Assessing the Phenotype of a Homologous Recombination Deficiency Using High Resolution Array-Based Comparative Genome Hybridization in Ovarian Cancer
Abstract
:1. Introduction
2. Results
2.1. Determination of HRD Score Cut-Off
2.2. Panel Sequencing and HRD-Score
2.3. CNV Cluster Analysis in 132 Tumor Genes and 30 OC Cases
2.4. CNV Differences in 30 OC Cases with and without BRCA Mutation
2.5. Validation of HRD Detection Using aCGH on 19 OC
3. Discussion
4. Materials and Methods
4.1. Biomaterial
4.2. Panel Sequencing
4.3. aCGH
4.4. Determination of the HRD Score
4.5. Evaluation of the HRD Score
4.6. Statistics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patient-ID | Mutation BRCA1/2 | LOH | TAI | LST-Break Points | HRD-Score |
---|---|---|---|---|---|
51-J-69 | 1 | 24 | 28 | 98 | 150 |
31-J-53 | 2 | 13 | 10 | 74 | 97 |
85-K-49 | 1 | 22 | 15 | 64 | 101 |
21-R-22 | 2 | 9 | 19 | 58 | 86 |
24-S-35 | 1 | 1 | 17 | 53 | 71 |
74-R-62 | 1 | 17 | 20 | 47 | 84 |
47-G-58 | 2 | 15 | 17 | 44 | 76 |
29-B-70 | 1 | 37 | 14 | 43 | 94 |
36-B-63 | 2 | 9 | 18 | 32 | 59 |
72-S-59 | 1 | 0 | 7 | 29 | 36 |
16-P-38 | 2 | 0 | 0 | 7 | 7 |
Mean | 13 | 15 | 50 | ||
Std. dev. | 11 | 7 | 24 | ||
Mean–std. dev. | 2 | 8 | 26 | Sum 35 |
Patient-Code | BRCA1 | BRCA2 | TP53 | Further Genes | LOH | TAI | LST-Break Points | HRD- Score |
---|---|---|---|---|---|---|---|---|
51-J-69 | c.5266_5267 insC (89%) | c.520A>T (85%) | 24 | 28 | 98 | 150 | ||
71-T-53 | c.375G>A (31%), c.764T>G (59%) | 3 | 25 | 97 | 125 | |||
49-J-56 | c.268_269delTC (68%) | 24 | 20 | 66 | 110 | |||
85-K-49 | c.1166delG (53%) | c.463A>C (36%) | CHEK2 (42%) | 22 | 15 | 64 | 101 | |
31-J-53 | c.5466_5467insA (64%) | c.659A>G (54%) | 13 | 10 | 74 | 97 | ||
29-B-702 | c.1687C>T (68%) | c.375+2T>A (34%) | MLH1 (48%) | 37 | 14 | 43 | 94 | |
23-S-36 | c.452C>A (91%) | 16 | 20 | 51 | 87 | |||
21-R-22 | c.657_658delTG (71%) | c.1013_1014insT (42%) | MUTYH (25%), SLX4 (49%) | 9 | 19 | 58 | 86 | |
74-R-62 | c.4035delA (71%) | c.659A>G (49%) | 17 | 20 | 47 | 84 | ||
8-T-45 | c.824G>T (95%) | 15 | 21 | 46 | 82 | |||
38-B-55 | c.402T>A (37%) | RECQL (50%), RAD51D (67%), RAD51C (31%) | 20 | 16 | 43 | 79 | ||
42-H-37 | c.524G>A (92%) | 16 | 17 | 46 | 79 | |||
47-G-58 | c.8933C>G (70%) | c.638G>T (64%) | NF1 (30%) | 15 | 17 | 44 | 76 | |
24-S-35 | c.2908A>T (44%) | c.224delC (44%) | Fam175A (62%) | 1 | 17 | 53 | 71 | |
25-S-37 | c.814G>A (36%) | FANCM (43%) | 21 | 12 | 9 | 62 | ||
36-B-63 | c.4363G>T (73%) | c.949C>T (70%) | 9 | 18 | 32 | 59 | ||
73-W-39 | c.559+1G>C (59%) | MAP3K1 (44%), RAD50 (75%), SMARCA4 (54%) | 1 | 17 | 30 | 48 | ||
59-S-54 | c.764_766delTCA (79%) | 12 | 13 | 19 | 44 | |||
17-P-40 | c.517G>A (84%) | CDH1 (36%) | 3 | 12 | 28 | 43 | ||
72-S-59 | c.906delT (30%) | c.626_627delGA (28%) | PMS2 (47%) | 0 | 7 | 29 | 36 | |
33-T-36 | c.536A>G (66%) | 10 | 9 | 6 | 25 | |||
45-K-67 | MSH2 (49%) | 4 | 4 | 4 | 12 | |||
97-W-65 | 9 | 0 | 0 | 9 | ||||
16-P-38 | c.5164_5165delAG (56%) | 0 | 0 | 7 | 7 | |||
99-T-47 | c.626_627delGA (38%) | 0 | 2 | 3 | 5 | |||
107-S-59 | FANCM (49%) | 1 | 0 | 2 | 3 | |||
92-W-69 | CDH1 (50%) | 0 | 1 | 1 | 2 | |||
88-K-51 | MSH6 (50%) | 0 | 0 | 0 | 0 | |||
12-L-52 | 0 | 0 | 0 | 0 | ||||
54-D-39 | 0 | 0 | 0 | 0 | ||||
Mutation (Frequency) |
Cases with BRCA 1/2 Mutation | Cases without BRCA 1/2 Mutation | |||||||
---|---|---|---|---|---|---|---|---|
Chr. Region (bp-Position) | Incl. Tumor Gene | No. Gains | No. Balance | No. Losses | No. Gains | No. Balance | No. Losses | Chi2 |
10p15.3 (171262–1306517) | no | 8 | 3 | 0 | 3 | 15 | 1 | 0.0073 |
10p15.3 (1306517–3793806) | no | 7 | 4 | 0 | 3 | 15 | 1 | 0.0252 |
11p15.4 (2976948–5785900) | no | 0 | 5 | 6 | 1 | 16 | 2 | 0.0282 |
11p15.4 (5785900–5809417) | no | 0 | 4 | 7 | 1 | 16 | 2 | 0.0086 |
11p15.4 (5809417–9463851) | no | 0 | 5 | 6 | 1 | 16 | 2 | 0.0282 |
11p15.4 (9463851–9516249) | no | 0 | 5 | 6 | 2 | 15 | 2 | 0.0248 |
11p15.4–11p15.3 (9516249–12042992) | no | 0 | 5 | 6 | 1 | 16 | 2 | 0.0282 |
Patient-Code | Extern HRD Examination | LOH | TAI | LST-Break Points | HRD- Score | HRD |
---|---|---|---|---|---|---|
Valid-01 | HRD detected | 18 | 11 | 63 | 92 | yes |
Valid-02 | mutated BRCA1 | 5 | 14 | 61 | 80 | yes |
Valid-03 | mutated BRCA2 | 15 | 18 | 36 | 69 | yes |
Valid-04 | mutated BRCA1 | 18 | 9 | 32 | 59 | yes |
Valid-05 | mutated BRCA1 | 9 | 8 | 38 | 55 | yes |
Valid-06 | mutated BRCA1 | 0 | 12 | 43 | 55 | yes |
Valid-07 | BRCA1/2 wt | 5 | 14 | 32 | 51 | yes |
Valid-08 | BRCA1/2 wt | 12 | 9 | 22 | 43 | yes |
Valid-09 | mutated BRCA2 | 10 | 17 | 15 | 42 | yes |
Valid-10 | BRCA1/2 wt | 13 | 14 | 14 | 41 | no |
Valid-11 | mutated BRCA1 | 11 | 16 | 14 | 41 | no |
Valid-12 | BRCA1/2 wt; HRD negative | 0 | 14 | 26 | 40 | no |
Valid-13 | BRCA1/2 wt | 0 | 1 | 23 | 24 | no |
Valid-14 | mutated BRCA2 | 0 | 4 | 6 | 10 | no |
Valid-15 | BRCA1/2 wt | 4 | 0 | 0 | 4 | no |
Valid-16 | HRD negative | 0 | 1 | 2 | 3 | no |
Valid-17 | BRCA1/2 wt | 0 | 0 | 2 | 2 | no |
Valid-18 | BRCA1/2 wt | 0 | 0 | 0 | 0 | no |
Valid-19 | BRCA1/2 wt | 0 | 0 | 0 | 0 | no |
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Magadeeva, S.; Qian, X.; Korff, N.; Flörkemeier, I.; Hedemann, N.; Rogmans, C.; Forster, M.; Arnold, N.; Maass, N.; Bauerschlag, D.O.; et al. Assessing the Phenotype of a Homologous Recombination Deficiency Using High Resolution Array-Based Comparative Genome Hybridization in Ovarian Cancer. Int. J. Mol. Sci. 2023, 24, 17467. https://doi.org/10.3390/ijms242417467
Magadeeva S, Qian X, Korff N, Flörkemeier I, Hedemann N, Rogmans C, Forster M, Arnold N, Maass N, Bauerschlag DO, et al. Assessing the Phenotype of a Homologous Recombination Deficiency Using High Resolution Array-Based Comparative Genome Hybridization in Ovarian Cancer. International Journal of Molecular Sciences. 2023; 24(24):17467. https://doi.org/10.3390/ijms242417467
Chicago/Turabian StyleMagadeeva, Svetlana, Xueqian Qian, Nadine Korff, Inken Flörkemeier, Nina Hedemann, Christoph Rogmans, Michael Forster, Norbert Arnold, Nicolai Maass, Dirk O. Bauerschlag, and et al. 2023. "Assessing the Phenotype of a Homologous Recombination Deficiency Using High Resolution Array-Based Comparative Genome Hybridization in Ovarian Cancer" International Journal of Molecular Sciences 24, no. 24: 17467. https://doi.org/10.3390/ijms242417467