한빛사논문
- 조회2,448
Ji-Yong Sung1, Jae-Ho Cheong1,2,3,4,5,6,*
1Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
2Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
3Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Korea
4Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
5Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Korea
6Department of Research & development, VeraVerse Inc., Seoul, Korea
*Correspondence : Jae-Ho Cheong
Abstract
Dear Editor,
Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism (TMM) frequently observed in recalcitrant cancer. However, the TMM in the cancer stem-like subtype of gastric cancer (GC) is unknown. To assess the therapeutic targetability of the TMM, we analyzed transcriptome data of 497 GC patients,1 classified into ALT-like and non-ALT tumor groups based on chromatin decompaction. Among five GC subtypes (Figure 1A,C), 92.3% of stem-like subtype samples exhibited high-level chromatin decompaction. According to currently proposed ALT mechanisms, ZNF827 recruits the NuRD complex to telomeres. The resultant NuRD-ZNF827 complex has ALT-promoting activity.2 ALT-like tumors were detected predominantly in the stem-like GC subtype (45%), whereas non-ALT tumors were detected primarily in the inflammatory and intestinal subtypes (both 30%; Figure 1B). Of the 117 stem-like subtype samples, 108 (92.3%) were classified as ALT-like tumors (Figure 1D). The five subtypes have different molecular characteristics and prognoses1 (Figures S1, S2). Compared with that in other subtypes, telomerase activity was substantially decreased or absent in the stem-like subtype (Figure S2A). We evaluated 97 TMM-related genes (Table S1) and determined differentially expressed genes in ALT-like and non-ALT tumors (Figure 1F). NR2F2 (–log p = 15.65) and ZNF827 (–log p = 15.65) had significantly higher expression levels in ALT-like tumors than in non-ALT tumors. Compared with those in non-ALT tumors, ABL1 (–log p = 15.65), ZCCHC7 (–log p = 15.65), and HSPA1A (–log p = 15.65) were overexpressed in ALT-like tumors (Figure 1G, Table S2). Histone modifiers trigger telomeric chromatin decompaction, thus reducing telomeric chromatin compaction and causing an ALT-like phenotype.3 The highest chromatin group showed low or no telomerase activity in different GC cohorts (Figures 1E and 2A). When stratified by chromatin decompaction, non-ALT tumors were associated with a better prognosis (p = 0.017) than ALT-like tumors (Figure 1H,I; Table S3). This is consistent with previous findings that low ALT activity is associated with a better prognosis than high ALT activity in most cancer types.4
논문정보
- Research article
- 2021년 09월 (BRIC 등록일 2021-10-08)
- 국내 연구진
- 의약학 > 종양의학
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