Somatic Mutations and Intratumoral Heterogeneity of Cancer-Related Genes NLK, YY1 and PA2G4 in Gastric and Colorectal Ca
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LETTER TO THE EDITOR
Somatic Mutations and Intratumoral Heterogeneity of Cancer-Related Genes NLK, YY1 and PA2G4 in Gastric and Colorectal Cancers Hyun Ji Son 1 & Eun Ji Choi 1 & Nam Jin Yoo 1 & Sug Hyung Lee 1 Received: 27 June 2019 / Accepted: 5 December 2019 # Arányi Lajos Foundation 2019
Abstract Many genes act as both tumor suppressor gene (TSG) and proto-oncogene depending on cellular context and cancer type. Nemolike kinase (NLK) encoding a serine/threonine kinase, Yin Yang 1 (YY1) encoding a zinc-finger transcription factor and PA2G4 encoding an ErbB3 binding protein have both of these two opposing functions. In the present study, we analyzed NLK, YY1 and PA2G4 frameshift mutations in sporadic GC and CRC with high microsatellite instability (MSI-H). Also, regional intratumoral heterogeneity (ITH) of frameshift mutations of these genes was analyzed in CRCs. We found frameshift mutations of NLK, YY1 and PA2G4 in CRC and GC with MSI-H (17/132: 12.9%), but not in those with MSS (0/90). Two (12.5%), one (6.3%) and one (6.3%) CRC (s) of the 16 CRCs exhibited ITH of NLK, YY1 and PA2G4 mutations among the 4–7 regions, suggesting that ITH of the frameshift mutations might be frequent in the CRCs. These results suggest that frameshift mutations of NLK, YY1 and PA2G4 along with the ITH might contribute to MSI-H cancer pathogenesis. Keywords NLK . YY1 . PG2G4 . Mutation . Cancer . Microsatellite instability
Dear Editor, Two main types of genes involved in cancer pathogenesis are proto-oncogenes and tumor suppressor genes (TSGs). Proto-oncogenes normally help cancer cell development and metastasis while TSGs inhibit these processes by slowing down cell division, repairing DNA mistakes and inducing cell death [1]. However, many genes display both proto-oncogenic and TSG functions during cancer pathogenesis. For example, many genes involved in autophagy pathways possess both functions depending on cellular context [2]. Nemo-like kinase (NLK) encodes a serine/threonine kinase that is involved in the regulation of multiple transcription factors for Wnt and Notch signaling pathways [3]. NLK knock-down suppresses cell
* Sug Hyung Lee [email protected] 1
Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea
growth and tumorigenesis in some cancers, but it results in opposite effects in other cancers [3]. Yin Yang 1 (YY1) is a zinc-finger transcription factor that regulates expression of many genes involved in cancer pathogenesis (cell growth, survival and epithelial to mesenchymal transition) [4]. YY1 is over-expressed in many cancers, but sometimes underexpressed in other cancers [4]. PA2G4, also known as ErbB3 binding protein 1, is known to inhibit tumor growth in prostate cancer, but it can promote tumor growth in colon cancer [5], indicating its dual roles in cancer pathogenesis. Approximately 10–20% of gastric (GC) and colorectal (CRC) are high microsatellite instability (MSI-H) cancers that exhibit genetic hypermutability caused by
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