RhoA, Claudin 18, and c-MET in Gastric Cancer: Clinicopathological Characteristics and Prognostic Significance in Curative Resected Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Tissue Microarray Construction (TMA)
2.3. Immunohistochemistry
2.4. Statistical Analysis
3. Results
3.1. C-MET and Clinicopathological Characteristics
3.2. RhoA and Clinicopathological Characteristics
3.3. CLDN18 and Clinicopathological Characteristics
3.4. Immunohistochemical Analysis and Correlation between c-MET, RhoA, and CLDN18
3.5. Survival Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variables | c-MET-Negative n = 180 (%) | c-MET-Positive n = 169 (%) | p | |
---|---|---|---|---|
Sex | 0.358 | |||
Female | 68 (37.8) | 72 (42.6) | ||
Male | 112 (62.2) | 97 (57.4) | ||
Age (years) | 0.173 | |||
Mean (SD) | 63.1 (11.9) | 61.4 (11.6) | ||
ASA classification | 0.686 | |||
I/II | 155 (86.1) | 148 (87.6) | ||
III/IV | 25 (13.9) | 21 (12.4) | ||
Type of resection | 0.026 | |||
Subtotal | 83 (46.1) | 98 (58) | ||
Total | 97 (53.9) | 71 (42) | ||
Tumor size (cm) | 0.143 | |||
Mean (SD) | 5.3 (3.2) | 4.8 (3.3) | ||
Lauren type | 0.619 | |||
Intestinal | 90 (50) | 89 (52.7) | ||
Diffuse/mixed | 90 (50) | 80 (47.3) | ||
Grade of histological differentiation | 0.004 | |||
Well/moderately differentiated | 68 (37.8) | 90(53.3) | ||
Poorly differentiated | 112 (62.2) | 79 (46.7) | ||
Peritumoral inflammatory infiltrate | 0.001 | |||
Absent/mild | 104 (58.4) | 128 (75.7) | ||
Moderate/intense | 74 (41.6) | 41 (24.3) | ||
Lymphatic invasion | 0.097 | |||
No | 82 (45.6) | 92 (54.4) | ||
Yes | 98 (54.4) | 77 (45.6) | ||
Venous invasion | 0.680 | |||
No | 122 (67.8) | 118 (69.8) | ||
Yes | 58 (32.2) | 51 (30.2) | ||
Perineural Invasion | 0.879 | |||
No | 88 (48.9) | 84 (49.7) | ||
Yes | 91 (51.1) | 85 (50.3) | ||
pT status | 0.058 | |||
pT1/T2 | 59 (32.8) | 72 (42.6) | ||
pT3/T4 | 121 (67.2) | 97 (57.4) | ||
No of lymph nodes | 0.600 | |||
Mean (SD) | 38.6 (18.4) | 39.6 (18.6) | ||
pN status | 0.088 | |||
pN0 | 70 (38.9) | 81 (47.9) | ||
pN+ | 110 (61.1) | 88 (52.1) | ||
pTNM status | 0.164 | |||
I/II | 91 (50.6) | 98 (58) | ||
III/IV | 89 (49.4) | 71 (42) | ||
RhoA | <0.001 | |||
Low-RhoA | 116 (64.4) | 58 (34.3) | ||
High-RhoA | 64 (35.6) | 111 (65.7) | ||
Claudin 18 | 0.122 | |||
Low-CLDN18 | 82 (45.6) | 91 (53.8) | ||
High-CLDN18 | 90 (54.4) | 78 (46.2) | ||
HER2 * | 0.014 | |||
HER2 (0/+1) | 151 (86.8) | 119 (76.3) | ||
HER2 (+2/+3) | 23 (13.2) | 37 (23.7) | ||
E-cadherin * | 0.013 | |||
Normal | 150 (86.7) | 146 (94.8) | ||
Loss of expression | 23 (13.3) | 8 (5.2) |
Variables | Low-RhoA n = 174 (%) | High-RhoA n = 169 (%) | p | |
---|---|---|---|---|
Sex | 0.793 | |||
Female | 71 (40.8) | 69 (39.4) | ||
Male | 103 (59.2) | 106 (60.6) | ||
Age (years) | 0.260 | |||
Mean (SD) | 61.5 (12.8) | 63.0 (10.7) | ||
ASA classification | 0.198 | |||
I/II | 147 (84.5) | 156 (89.1) | ||
III/IV | 27 (15.5) | 19 (10.9) | ||
Type of resection | 0.871 | |||
Subtotal | 91 (52.3) | 90 (51.4) | ||
Total | 83 (47.7) | 85 (48.6) | ||
Tumor size (cm) | 0.170 | |||
Mean (SD) | 5.3 (3.3) | 4.8 (3.3) | ||
Lauren type | <0.001 | |||
Intestinal | 72 (41.4) | 107 (61.1) | ||
Diffuse/mixed | 102 (58.6) | 68 (38.9) | ||
Grade of histological differentiation | ||||
Well/moderately differentiated | 62 (35.6) | 96 (54.9) | <0.001 | |
Poorly differentiated | 112 (64.4) | 79 (45.1) | ||
Peritumoral inflammatory infiltrate | 0.012 | |||
Absent/mild | 104 (60.5) | 128 (73.1) | ||
Moderate/intense | 68 (39.5) | 47 (26.9) | ||
Lymphatic invasion | 0.097 | |||
No | 79 (45.4) | 95 (54.3) | ||
Yes | 95 (54.6) | 80 (45.7) | ||
Venous invasion | 0.191 | |||
No | 114 (65.5) | 126 (72) | ||
Yes | 60 (34.5) | 49 (28) | ||
Perineural Invasion | 0.872 | |||
No | 85 (48.9) | 87 (49.7) | ||
Yes | 89 (51.1) | 88 (50.3) | ||
pT status | 0.023 | |||
pT1/T2 | 55 (31.6) | 76 (43.4) | ||
pT3/T4 | 119 (68.4) | 99 (56.6) | ||
No of lymph nodes | 0.269 | |||
Mean (SD) | 40.2 (18.1) | 38.0 (18.8) | ||
pN status | 0.355 | |||
pN0 | 71 (40.8) | 80 (45.7) | ||
pN+ | 103 (59.2) | 95 (54.3) | ||
pTNM status | 0.047 | |||
I/II | 85 (48.9) | 104 (59.4) | ||
III/IV | 89 (51.1) | 71 (40.6) | ||
c-MET | <0.001 | |||
c-MET-negative | 116 (66.7) | 64 (36.6) | ||
c-MET-positive | 58 (33.3) | 111 (63.4) | ||
Claudin 18 | 0.422 | |||
Low-CLDN18 | 90 (51.7) | 83 (47.4) | ||
High-CLDN18 | 84 (48.3) | 91 (52.6) | ||
HER2 * | 0.533 | |||
HER2 (0/+1) | 138 (83.1) | 132 (80.5) | ||
HER2 (+2/+3) | 28 (16.9) | 32 (19.5) | ||
E-cadherin * | 0.040 | |||
Normal | 143 (87.2) | 153 (93.9) | ||
Loss of expression | 21 (12.8) | 10 (6.1) |
Variables | Low-CLDN18 n = 173 (%) | High-CLDN18 n = 176 (%) | p | |
---|---|---|---|---|
Sex | 0.931 | |||
Female | 69 (39.3) | 71 (40.3) | ||
Male | 104 (60.1) | 105 (59.7) | ||
Age (years) | 0.407 | |||
Mean (SD) | 62.8 (12.0) | 61.7 (11.6) | ||
ASA classification | 0.705 | |||
I/II | 149 (86.1) | 154 (87.5) | ||
III/IV | 24 (13.9) | 22 (12.5) | ||
Type of resection | 0.258 | |||
Subtotal | 95 (54.9) | 86 (48.9) | ||
Total | 78 (45.1) | 90 (51.1) | ||
Tumor size (cm) | 0.145 | |||
Mean (SD) | 5.3 (3.4) | 4.8 (3.1) | ||
Lauren type | 0.627 | |||
Intestinal | 91 (52.6) | 88 (50) | ||
Diffuse/mixed | 82 (47.4) | 88 (50) | ||
Grade of histological differentiation | 0.151 | |||
Well/moderately differentiated | 85 (49.1) | 73 (41.5) | ||
Poorly differentiated | 88 (50.9) | 103 (58.5) | ||
Peritumoral inflammatory infiltrate | 0.080 | |||
Absent/mild | 122 (71,3) | 110 (62.5) | ||
Moderate/intense | 49 (28.7) | 66 (37.5) | ||
Lymphatic invasion | 0.120 | |||
No | 79 (45.7) | 95 (54) | ||
Yes | 94 (54.3) | 81 (46) | ||
Venous invasion | 0.038 | |||
No | 110 (63.6) | 130 (73.9) | ||
Yes | 63 (36.4) | 46 (26.1) | ||
Perineural Invasion | 0.874 | |||
No | 86 (49.7) | 86 (48.9) | ||
Yes | 87 (50.3) | 90 (51.1) | ||
pT status | 0.079 | |||
pT1/T2 | 57 (32.9) | 74 (42) | ||
pT3/T4 | 116 (67.1) | 102 (58) | ||
No of lymph nodes | 0.562 | |||
Mean (SD) | 39.7 (17.8) | 38.5 (19.1) | ||
pN status | 0.854 | |||
pN0 | 74 (42.8) | 77 (43.8) | ||
pN+ | 99 (57.2) | 99 (56.2) | ||
pTNM status | 0.883 | |||
I/II | 93 (53.8) | 96 (54.5) | ||
III/IV | 80 (46.2) | 80 (45.5) | ||
c-MET | 0.122 | |||
c-MET-negative | 82 (47.4) | 98 (55.7) | ||
c-MET-positive | 91 (52.6) | 78 (44.3) | ||
RhoA | 0.422 | |||
Low-RhoA | 90 (52) | 84 (47.7) | ||
High-RhoA | 83 (48) | 92 (52.3) | ||
HER2 * | 0.046 | |||
HER2 (0/+1) | 128 (77.6) | 142 (86.1) | ||
HER2 (+2/+3) | 37 (22.4) | 23 (13.9) | ||
E-cadherin * | 0.608 | |||
Normal | 148 (91.4) | 148 (89.7) | ||
Loss of expression | 14 (8.6) | 17 (10.3) |
Disease-Free Survival | Univariate Analysis | Multivariate Analysis | ||||
Variables | HR | 95% CI | p | HR | 95% CI | p |
Male (vs female) | 1.12 | 0.75–1.66 | 0.579 | ― | ― | ― |
Age > 65 (vs <65 years) | 0.84 | 0.57–1.24 | 0.384 | ― | ― | ― |
Total Gastrectomy (vs. subtotal) | 2.52 | 1.69–3.76 | <0.001 | 2.05 | 1.37–3.09 | 0.001 |
Diffuse/mixed Lauren type (vs. others) | 1.65 | 0.12–2.44 | 0.011 | 1.11 | 0.74–1.65 | 0.620 |
pT3/T4 status (vs. pT1/T2) | 7.68 | 4.00–14.75 | <0.001 | 3.83 | 1.92–7.64 | <0.001 |
pN+ (vs. pN0) | 5.92 | 3.42–10.24 | <0.001 | 3.32 | 1.86–5.92 | <0.001 |
c-MET-negative (vs. c-MET-positive) | 1.70 | 1.14–2.52 | 0.009 | 1.26 | 0.84–1.90 | 0.258 |
Low-RhoA (vs. High-RhoA) | 1.67 | 1.13–2.47 | 0.010 | 1.35 | 0.90–2.02 | 0.152 |
Low-CLDN18 (vs. High-CLDN18) | 0.93 | 0.64–1.37 | 0.719 | ― | ― | ― |
non-CMT (vs. CMT) | 0.72 | 0.48–1.07 | 0.099 | ― | ― | ― |
Overall Survival | Univariate Analysis | Multivariate Analysis | ||||
Variables | HR | 95% CI | p | HR | 95% CI | p |
Male (vs. female) | 1.21 | 0.87–1.67 | 0.253 | ― | ― | ― |
Age > 65 (vs <65 years) | 1.22 | 0.89–1.67 | 0.218 | ― | ― | ― |
Total Gastrectomy (vs. subtotal) | 2.08 | 1.51–2.86 | <0.001 | 1.87 | 1.35–2.58 | <0.001 |
Diffuse/mixed Lauren type (vs. others) | 1.25 | 0.91–1.71 | 0.162 | ― | ― | ― |
pT3/T4 status (vs. pT1/T2) | 3.07 | 2.08–4.54 | <0.001 | 2.21 | 1.44–3.39 | <0.001 |
pN+ (vs. pN0) | 2.55 | 1.79–3.62 | <0.001 | 1.74 | 1.18–2.56 | 0.005 |
c-MET-negative (vs. c-MET-positive) | 1.26 | 0.92–1.73 | 0.149 | ― | ― | ― |
Low-RhoA (vs. High-RhoA) | 1.08 | 0.79–1.47 | 0.648 | ― | ― | ― |
Low-CLDN18 (vs. High-CLDN18) | 1.11 | 0.81–1.51 | 0.525 | ― | ― | ― |
non-CMT (vs. CMT) | 1.01 | 0.74–1.39 | 0.932 | ― | ― | ― |
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Pereira, M.A.; Ramos, M.F.K.P.; Dias, A.R.; Cardili, L.; Ribeiro, R.R.e.; de Castria, T.B.; Zilberstein, B.; Nahas, S.C.; Ribeiro, U., Jr.; de Mello, E.S. RhoA, Claudin 18, and c-MET in Gastric Cancer: Clinicopathological Characteristics and Prognostic Significance in Curative Resected Patients. Med. Sci. 2022, 10, 4. https://doi.org/10.3390/medsci10010004
Pereira MA, Ramos MFKP, Dias AR, Cardili L, Ribeiro RRe, de Castria TB, Zilberstein B, Nahas SC, Ribeiro U Jr., de Mello ES. RhoA, Claudin 18, and c-MET in Gastric Cancer: Clinicopathological Characteristics and Prognostic Significance in Curative Resected Patients. Medical Sciences. 2022; 10(1):4. https://doi.org/10.3390/medsci10010004
Chicago/Turabian StylePereira, Marina Alessandra, Marcus Fernando Kodama Pertille Ramos, Andre Roncon Dias, Leonardo Cardili, Renan Ribeiro e Ribeiro, Tiago Biachi de Castria, Bruno Zilberstein, Sergio Carlos Nahas, Ulysses Ribeiro, Jr., and Evandro Sobroza de Mello. 2022. "RhoA, Claudin 18, and c-MET in Gastric Cancer: Clinicopathological Characteristics and Prognostic Significance in Curative Resected Patients" Medical Sciences 10, no. 1: 4. https://doi.org/10.3390/medsci10010004
APA StylePereira, M. A., Ramos, M. F. K. P., Dias, A. R., Cardili, L., Ribeiro, R. R. e., de Castria, T. B., Zilberstein, B., Nahas, S. C., Ribeiro, U., Jr., & de Mello, E. S. (2022). RhoA, Claudin 18, and c-MET in Gastric Cancer: Clinicopathological Characteristics and Prognostic Significance in Curative Resected Patients. Medical Sciences, 10(1), 4. https://doi.org/10.3390/medsci10010004