High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Collective
2.2. Protein Expression Analysis and Immunohistochemistry
2.3. Gene Expression Analysis
2.4. Post-Hoc Correlations with Cancer Associated Fibroblasts
2.5. Statistical Analysis
3. Results
3.1. Protein Expression Cohort Analysis
3.2. Gene Expression Cohort Analysis
3.3. NT5DC2 Protein and Gene Expression
3.4. p53 Clinical Characterization in the Context of NT5DC2
3.5. Post-Hoc Correlation of NT5DC2 and p53 Protein Expression with Cancer Associated Fibroblasts (CAFs)
4. Discussion
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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Variables | Total Cohort | NT5DC2 Low | NT5DC2 High | |||||
---|---|---|---|---|---|---|---|---|
ntotal = 252 | % * | n = 107 | % * | n = 145 | % * | p-Value | ||
Age (Years) | Mean (±SD) | 65.9 (±8.5) | 64.8 (±7.6) | 66.8 (±9.0) | 0.059 a | |||
Sex | male | 206 | 81.7 | 86 | 80.4 | 120 | 58.3 | 0.625 c |
female | 46 | 18.3 | 21 | 19.6 | 25 | 17.2 | ||
ECOG | 0 | 33 | 13.1 | 16 | 15.0 | 17 | 11.7 | 0.253 b |
I | 200 | 79.4 | 85 | 79.4 | 115 | 79.3 | ||
II–III | 19 | 7.5 | 6 | 5.6 | 13 | 9.0 | ||
FEV1 (% pred.) | mean (±SD) | 80.5 (±20.3) | 80.6 (±20.8) | 80.4 (±20.0) | 0.950 a | |||
median (Q1–Q3) | 81 (65–96) | 82 (64–95.5) | 81 (65.5–96.0) | 0.999 b | ||||
Smoking status | non-smoker | 54 | 21.5 | 20 | 18.7 | 34 | 23.6 | 0.438 c |
(* n = 251) | smoker | 197 | 78.5 | 87 | 81.3 | 110 | 76.4 | |
Histopathology | squamous cell (SCC) | 121 | 48.0 | 55 | 51.4 | 66 | 45.5 | 0.534 d |
adeno (ADC) | 89 | 35.3 | 37 | 34.6 | 52 | 35.9 | ||
large cell (LCC) | 42 | 16.7 | 15 | 14.0 | 27 | 18.6 | ||
p53 IHC | low (IRS 0–3) | 151 | 64.3 | 70 | 73.7 | 81 | 57.9 | 0.018 c |
(* n = 235) | high (IRS 4–12) | 84 | 35.7 | 25 | 26.3 | 59 | 42.1 | |
p53 IHC | mean (±SD) | 2.8 (±3.4) | 2.1 (±3.2) | 3.3 (±3.5) | 0.009 a | |||
(* n = 235) | median (Q1–Q3) | 1.0 (0.0–5.0) | 0.0 (0.0–4.0) | 1.8 (0.0–6.0) | 0.002 b | |||
Grade (* n = 249) | G1 | 1 | 0.4 | 1 | 0.9 | 0 | 0.0 | 0.080 b |
G2 | 78 | 31.0 | 41 | 38.3 | 37 | 26.1 | ||
G3 | 135 | 53.6 | 50 | 46.7 | 85 | 59.9 | ||
G4 | 35 | 13.9 | 15 | 14.0 | 20 | 14.1 | ||
Resection | R0 | 237 | 94.0 | 98 | 91.6 | 139 | 95.9 | 0.159 b |
R1 | 13 | 5.2 | 8 | 7.5 | 5 | 3.4 | ||
R2 | 2 | 0.8 | 1 | 0.9 | 1 | 0.7 | ||
UICC6 pT | pT1 | 163 | 27.4 | 36 | 33.6 | 33 | 22.8 | 0.251 b |
pT2 | 55 | 58.3 | 54 | 50.5 | 93 | 64.1 | ||
pT3 | 34 | 10.3 | 13 | 12.1 | 13 | 9.0 | ||
pT4 | 10 | 4.0 | 4 | 3.7 | 6 | 4.1 | ||
UICC6 pN | pN0 | 163 | 64.7 | 73 | 68.2 | 90 | 62.1 | 0.372 b |
pN1 | 55 | 21.8 | 20 | 18.7 | 35 | 24.1 | ||
pN2 | 34 | 13.5 | 14 | 13.1 | 20 | 13.8 | ||
UICC6 cM | cM0 | 252 | 100.0 | 107 | 100.0 | 145 | 100.0 | 1.000 b |
UICC6 pTNM | stage I | 140 | 55.6 | 64 | 59.8 | 76 | 52.4 | 0.331 b |
stage II | 66 | 26.2 | 24 | 22.4 | 42 | 29.0 | ||
stage III | 46 | 18.3 | 19 | 17.8 | 27 | 18.6 | ||
PFS (months) | median (95% CI) | 32.7 (22.4–42.9) | 44.3 (9.2–79.4) | 30.8 (22.0–39.5) | 0.144 e | |||
OS (months) | median (95% CI) | 43.9 (32.2–55.5) | 58.1 (32.6–83.6) | 38.6 (29.0–48.1) | 0.146 e | |||
Follow up (months) | median (95% CI) | 89.4 (84.1–94.7) | 94.7 (86.8–102.6) | 85.3 (82.5–88.1) | 0.206 e |
Variables | Total Cohort | NT5DC2 mRNA Low | NT5DC2 mRNA High | p-Value | ||||
---|---|---|---|---|---|---|---|---|
ntotal = 1925 | % * | n = 963 | % * | n = 962 | % * | |||
Sex (* n = 1814) | male | 1100 | 60.6 | 550 | 60.6 | 550 | 60.7 | # |
female | 714 | 39.4 | 358 | 39.4 | 356 | 39.3 | ||
unknown | 111 | 55 | 56 | |||||
Smoking status (* n = 1025) | non-smoker | 205 | 20.0 | 102 | 19.9 | 103 | 20.1 | # |
smoker | 820 | 80.0 | 410 | 80.1 | 410 | 79.9 | ||
unknown | 900 | 451 | 449 | |||||
Histopathology (* n = 1243) | squamous cell (SCC) | 524 | 42.2 | 262 | 42.1 | 262 | 42.1 | 1.000 c |
adeno (ADC) | 719 | 57.8 | 360 | 57.9 | 359 | 57.9 | ||
unknown | 682 | 341 | 341 | |||||
TP53 mRNA | low (<median expr.) | 962 | 50.0 | 666 | 69.2 | 296 | 30.8 | <0.001 c |
high (≥median expr.) | 963 | 50.0 | 297 | 30.8 | 666 | 69.2 | ||
TP53 mRNA | mean (±SD) | 584.2 (±428.4) | 423.2 (±346.2) | 745.4 (±442.1) | <0.001 a <0.001 b | |||
median (Q1–Q3) | 488.0 (253.0–795.0) | 303.0 (101.0–570.0) | 681.5 (432.8–972.0) | |||||
Grade (* n = 588) | G1 | 201 | 34.2 | 100 | 34.1 | 101 | 34.2 | # |
G2 | 310 | 52.7 | 155 | 52.9 | 155 | 52.5 | ||
G3 | 77 | 13.1 | 38 | 13.0 | 39 | 23.2 | ||
unknown | 1337 | 670 | 667 | |||||
Resection (* n = 726) | R0 | 726 | 100.0 | 363 | 100.0 | 363 | 100.0 | - |
unknown | 1199 | 0 | 600 | 0 | 599 | |||
AJCC pT (* n = 1153) | pT1 | 437 | 37.9 | 218 | 37.9 | 219 | 37.9 | # |
pT2 | 589 | 51.1 | 294 | 51.1 | 295 | 51.0 | ||
pT3 | 81 | 7.0 | 40 | 7.0 | 41 | 7.1 | ||
pT4 | 46 | 4.0 | 23 | 4.0 | 23 | 4.0 | ||
unknown | 772 | 388 | 384 | |||||
AJCC pN (* n = 1144) | pN0 | 781 | 68.3 | 392 | 68.3 | 389 | 68.2 | # |
pN1 | 252 | 22.0 | 126 | 22.0 | 126 | 22.1 | ||
pN2 | 111 | 9.7 | 56 | 9.8 | 55 | 9.6 | ||
unknown | 781 | 389 | 392 | |||||
AJCC pM1 (* n = 691) | pM0 | 681 | 98.6 | 341 | 98.6 | 340 | 98.6 | # |
pM1 | 10 | 1.4 | 5 | 1.4 | 5 | 1.4 | ||
unknown | 1234 | 617 | 617 | |||||
AJCC pTNM (* n = 895) | stage I | 577 | 64.5 | 288 | 64.4 | 289 | 64.5 | # |
stage II | 244 | 27.3 | 122 | 27.3 | 122 | 27.2 | ||
stage III | 70 | 7.8 | 35 | 7.8 | 35 | 7.8 | ||
stage IV | 4 | 0.4 | 2 | 0.4 | 2 | 0.4 | ||
unknown | 1030 | 516 | 514 | |||||
PFS (months) (* n = 982) | median (95% CI) | 88.7 (n.e.–n.e.) | n.e. (n.e.–n.e.) | 53.2 (36.1–70.2) | <0.001 d | |||
OS (months) | median (95% CI) | 69.0 (62.9–75.1) | 77.8 (67.4–88.1) | 59.0 (50.5–67.5) | <0.001 d | |||
Follow up (months) | median (95% CI) | 69.4 (66.9–71.9) | 69.0 (65.7–72.3) | 71.8 (68.0–75.6) | 0.081 d |
NT5DC2 Protein Expression | Mean (±SD) IHC IRS | p-Value | Median (Q1–Q3) IHC IRS | p-Value | ||||
---|---|---|---|---|---|---|---|---|
Overall | 4.21 (±3.03) | 4.0 (2.0–6.0) | ||||||
Histology | ||||||||
SCC | 3.95 (±2.88) | 0.221 a | 4.0 (2.0–5.0) | 0.328 b | ||||
ADC | 4.49 (±3.37) | 4.0 (2.0–8.0) | ||||||
UICC 6 pT | 0.181 c | 0.122 d | ||||||
pT1 | 3.78 (±2.96) | 0.073 a | 3.0 (2.0–6.0) | 0.045 b | ||||
pT2 | 4.57 (±3.04) | 0.157 a | 4.0 (2.0–6.0) | 0.092 b | ||||
pT3 | 3.62 (±3.11) | 0.988 a | 3.5 (1.8–4.0) | 0.718 b | ||||
pT4 | 3.60 (±2.63) | 4.0 (1.5–6.0) | ||||||
UICC 6 pN | 0.114 c | 0.345 d | ||||||
pN0 | 3.95 (±2.78) | 0.259 a | 4.0 (2.0–6.0) | 0.282 b | ||||
pN1 | 4.49 (±3.13) | 0.467 a | 4.0 (2.0–8.0) | 0.706 b | ||||
pN2 | 5.06 (±3.80) | 4.0 (2.0–8.0) | ||||||
Grading | 0.342 c | 0.259 d | ||||||
G1 | 1.00 (±n.e.) | 0.333 a | 1.0 (1.0–1.0) | 0.221 b | ||||
G2 | 3.79 (±2.85) | 0.132 a | 3.0 (2.0–6.0) | 0.140 b | ||||
G3 | 4.44 (±3.21) | 0.607 a | 4.0 (2.0–6.0) | 0.814 b | ||||
G4 | 4.17 (±2.56) | 4.0 (2.0–6.0) | ||||||
p53 IHC | ||||||||
low (IRS 0–3) | 4.02 (±3.13) | 0.071 a | 4.0 (2.0–6.0) | 0.073 b | ||||
high (IRS 4–12) | 4.75 (±2.85) | 4.0 (3.0–6.0) | ||||||
NT5DC2 Gene Expression | Mean (±SD) mRNA Count | p-Value | Median (Q1–Q3) mRNA Count | p-Value | ||||
Overall | 636.2 (±454.6) | 547.0 (330.0–835.0) | ||||||
Histology | ||||||||
SCC | 641.7 (±434.4) | <0.001 a | 570.5 (335.3–858.5) | <0.001 b | ||||
ADC | 478.3 (±355.6) | 387.0 (257.0–613.0) | ||||||
AJCC pT | 0.568 c | 0.647 d | ||||||
pT1 | 706.0 (±431.6) | 0.485 a | 635.0 (464.5–866.0) | 0.981 b | ||||
pT2 | 725.0 (±427.9) | 0.554 a | 621.0 (434.5–902.0) | 0.829 b | ||||
pT3 | 698.5 (±370.7) | 0.244 a | 652.0 (384.0–972.0) | 0.321 b | ||||
pT4 | 791.2 (±457.2) | 705.5 (470.5–1071.3) | ||||||
AJCC pN | 0.001 c | 0.001 d | ||||||
pN0 | 707.5 (±426.5) | 0.354 a | 636.0 (449.0–870.0) | 0.183 b | ||||
pN1 | 680.5 (±392.4) | 0.001 a | 576.5 (407.5–886.3) | <0.001 b | ||||
pN2 | 848.9 (±436.4) | 770.0 (528.0–1122.0) | ||||||
Grading | 0.273 c | 0.821 d | ||||||
G1 | 844.8 (±580.2) | 0.364 a | 736.0 (479.0–1066.0) | 0.898 b | ||||
G2 | 802.9 (±374.9) | 0.190 a | 722.0 (558.0–947.0) | 0.521 b | ||||
G3 | 751.8 (±284.0) | 695.0 (563.0–888.0) | ||||||
TP53 mRNA | ||||||||
low (<median) | 501.1 (±380.8) | <0.001 a | 390.5 (251.0–635.3) | <0.001 b | ||||
high (≥median) | 771.2 (±481.5) | 679.0 (484.0–952.0) |
(A) Protein Expression Cohort | ||||||
Histology | p53 Expression (IRS) 1 | NT5DC2 Expression (IRS) 1 | Median OS (95% CI) (Months) | p4 | Hazard Ratio (95% CI) | p5 |
SCC | Low | Low | 23.8 (15.3–32.3) | 0.402 | * | 0.403 |
High | 29.4 (17.1–41.7) | 0.78 (0.44–1.39) | ||||
High | Low | 43.9 (3.8–83.9) | 0.466 | * | 0.467 | |
High | 38.6 (15.6–61.5) | 0.78 (0.39–1.54) | ||||
ADC | Low | Low | n.e. (n.e.) 3 | 0.021 | * | 0.025 |
High | 48.7 (33.0–64.3) | 2.35 (1.12–4.97) | ||||
High | Low | 10.4 (5.8–15.0) | 0.017 | * | 0.032 | |
High | 90.9 (30.4–151.3) | 0.19 (0.04–0.86) | ||||
(B) Gene Expression Cohort | ||||||
Histology | TP53 Expression (mRNA) 2 | NT5DC2 Expression (mRNA) 2 | Median OS (95% CI) (Months) | p4 | Hazard Ratio (95% CI) | p5 |
SCC | Low | Low | 51.5 (31.5–71.6) | 0.200 | * | 0.201 |
High | 62.2 (39.7–84.7) | 0.78 (0.53–1.14) | ||||
High | Low | 37.6 (23.0–52.2) | 0.307 | * | 0.308 | |
High | 64.1 (35.8–92.4) | 0.84 (0.59–1.18) | ||||
ADC | Low | Low | 136.3 (n.e.) 3 | <0.001 | * | 0.001 |
High | 63.0 (23.6–102.4) | 1.86 (1.31–2.64) | ||||
High | Low | 109.0 (101.6–116.4) | 0.106 | * | 0.108 | |
High | 75.4 (58.3–92.6) | 1.35 (0.94–1.93) |
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Schulze, A.B.; Kuntze, A.; Schmidt, L.H.; Mohr, M.; Marra, A.; Hillejan, L.; Schulz, C.; Görlich, D.; Hartmann, W.; Bleckmann, A.; et al. High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma. Cancers 2022, 14, 1395. https://doi.org/10.3390/cancers14061395
Schulze AB, Kuntze A, Schmidt LH, Mohr M, Marra A, Hillejan L, Schulz C, Görlich D, Hartmann W, Bleckmann A, et al. High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma. Cancers. 2022; 14(6):1395. https://doi.org/10.3390/cancers14061395
Chicago/Turabian StyleSchulze, Arik Bernard, Anna Kuntze, Lars Henning Schmidt, Michael Mohr, Alessandro Marra, Ludger Hillejan, Christian Schulz, Dennis Görlich, Wolfgang Hartmann, Annalen Bleckmann, and et al. 2022. "High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma" Cancers 14, no. 6: 1395. https://doi.org/10.3390/cancers14061395