Yeon Su Yeon, Jo Yun Sol, Choi Eun Ji, Kim Min Sung, Yoo Nam Jin, Lee Sug Hyung
Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul, 137-701, South Korea.
Pathol Oncol Res. 2018 Jul;24(3):617-622. doi: 10.1007/s12253-017-0287-2. Epub 2017 Aug 12.
Diminished ANK3 contributes to cell survival by inhibiting detachment-induced apoptosis. TP53BP1 that interacts with p53 and MFN1 that encodes a mitochondrial membrane protein are considered to have tumor suppressor gene (TSG) functions. HACD4 involving fatty acid synthesis and TCPL10 with transcription regulation functions are considered TSGs. Many genes involved in DNA methylations such as LCMT2, RNMT, TRMT6, METTL8 and METTL16 are often perturbed in cancer. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbored 11 (13.9%), 3 (3.8%), 0 (0%), 5 (6.3%), 1 (1.3%), 2 (2.5%), 4 (5.1%), 3 (3.8%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. There were ITH of the frameshift mutations of ANK3, MFN1 and TP53BP1 in 1 (6.3%), 1 (6.3%) and 1 (6.3%) cases, respectively. Our data exhibit that cancer-related genes ANK3, HACD4, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC.
ANK3减少通过抑制脱离诱导的凋亡促进细胞存活。与p53相互作用的TP53BP1和编码线粒体膜蛋白的MFN1被认为具有肿瘤抑制基因（TSG）功能。涉及脂肪酸合成的HACD4和具有转录调控功能的TCPL10被认为是TSG。许多参与DNA甲基化的基因，如LCMT2、RNMT、TRMT6、METTL8和METTL16，在癌症中经常受到干扰。我们研究的目的是发现这些基因在结直肠癌（CRC）中是否发生突变。在一个基因组数据库中，我们观察到这些基因中的每一个在编码序列中都含有单核苷酸重复序列，在微卫星高度不稳定（MSI-H）的癌症中可能发生突变。为此，我们研究了124例CRC中这些基因的移码突变及其肿瘤内异质性（ITH）。在79例MSI-H的CRC中，ANK3、HACD4、TCP10L、TP53BP1、MFN1、LCMT2、RNMT、TRMT6、METTL8和METTL16分别有11例（13.9%）、3例（3.8%）、0例（0%）、5例（6.3%）、1例（1.3%）、2例（2.5%）、4例（5.1%）、3例（3.8%）、2例（2.5%）和2例（2.5%）发生突变。然而，我们在微卫星稳定（MSS）癌症的核苷酸重复序列中未发现此类突变。ANK3、MFN1和TP53BP1的移码突变在1例（6.3%）、1例（6.3%）和1例（6.3%）病例中存在ITH。我们的数据显示，癌症相关基因ANK3、HACD4、TP53BP1、MFN1、LCMT2、RNMT、TRMT6、METTL8和METTL16在MSI-H的CRC中存在突变性ITH以及移码突变。此外，结果表明这些基因的移码突变可能通过在CRC中的失活在肿瘤发生中发挥作用。
