发现 VPS4B、VPS13A、VPS13B、VPS13C、VPS33A、VPS35、VPS37B、VPS37D、VPS41 和 VPS54 的编码序列中存在单核苷酸重复。为了研究这些基因是否在微卫星不稳定的癌症中发生突变，我们通过单链构象多态性分析了 30 例高微卫星不稳定胃癌、13 例低微卫星不稳定胃癌、45 例微卫星稳定胃癌、40 例高微卫星不稳定结直肠癌、14 例低微卫星不稳定结直肠癌和 45 例微卫星稳定结直肠癌中的单核苷酸重复。我们发现 VPS13A、VPS13B、VPS13C、VPS33A、VPS35、VPS37B、VPS41 和 VPS54 分别在 9、3、12、3、5、9、2 和 2 例癌症中发生突变，且均为高微卫星不稳定癌症。高微卫星不稳定的胃癌和结直肠癌中分别有 53.3%和 50.0%携带一个或多个 VPS 基因突变。Vps13A 的表达缺失在 30%的胃癌和 35%的结直肠癌中观察到，而 Vps35 的缺失在 55%的胃癌和 55%的结直肠癌中观察到。我们的数据表明，VPS 基因的移码突变以及 Vps13A 和 Vps35 蛋白的表达缺失在高微卫星不稳定的胃癌和结直肠癌中很常见，提示这些改变可能通过扰乱液泡分选蛋白而导致微卫星不稳定的癌症的发生。
