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http://ir.nhri.org.tw/handle/3990099045/14236
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| Title: | Characterization of aberrations in DNA damage repair pathways in gastrointestinal stromal tumors: The clinicopathologic relevance of gamma H2AX and 53BP1 in correlation with heterozygous deletions of CHEK2, BRCA2, and RB1 |
| Other Titles: | Characterization of aberrations in DNA damage repair pathways in gastrointestinal stromal tumors: The clinicopathologic relevance of γH2AX and 53BP1 in correlation with heterozygous deletions of CHEK2, BRCA2, and RB1 |
| Authors: | Liu, TT;Li, CF;Tan, EA;Jan, YH;Lee, PH;Huang, CH;Yu, SC;Tsao, CF;Wang, JC;Huang, HY |
| Contributors: | National Institute of Cancer Research |
| Abstract: | Genetic aberrations involving DNA damage repair (DDR) remain underexplored in gastrointestinal stromal tumors (GISTs). We characterized DDR abnormalities using targeted next-generation sequencing and multiplex ligation-dependent probe amplification, and performed immunofluorescence (IF) and immunohistochemistry (IHC) analyses of gamma H2AX and 53BP1. Consistent with IF-validated nuclear co-localization, gamma H2AX and 53BP1 showed robust correlations in expression levels, as did both biomarkers between IF and IHC. Without recurrent pathogenic single-nucleotide variants, heterozygous deletions (HetDels) frequently targeted DNA damage-sensing genes, with CHEK2-HetDel being the most prevalent. Despite their chromosomal proximity, BRCA2 and RB1 were occasionally hit by HetDels and were seldom co-deleted. HetDels of CHEK2 and BRCA2 showed a preference for older age groups, while RB1-HetDel predominated in the non-gastric, high-risk, and 53BP1-overexpressing GISTs. Higher risk levels were consistently related to gamma-H2AX or 53BP1 overexpression (all p < 0.01) in two validation cohorts, while only 53BP1 overexpression was associated with the deletion of KIT exon 11 (KITex11-del) among genotyped GISTs. Low expressers of dual biomarkers were shown by univariate analysis to have longer disease-free survival (p = 0.031). However, higher risk levels, epithelioid histology, and KITex11-del retained prognostic independence. Conclusively, IHC is a useful surrogate of laborious IF in the combined assessment of 53BP1 and gamma-H2AX to identify potential DDR-defective GISTs, which were frequently aberrated by HetDels and a harbinger of progression. |
| Date: | 2022-03-31 |
| Relation: | Cancers. 2022 Mar 31;14(7):Article number 1787. |
| Link to: | http://dx.doi.org/10.3390/cancers14071787 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2072-6694&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000781460400001 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85127394855 |
| Appears in Collections: | [其他] 期刊論文
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| ISI000781460400001.pdf | | 2564Kb | Adobe PDF | 144 | View/Open |
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