Relationship between the Expression of CHK2 and p53 in Tumor Tissue and the Course of Papillary Thyroid Cancer in Patients with CHEK2 Germline Mutations
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Description of the Test Procedure
2.3. Detection of CHEK2 Mutation
2.4. Fluorescence In Situ Hybridization (FISH)
2.5. Immunohistochemistry (IHC)
IHC Staining
2.6. Analysis of Immunohistochemical Results
2.7. Statistical Analyses
3. Results
3.1. Baseline Characteristics
3.1.1. CHK2 and p53 Expression: Impact on Clinicopathological Features, Treatment Response and Outcomes in PTC Patients with and without CHEK2 Mutations
3.1.2. Impact of CHEK2 and TP53 Gene Status, and p53 Expression on Clinicopathological Features, Treatment Response and Outcomes in PTC Patients with and without CHEK2 Mutations
3.1.3. Prognostically Favorable and Predictive Results Defined as Categories of Interest in Groups of PTC Patients with and without CHEK2 Mutations
3.1.4. Predictive Value of Clinicopathological Features, Treatment Response, and Outcome Correlations with CHK2, TP53 Status, and p53 Expression in PTC Patients with and without CHEK2 Mutations
3.1.5. Posterior Distribution of Odds Log Ratio for Clinicopathological Correlations with CHK2, TP53 Status, and p53 Expression in PTC Patients with and without CHEK2 Mutations
3.1.6. Sequential Analysis of Clinicopathological Correlations with CHK2, TP53 Status, and p53 Expression in PTC Tumors with and without CHEK2 Mutations
3.1.7. Correlation of Germline CHEK2 Mutation with p53 and CHK2 Expression, and CHEK2 and TP53 Gene Statuses in PTC Patients with and without CHEK2 Mutations
3.1.8. The Incidence of Unfavorable Prognostic Factors Linked to CHEK2 and TP53 Gene Alterations, CHK2 and p53 Expression in PTC Patients with and without CHEK2 Mutations
3.1.9. Predictive Value of CHEK2 and TP53 Gene Status, CHK2 and p53 Expression in PTC Patients with WT and/or I157T CHEK2 Mutations
3.1.10. Posterior Odds Log Ratio Distribution for CHEK2 and TP53 Gene Status, CHK2 and p53 Expression in PTC Patients with and without CHEK2 Mutations
3.1.11. Sequential Analysis of Associations Involving CHEK2 and TP53 Gene Status, CHK2 and p53 Expression in PTC Patients with and without CHEK2 Mutations
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Correction Statement
References
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Characteristic | Total n = 156 (100%) |
---|---|
Sex | |
Female | 138 (88.5%) |
Male | 18 (11.5%) |
Age at diagnosis (years) | |
<55 | 98 (62.8%) |
≥55 | 58 (37.2%) |
Mean (SD) | 48.5 (13.6) |
Median (Q1–Q3) | 49.5 (39.0–59.0) |
Range | 18.0–73.0 |
Tumor diameter (mm) | |
Mean (SD) | 13.1 (13.0) |
Median (Q1–Q3) | 8.0 (5.0–16.5) |
Range | 1.0–84.0 |
Tumor diameter (mm) | |
≤10 | 94 (60.3%) |
>10–20 | 32 (20.5%) |
>20–40 | 25 (16.0%) |
>40 | 5 (3.2%) |
Papillary cancer histologic variant | |
Classic | 107 (68.6%) |
Follicular | 35 (22.4%) |
Oxyphilic | 3 (1.9%) |
Diffuse sclerosing | 3 (1.9%) |
Tall cell | 1 (0.6%) |
Other * | 7 (4.5%) |
Surgical treatment | |
Total thyroidectomy | 152 (97.4%) |
Lobectomy | 4 (2.6%) |
Nodal dissection | |
Central | 94 (60.3%) |
Lateral | 17 (10.9%) |
No dissection | 45 (28.8%) |
Multifocality | |
No | 106 (68.0%) |
Yes | 50 (32.1%) |
Lymph node metastases ** | |
N0a | 76 (48.7%) |
N0b | 45 (28.9%) |
N1a | 18 (11.5%) |
N1b | 17 (10.9%) |
Distant metastases | |
M0 | 155 (99.4%) |
M1 | 1 (0.6%) |
Extrathyroidal extension | |
Negative | 124 (79.5%) |
Microscopic | 30 (19.2%) |
Gross | 2 (1.3%) |
Vascular invasion | |
No | 145 (93%) |
Yes | 11 (7.1%) |
Margin status | |
R0 | 137 (87.8%) |
R1 | 19 (12.2%) |
Tumor stage | |
pT1a | 94 (60.3%) |
pT1b | 32 (20.5%) |
pT2 | 23 (14.7%) |
pT3a | 5 (3.2%) |
pT3b | 2 (1.3%) |
CHEK2 mutation status | |
CHEK2 WT | 52 (33.3%) |
CHEK2 mutation any | 104 (66.7%) |
CHEK2 I157T missense mutation (any) | 60 (38.5%) |
I157T heterozygous | 53 (34.0%) |
I157T homozygous | 7 (4.5%) |
CHEK2 truncating heterozygous mutation (any) | 38 (24.4%) |
IVS2 + 1G > A | 16 (10.3%) |
Del5395 | 10 (6.4%) |
1100delC | 12 (7.7%) |
Coexistence of two heterozygous CHEK2 mutations | 6 (3.8%) |
I157T and IVS2 + 1G > A | 3 (1.9%) |
I157T and Del5395 | 1 (0.6%) |
IVS2 + 1G > A and Del5395 | 2 (1.3%) |
TNM (8th edition) | |
I | 144 (92.3%) |
II | 12 (7.7%) |
ATA initial risk stratification system | |
Low | 97 (62.2%) |
Intermediate | 34 (21.8%) |
High | 25 (16.0%) |
Radioactive iodine (I-131) therapy | |
No | 45 (28.9%) |
Yes | 111 (71.2%) |
More than one course of radioactive iodine therapy (I-131) | |
No | 138 (88.5%) |
Yes | 18 (11.5%) |
Response to therapy | |
Excellent | 127 (81.4%) |
Indeterminate | 24 (15.4%) |
Biochemically incomplete | 2 (1.3%) |
Structurally incomplete | 3 (1.9%) |
Final follow-up (disease outcome) | |
NED | 145 (93.0%) |
Indeterminate | 7 (4.5%) |
Biochemically persistent | 1 (0.6%) |
Structurally persistent | 3 (1.9%) |
Follow-up, recurrence | |
No | 151 (96.8%) |
Yes | 5 (3.2%) |
Death | |
No | 151 (96.8%) |
Yes | 5 (3.2%) |
Follow-up (years) | |
Median (range) | 7.0 (1.0–23.0) |
Variable | p53, n = 156 (100%) | CHK2, n = 156 (100%) | CHEK2 (FISH), n = 151 (100%) | TP53 (FISH), n = 151 (100%) | Positive p53 with TP53 Deletion (FISH) | |||||
---|---|---|---|---|---|---|---|---|---|---|
Positive n = 8 (5.1%) | High Expression n = 23 (14.7%) | Deletion n = 44 (29.1%) | Deletion n = 7 (4.6%) | n = 15 out of 151 (9.9%) | ||||||
OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | |
Sex | ||||||||||
Female vs. male | NA (0 in cell) | 1.44 (0.31–6.71) | 0.645 | 1.08 (0.36–3.23) | 0.892 | 1.09 (0.13–9.24) | 0.938 | NA (0 in cell) | ||
Age group | ||||||||||
≥55 years vs. <55 years | 2.99 (0.69–13.00) | 0.145 | 0.55 (0.20–1.49) | 0.238 | 0.75 (0.36–1.58) | 0.451 | 3.92 (0.94–16.35) | 0.061 | 3.03 (1.02–9.05) | 0.047 |
Tumor stage | ||||||||||
pT1a vs. pT1b, pT2, pT3a, pT3b | NA (0 in cell) | 0.96 (0.11–8.38) | 0.972 | 0.97 (0.18–5.21) | 0.973 | 0.81 (0.21–3.16) | 0.766 | 0.99 (0.33–2.93) | 0.982 | |
TNM (8th edition) | ||||||||||
TNM II vs. TNM I | NA (0 in cell) | 1.17 (0.24–5.73) | 0.845 | 0.52 (0.11–2.50) | 0.414 | 1.65 (0.19–14.54) | 0.652 | 0.90 (0.11–7.56) | 0.923 | |
Multifocality | ||||||||||
Yes vs. no | 0.69 (0.14–3.57) | 0.662 | 0.92 (0.35–2.39) | 0.857 | 1.00 (0.47–2.13) | 0.996 | 0.62 (0.12–3.08) | 0.555 | 0.52 (0.14–1.95) | 0.334 |
Lymph node metastasis * | ||||||||||
N1a, N1b vs. N0b, N0a | NA (0 in cell) | 0.95 (0.33–2.78) | 0.931 | 1.02 (0.44–2.35) | 0.968 | 0.40 (0.05–3.29) | 0.392 | 0.21 (0.03–1.69) | 0.144 | |
Distant metastasis | ||||||||||
M1 vs. M0 | NA (0 in cell) | NA (0 in cell) | NA (0 in cell) | NA (0 in cell) | 0.993 | NA (0 in cell) | ||||
Tumor diameter | ||||||||||
>10 and ≤20 mm vs. ≤10 mm | 1.84 (0.41–8.18) | 0.422 | 2.80 (1.00–7.88) | 0.051 | 0.78 (0.31–1.95) | 0.592 | 1.84 (0.41–8.21) | 0.422 | 1.75 (0.54–5.70) | 0.351 |
>20 and ≤40 mm vs. ≤10 mm | NA (0 in cell) | 2.10 (0.65–6.83) | 0.217 | 1.31 (0.52–3.34) | 0.568 | 0.72 (0.08–6.43) | 0.766 | 0.38 (0.05–3.15) | 0.370 | |
>40 mm vs. ≤10 mm | NA (0 in cell) | NA (0 in cell) | NA (0 in cell) | NA (0 in cell) | NA (0 in cell) | |||||
Papillary cancer histologic variant | ||||||||||
Follicular vs. Classic | 1.24 (0.23–6.68) | 0.805 | 1.02 (0.34–3.05) | 0.969 | 1.24 (0.54–2.86) | 0.618 | 0.44 (0.05–3.69) | 0.447 | 0.95 (0.25–3.68) | 0.941 |
Other ** aggressive vs. Classic | NA (0 in cell) | 6.13 (0.80–46.91) | 0.081 | 0.86 (0.09–8.63) | 0.900 | 4.67 (0.43–50.91) | 0.206 | 3.17 (0.30–33.37) | 0.337 | |
Other *** non-aggressive vs. Classic | 2.27 (0.24–21.56) | 0.476 | 0.68 (0.08–5.77) | 0.725 | 1.29 (0.30–5.52) | 0.728 | NA (0 in cell) | 1.19 (0.13–10.49) | 0.877 | |
Extrathyroidal extension | ||||||||||
Micro and gross vs. negative | 1.31 (0.25–6.83) | 0.748 | 1.09 (0.37–3.20) | 0.875 | 1.45 (0.63–3.35) | 0.385 | 1.11 (0.22–5.65) | 0.897 | 0.68 (0.20–2.31) | 0.537 |
Vascular invasion | ||||||||||
Yes vs. no | NA (0 in cell) | 1.31 (0.27–6.50) | 0.739 | 2.62 (0.72–9.53) | 0.145 | 8.38 (1.76–39.80) | 0.008 | 4.00 (0.94–17.10) | 0.061 | |
Margin status | ||||||||||
R1 vs. R0 | NA (0 in cell) | 0.65 (0.14–3.02) | 0.583 | 0.85 (0.29–2.53) | 0.772 | 0.92 (0.11–7.81) | 0.938 | 0.50 (0.06–4.05) | 0.516 | |
ATA | ||||||||||
Low vs intermediate, high | 1.01 (0.23–4.41) | 0.985 | 0.62 (0.25–1.50) | 0.287 | 1.05 (0.50–2.17) | 0.906 | 0.72 (0.19–2.81) | 0.639 | 1.55 (0.53–4.54) | 0.421 |
Response to therapy | ||||||||||
Excellent vs. others | NA (0 in cell) | 0.28 (0.11–0.72) | 0.009 | 0.85 (0.34–2.14) | 0.731 | 1.63 (0.19–13.61) | 0.653 | 0.33 (0.04–2.66) | 0.300 | |
Radioactive iodine (I-131) therapy | ||||||||||
Yes vs. no | 0.66 (0.15–2.89) | 0.581 | 2.12 (0.68–6.61) | 0.197 | 0.72 (0.34–1.53) | 0.391 | 3.48 (0.42–28.64) | 0.247 | 1.15 (0.34–3.81) | 0.824 |
Number of I-131 courses | ||||||||||
2–9 courses vs. 0–1 course | 2.75 (0.51–14.79) | 0.239 | 0.70 (0.15–3.25) | 0.646 | 2.16 (0.79–5.89) | 0.134 | 0.92 (0.11–7.81) | 0.938 | 2.02 (0.51–7.97) | 0.317 |
Final follow-up | ||||||||||
NED vs. others | NA (0 in cell) | 0.17 (0.05–0.62) | 0.007 | 0.96 (0.24–3.88) | 0.951 | 0.54 (0.06–4.82) | 0.582 | 0.99 (0.12–8.42) | 0.994 | |
Follow-up recurrence | ||||||||||
Yes vs. no | NA (0 in cell) | 1.47 (0.16–13.74) | 0.738 | NA (0 in cell) | NA (0 in cell) | NA (0 in cell) | ||||
Death | ||||||||||
Yes vs. no | NA (0 in cell) | NA (0 in cell) | 0.60 (0.07–5.51) | 0.651 | 4.31 (0.43–43.20) | 0.214 | 2.36 (0.25–22.58) | 0.457 |
Group | Category of Interest | Counts | Total | Proportion |
---|---|---|---|---|
Response to therapy | Excellent | |||
Low CHK2 | 113 | 133 | 0.850 | |
High CHK2 | 14 | 23 | 0.609 | |
Final follow-up | NED | |||
Low CHK2 | 127 | 133 | 0.955 | |
High CHK2 | 18 | 23 | 0.783 | |
Tumor diameter | ≤10 mm | |||
Low CHK2 | 84 | 108 | 0.788 | |
High CHK2 | 10 | 18 | 0.556 | |
Papillary cancer histologic variant | Classic | |||
Low CHK2 | 92 | 94 | 0.979 | |
High CHK2 | 15 | 17 | 0.882 | |
Age | <55 years | |||
No loss of TP53 | 94 | 142 | 0.662 | |
Deletion of TP53 | 3 | 9 | 0.333 | |
Vascular invasion | No | |||
No loss of TP53 | 134 | 142 | 0.944 | |
Deletion of TP53 | 6 | 9 | 0.667 | |
Age | <55 years | |||
Negative p53 + no loss of TP53 | 91 | 136 | 0.669 | |
Positive p53 + Deletion of TP53 | 6 | 15 | 0.400 | |
Vascular invasion | No | |||
Negative p53 + no loss of TP53 | 128 | 136 | 0.941 | |
Positive p53 + Deletion of TP53 | 12 | 15 | 0.800 |
Variable | CHEK2 Truncating vs. WT | CHEK2 Missense vs. WT | CHEK2 Truncating vs. WT + Missense I157T | |||
---|---|---|---|---|---|---|
OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | |
p53 expression | ||||||
Positive vs. negative | 0.42 (0.04–4.19) | 0.459 | 1.17 (0.25–5.47) | 0.845 | 0.35 (0.04–2.92) | 0.331 |
CHK2 expression | ||||||
High vs. low | 3.48 (0.99–12.30) | 0.052 | 2.12 (0.61–7.33) | 0.236 | 2.24 (0.90–5.58) | 0.083 |
CHEK2 gene status | ||||||
Deletion vs. no loss of gene copy | 62.67 (16.37–239.93) | <0.001 | 1.31 (0.35–4.91) | 0.693 | 57.23 (19.36–169.24) | <0.001 |
TP53 gene status | ||||||
Deletion vs. no loss of gene copy | NA (0 in cell) | NA (0 in cell) | NA (0 in cell) | |||
p53 expression and TP53 gene status | ||||||
Positive vs. negative and deletion vs. no loss of gene copy | 3.47 (0.84–14.37) | 0.087 | 1.17 (0.25–5.47) | 0.845 | 3.33 (1.13–9.84) | 0.029 |
Variable | CHEK2 Truncating and WT | CHEK2 Truncating and WT + Missense I157T | |||||
---|---|---|---|---|---|---|---|
Group | Counts | Total | Proportion | Counts | Total | Proportion | |
CHEK2 deletion | No mutation | 4 | 51 | 0.078 | 10 | 111 | 0.090 |
Mutation | 32 | 38 | 0.842 | 34 | 40 | 0.850 | |
High expression of CHK2 | No mutation | 4 | 52 | 0.077 | 13 | 112 | 0.116 |
Mutation | 9 | 40 | 0.225 | 10 | 44 | 0.227 | |
Positive p53 and TP53 deletion | No mutation | 3 | 51 | 0.059 | 7 | 111 | 0.063 |
Mutation | 7 | 38 | 0.184 | 8 | 40 | 0.200 |
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Gąsior-Perczak, D.; Kowalik, A.; Kopczyński, J.; Macek, P.; Niemyska, K.; Walczyk, A.; Gruszczyński, K.; Siołek, M.; Dróżdż, T.; Kosowski, M.; et al. Relationship between the Expression of CHK2 and p53 in Tumor Tissue and the Course of Papillary Thyroid Cancer in Patients with CHEK2 Germline Mutations. Cancers 2024, 16, 815. https://doi.org/10.3390/cancers16040815
Gąsior-Perczak D, Kowalik A, Kopczyński J, Macek P, Niemyska K, Walczyk A, Gruszczyński K, Siołek M, Dróżdż T, Kosowski M, et al. Relationship between the Expression of CHK2 and p53 in Tumor Tissue and the Course of Papillary Thyroid Cancer in Patients with CHEK2 Germline Mutations. Cancers. 2024; 16(4):815. https://doi.org/10.3390/cancers16040815
Chicago/Turabian StyleGąsior-Perczak, Danuta, Artur Kowalik, Janusz Kopczyński, Paweł Macek, Kornelia Niemyska, Agnieszka Walczyk, Krzysztof Gruszczyński, Monika Siołek, Tomasz Dróżdż, Marcin Kosowski, and et al. 2024. "Relationship between the Expression of CHK2 and p53 in Tumor Tissue and the Course of Papillary Thyroid Cancer in Patients with CHEK2 Germline Mutations" Cancers 16, no. 4: 815. https://doi.org/10.3390/cancers16040815