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