Choi Eun Ji, Lee Ju Hwa, Kim Min Sung, Song Sang Yong, 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.
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Pathol Oncol Res. 2018 Oct;24(4):827-832. doi: 10.1007/s12253-017-0297-0. Epub 2017 Aug 26.
Both NRIP1 and DOK1 genes are considered candidate tumor suppressor genes (TSGs). Also, cell polarity-related genes PARD3, PRKCI and DLGAP3, and autophagy-related genes ULK1 and ULK2 genes are considered to play crucial roles in tumorigenesis. 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). NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 harbored 18 (22.8%), 2 (2.5%), 2 (2.5%), 2 (2.5%), 5 (6.3%), 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. We also studied ITH for the frameshift mutations in 16 cases of CRCs and detected that the frameshift mutations of NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 showed regional ITH in 5 (31.3%), 2 (12.5%), 0 (0%), 0 (0%), 1 (6.3%), 1 (6.3%) and 3 (18.8%) cases, respectively. Our data exhibit that candidate cancer-related genes NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 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.
NRIP1和DOK1基因均被视为候选肿瘤抑制基因（TSG）。此外，细胞极性相关基因PARD3、PRKCI和DLGAP3，以及自噬相关基因ULK1和ULK2基因被认为在肿瘤发生中起关键作用。我们研究的目的是确定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，这些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，NRIP1、DOK1、PARD3、PRKCI、DLGAP3、ULK1和ULK2分别有18例（22.8%）、2例（2.5%）、2例（2.5%）、2例（2.5%）、5例（6.3%）、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。我们还研究了16例CRC中移码突变的ITH，发现NRIP1、DOK1、PARD3、PRKCI、DLGAP3、ULK1和ULK2的移码突变分别在5例（31.3%）、2例（12.5%）、0例（0%）、0例（0%）、1例（6.3%）、1例（6.3%）和3例（18.8%）病例中表现出区域ITH。我们的数据表明，候选癌症相关基因NRIP1、DOK1、PARD3、PRKCI、DLGAP3、ULK1和ULK2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其在CRC中的失活在肿瘤发生中起作用。
