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
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Cohorts
2.2. Targeted NGS
2.3. IHC Analysis for γH2AX and 53BP1 in GISTs
2.4. IF Analyses of Expression Levels and Subcellular Spatial Association of γH2AX and 53BP1 in GISTs
2.5. MLPA
2.6. Statistical Analysis
3. Results
3.1. Targeted NGS for Primary Drivers and a Focused Appraisal of DDR Genes
3.2. Expression Status of γ-H2AX and 53BP1 by IHC and IF in the Training Cohort
3.3. Correlation and Co-Localization of γ-H2AX and 53BP1
3.4. The Dosages of RB1, BRCA2, and CHEK2 Genes Determined by MLPA and Their Associations with Clinicopathologic Factors, γ-H2AX and 53BP1 in GISTs
3.5. Independent Validation of Immunohistochemical Expression, Clinical and Molecular Correlates, and Prognostic Relevance of γ-H2AX and 53BP1 in TMA-Based GISTs
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameters | rH2AX H-Score | p-Value | rH2AX IF | p-Value | 53BP1 H-Score | p-Value | 53BP1 IF | p-Value | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Low | High | Low | High | Low | High | Low | High | |||||
Sex | 0.121 | 0.825 | 0.237 | 0.121 | ||||||||
Male | 21 | 28 | 24 | 25 | 26 | 23 | 28 | 21 | ||||
Female | 21 | 14 | 18 | 17 | 14 | 21 | 14 | 21 | ||||
Age (years) & | 60.5 ± 12.821 | 64.19 ± 12.451 | 0.243 | 60.5 ± 11.171 | 64.19 ± 13.952 | 0.088 | 60.7 ± 13.885 | 63.84 ± 11.471 | 0.373 | 62.48 ± 12.547 | 62.21 ± 12.998 | 0.9 |
Location | 0.005 * | 0.637 | 0.514 | 0.3445 | ||||||||
Gastric | 35 | 23 | 30 | 28 | 29 | 29 | 27 | 31 | ||||
Non-gastric | 7 | 19 | 12 | 14 | 11 | 15 | 15 | 11 | ||||
Histologic Type | 0.266 | 0.266 | 0.145 | 0.578 | ||||||||
Spindle | 36 | 32 | 36 | 32 | 35 | 33 | 35 | 33 | ||||
Epithelioid and mixed | 6 | 10 | 6 | 10 | 5 | 11 | 7 | 9 | ||||
Tumor size (cm) | 3.785 ± 1.877 | 6.227 ± 4.803 | 0.01 * | 4.212 ± 2.538 | 5.8 ± 4.681 | 0.128 | 4.128 ± 2.25 | 5.843 ± 4.757 | 0.091 | 4.622 ± 3.577 | 5.390 ± 4.068 | 0.244 |
<5 cm | 33 | 23 | 0.018 * | 31 | 25 | 0.154 | 30 | 26 | 0.203 | 30 | 26 | 0.342 |
>5 cm | 8 | 18 | 10 | 16 | 10 | 16 | 11 | 15 | ||||
Mitotic count (50HPFs) & | 1.74 ± 1.149 | 8.46 ± 9.998 | <0.001 * | 2.91 ± 6.818 | 7.26 ± 8.201 | <0.001 * | 3.08 ± 6.893 | 6.91 ± 8.214 | 0.016 * | 2.95 ± 6.811 | 7.22 ± 8.233 | 0.001 * |
NIH Risk | <0.001 * | 0.001 * | 0.001 * | 0.007 * | ||||||||
Low/very low | 34 | 14 | 32 | 16 | 30 | 18 | 31 | 17 | ||||
Intermediate | 8 | 9 | 7 | 10 | 8 | 9 | 6 | 11 | ||||
High | 0 | 19 | 3 | 16 | 2 | 17 | 5 | 14 | ||||
NCCN guideline | <0.001 * | <0.001 * | <0.001 * | 0.002 * | ||||||||
None/very low | 29 | 11 | 25 | 15 | 25 | 15 | 24 | 16 | ||||
Low | 12 | 4 | 13 | 3 | 11 | 5 | 12 | 4 | ||||
Moderate | 1 | 10 | 2 | 9 | 2 | 9 | 2 | 9 | ||||
High | 0 | 17 | 2 | 15 | 2 | 15 | 4 | 13 |
Parameters | RB1 Dosage | p-Value | BRCA2 Dosage | p-Value | CHEK2 Dosage | p-Value | |||
---|---|---|---|---|---|---|---|---|---|
DQ > 0.7 | DQ ≤ 0.7 | DQ > 0.7 | DQ ≤ 0.7 | DQ > 0.7 | DQ ≤ 0.7 | ||||
Sex | 0.107 | 0.564 | 0.201 | ||||||
Male | 26 | 1 | 24 | 3 | 5 | 22 | |||
Female | 11 | 3 | 12 | 2 | 5 | 9 | |||
Age (years) & | 64.08 ± 11.15 | 64.25 ± 17.86 | 1 | 62.39 ± 11.22 | 76.4 ± 6.5 | 0.005 * | 58.1 ± 9.28 | 66.03 ± 11.81 | 0.033 * |
Location | 0.013 * | 0.249 | 0.54 | ||||||
Gastric | 26 | 0 | 24 | 2 | 6 | 20 | |||
Non-gastric | 11 | 4 | 12 | 3 | 4 | 11 | |||
Histologic Type | 0.288 | 0.11 | 0.546 | ||||||
Spindle | 28 | 2 | 28 | 2 | 7 | 23 | |||
Epithelioid and mixed | 9 | 2 | 8 | 3 | 3 | 8 | |||
Tumor size (cm) | 0.283 | 0.308 | 0.475 | ||||||
<5 cm | 23 | 1 | 22 | 2 | 6 | 18 | |||
>5 cm | 13 | 3 | 13 | 3 | 3 | 13 | |||
Mitotic count (50HPFs) & | 4.14 ± 5.75 | 15.5 ± 12.58 | 0.005 * | 5.11 ± 7.64 | 6.4 ± 5.18 | 0.449 | 7.4 ± 10.8 | 4.57 ± 5.83 | 0.89 |
NIH Risk | 0.001 * | 0.086 | 0.405 | ||||||
Low/very low | 17 | 0 | 15 | 2 | 3 | 14 | |||
Intermediate | 14 | 0 | 14 | 0 | 3 | 11 | |||
High | 6 | 4 | 7 | 3 | 4 | 6 | |||
NCCN guideline | 0.003 * | 0.23 | 0.397 | ||||||
None/very low | 14 | 0 | 13 | 1 | 4 | 10 | |||
Low | 10 | 0 | 9 | 1 | 1 | 9 | |||
Moderate | 7 | 0 | 7 | 0 | 1 | 6 | |||
High | 6 | 4 | 7 | 3 | 4 | 6 | |||
rH2AX H-score | 0.143 | 0.341 | 0.612 | ||||||
Low | 16 | 0 | 15 | 1 | 4 | 12 | |||
High | 21 | 4 | 21 | 4 | 6 | 19 | |||
rH2AX IF | 0.143 | 0.071 | 0.325 | ||||||
Low | 16 | 0 | 16 | 0 | 5 | 11 | |||
High | 21 | 4 | 20 | 5 | 5 | 20 | |||
53BP1 H-score | 0.048 * | 0.156 | 0.607 | ||||||
Low | 21 | 0 | 20 | 1 | 5 | 16 | |||
High | 16 | 4 | 16 | 4 | 5 | 15 | |||
53BP1 IF | 0.118 | 0.258 | 0.535 | ||||||
Low | 18 | 0 | 17 | 1 | 4 | 14 | |||
High | 19 | 4 | 19 | 4 | 6 | 17 |
Parameters | rH2AX H-Score | p-Value | 53BP1 H-Score | p-Value | ||
---|---|---|---|---|---|---|
Low | High | Low | High | |||
Sex | 0.889 | 0.372 | ||||
Male | 65 | 69 | 63 | 71 | ||
Female | 72 | 79 | 79 | 72 | ||
Age (years) & | 60.57 ± 12.36 | 59.12 ± 12.01 | 0.395 | 58.82 ± 13.35 | 60.8 ± 10.94 | 0.158 |
Location | 0.097 | 0.359 | ||||
Gastric | 97 | 91 | 90 | 98 | ||
Non-gastric | 40 | 57 | 52 | 45 | ||
Histologic Type | 0.012 * | <0.001 * | ||||
Spindle | 108 | 98 | 118 | 88 | ||
Epithelioid and mixed | 27 | 49 | 23 | 53 | ||
Tumor size (cm) | 0.081 | 0.001 * | ||||
≤5 cm | 63 | 53 | 72 | 44 | ||
>5 cm | 74 | 95 | 70 | 99 | ||
Mitotic count (50HPFs) & | 8.72 ± 23.68 | 9.95 ± 21.95 | 0.021 * | 4.79 ± 16.08 | 13.89 ± 27.17 | <0.001 * |
NIH Risk | 0.002 * | <0.001 * | ||||
Low/very low | 52 | 30 | 63 | 19 | ||
Intermediate | 50 | 59 | 51 | 58 | ||
High | 35 | 59 | 28 | 66 | ||
NCCN guideline # | ||||||
None/very low | 38 | 17 | <0.001 * | 41 | 14 | <0.001 * |
Low | 51 | 37 | 60 | 28 | ||
Moderate | 19 | 45 | 17 | 47 | ||
High | 28 | 49 | 23 | 54 | ||
Genotypes | 0.449 | 0.015 * | ||||
Other mutant and wild types | 100 | 102 | 110 | 92 | ||
5′ deletion of KIT exon-11 | 37 | 46 | 32 | 51 |
Parameters | Univariate Analysis | Multivariate Analysis | ||||
---|---|---|---|---|---|---|
No. Case | No. Event | p-Value | HR | 95% CI | p-Value | |
Sex | 0.563 | |||||
Male | 134 | 30 | ||||
Female | 151 | 31 | ||||
Age (years) | 0.1 | |||||
<70 | 214 | 41 | ||||
≥70 | 71 | 20 | ||||
Location | 0.002 * | 0.237 | ||||
Gastric | 188 | 30 | 1 | - | ||
Non-gastric | 97 | 31 | 1.365 | 0.815–2.289 | ||
Histologic Type | <0.0001 * | 0.033 * | ||||
Spindle | 206 | 32 | 1 | - | ||
Epithelioid and mixed | 77 | 29 | 1.8 | 1.048–3.093 | ||
Tumor size (cm) | <0.001 * | |||||
≤5 cm | 116 | 10 | ||||
>5; ≤10 cm | 119 | 25 | ||||
≥10 cm | 50 | 26 | ||||
Mitotic count (50HPFs) | <0.001 * | |||||
0–5 | 197 | 24 | ||||
6–10 | 43 | 9 | ||||
>10 | 45 | 28 | ||||
NCCN guideline # | <0.001 * | <0.001 * | ||||
None/very low | 55 | 2 | 1 | - | ||
Low | 88 | 8 | 2.05 | 0.431–9.743 | ||
Moderate | 64 | 8 | 2.518 | 0.514–12.339 | ||
High | 77 | 43 | 14.612 | 3.355–63.641 | ||
Genotypes | <0.001 * | 0.005 * | ||||
Other mutant and wild types | 202 | 32 | 1 | - | ||
5′ deletion of KIT exon-11 | 83 | 29 | 2.12 | 1.23–3.568 | ||
rH2AX expression | 0.403 | |||||
Low expression | 137 | 26 | ||||
High expression | 148 | 35 | ||||
53BP1 expression | 0.125 | |||||
Low expression | 142 | 25 | ||||
High expression | 143 | 36 | ||||
Combinations of rH2AX and 53BP1 | 0.031 * | 0.537 | ||||
Low expression in both | 100 | 14 | 1 | - | ||
High expression in either or both | 185 | 47 | 0.815 | 0.426–1.559 |
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Liu, T.-T.; Li, C.-F.; Tan, K.-T.; Jan, Y.-H.; Lee, P.-H.; Huang, C.-H.; Yu, S.-C.; Tsao, C.-F.; Wang, J.-C.; Huang, H.-Y. 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. Cancers 2022, 14, 1787. https://doi.org/10.3390/cancers14071787
Liu T-T, Li C-F, Tan K-T, Jan Y-H, Lee P-H, Huang C-H, Yu S-C, Tsao C-F, Wang J-C, Huang H-Y. 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. Cancers. 2022; 14(7):1787. https://doi.org/10.3390/cancers14071787
Chicago/Turabian StyleLiu, Ting-Ting, Chien-Feng Li, Kien-Thiam Tan, Yi-Hua Jan, Pei-Hang Lee, Chih-Hao Huang, Shih-Chen Yu, Cheng-Feng Tsao, Jui-Chu Wang, and Hsuan-Ying Huang. 2022. "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" Cancers 14, no. 7: 1787. https://doi.org/10.3390/cancers14071787