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 <i>CHEK2</i>, <i>BRCA2</i>, and <i>RB1</i>
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 immunohi...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/7/1787 |
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| author | Ting-Ting Liu Chien-Feng Li Kien-Thiam Tan Yi-Hua Jan Pei-Hang Lee Chih-Hao Huang Shih-Chen Yu Cheng-Feng Tsao Jui-Chu Wang Hsuan-Ying Huang |
| author_facet | Ting-Ting Liu Chien-Feng Li Kien-Thiam Tan Yi-Hua Jan Pei-Hang Lee Chih-Hao Huang Shih-Chen Yu Cheng-Feng Tsao Jui-Chu Wang Hsuan-Ying Huang |
| author_sort | Ting-Ting Liu |
| collection | DOAJ |
| description | 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 γH2AX and 53BP1. Consistent with IF-validated nuclear co-localization, γH2AX 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 <i>CHEK2</i>-HetDel being the most prevalent. Despite their chromosomal proximity, <i>BRCA2</i> and <i>RB1</i> were occasionally hit by HetDels and were seldom co-deleted. HetDels of <i>CHEK2</i> and <i>BRCA2</i> showed a preference for older age groups, while <i>RB1</i>-HetDel predominated in the non-gastric, high-risk, and 53BP1-overexpressing GISTs. Higher risk levels were consistently related to γ-H2AX or 53BP1 overexpression (all <i>p</i> < 0.01) in two validation cohorts, while only 53BP1 overexpression was associated with the deletion of <i>KIT</i> exon 11 (<i>KIT</i>ex11-del) among genotyped GISTs. Low expressers of dual biomarkers were shown by univariate analysis to have longer disease-free survival (<i>p</i> = 0.031). However, higher risk levels, epithelioid histology, and <i>KIT</i>ex11-del retained prognostic independence. Conclusively, IHC is a useful surrogate of laborious IF in the combined assessment of 53BP1 and γ-H2AX to identify potential DDR-defective GISTs, which were frequently aberrated by HetDels and a harbinger of progression. |
| first_indexed | 2024-03-09T12:02:22Z |
| format | Article |
| id | doaj.art-141d05e921ff496094532452c5124619 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T12:02:22Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-141d05e921ff496094532452c51246192023-11-30T23:02:02ZengMDPI AGCancers2072-66942022-03-01147178710.3390/cancers14071787Characterization of Aberrations in DNA Damage Repair Pathways in Gastrointestinal Stromal Tumors: The Clinicopathologic Relevance of γH2AX and 53BP1 in Correlation with Heterozygous Deletions of <i>CHEK2</i>, <i>BRCA2</i>, and <i>RB1</i>Ting-Ting Liu0Chien-Feng Li1Kien-Thiam Tan2Yi-Hua Jan3Pei-Hang Lee4Chih-Hao Huang5Shih-Chen Yu6Cheng-Feng Tsao7Jui-Chu Wang8Hsuan-Ying Huang9Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Pathology, Chi-Mei Medical Center, Tainan 710, TaiwanDepartment of Medical Informatic, ACT Genomics Co., Ltd., Taipei 100, TaiwanDepartment of Medical Informatic, ACT Genomics Co., Ltd., Taipei 100, TaiwanDepartment of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanGenetic 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 γH2AX and 53BP1. Consistent with IF-validated nuclear co-localization, γH2AX 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 <i>CHEK2</i>-HetDel being the most prevalent. Despite their chromosomal proximity, <i>BRCA2</i> and <i>RB1</i> were occasionally hit by HetDels and were seldom co-deleted. HetDels of <i>CHEK2</i> and <i>BRCA2</i> showed a preference for older age groups, while <i>RB1</i>-HetDel predominated in the non-gastric, high-risk, and 53BP1-overexpressing GISTs. Higher risk levels were consistently related to γ-H2AX or 53BP1 overexpression (all <i>p</i> < 0.01) in two validation cohorts, while only 53BP1 overexpression was associated with the deletion of <i>KIT</i> exon 11 (<i>KIT</i>ex11-del) among genotyped GISTs. Low expressers of dual biomarkers were shown by univariate analysis to have longer disease-free survival (<i>p</i> = 0.031). However, higher risk levels, epithelioid histology, and <i>KIT</i>ex11-del retained prognostic independence. Conclusively, IHC is a useful surrogate of laborious IF in the combined assessment of 53BP1 and γ-H2AX to identify potential DDR-defective GISTs, which were frequently aberrated by HetDels and a harbinger of progression.https://www.mdpi.com/2072-6694/14/7/1787gastrointestinal stromal tumorDNA damage repairγ-H2AX53BP1<i>BRCA2</i><i>CHEK2</i> |
| spellingShingle | Ting-Ting Liu Chien-Feng Li Kien-Thiam Tan Yi-Hua Jan Pei-Hang Lee Chih-Hao Huang Shih-Chen Yu Cheng-Feng Tsao Jui-Chu Wang Hsuan-Ying Huang 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 <i>CHEK2</i>, <i>BRCA2</i>, and <i>RB1</i> Cancers gastrointestinal stromal tumor DNA damage repair γ-H2AX 53BP1 <i>BRCA2</i> <i>CHEK2</i> |
| title | 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 <i>CHEK2</i>, <i>BRCA2</i>, and <i>RB1</i> |
| title_full | 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 <i>CHEK2</i>, <i>BRCA2</i>, and <i>RB1</i> |
| title_fullStr | 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 <i>CHEK2</i>, <i>BRCA2</i>, and <i>RB1</i> |
| title_full_unstemmed | 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 <i>CHEK2</i>, <i>BRCA2</i>, and <i>RB1</i> |
| title_short | 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 <i>CHEK2</i>, <i>BRCA2</i>, and <i>RB1</i> |
| title_sort | 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 i chek2 i i brca2 i and i rb1 i |
| topic | gastrointestinal stromal tumor DNA damage repair γ-H2AX 53BP1 <i>BRCA2</i> <i>CHEK2</i> |
| url | https://www.mdpi.com/2072-6694/14/7/1787 |
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