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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (6) : 730-740    https://doi.org/10.1007/s11684-019-0687-7
LETTER TO FRONTIERS OF MEDICINE
Expression status of GATA3 and mismatch repair proteins in upper tract urothelial carcinoma
Yue Wang1, Jinxia Zhang1, Yunfan Wang1, Shufang Wang1, Yu Zhang1, Qi Miao1, Fei Gao2, Huiying He2()
1. Department of Pathology, Peking University Shougang Hospital, Beijing 100144, China
2. Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100083, China
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Abstract

GATA binding protein 3 (GATA3) and mismatch repair (MMR) deficiency contribute to the development of urothelial carcinoma. However, the combined expression of GATA3 and microsatellite instability (MSI) in upper tract urothelial carcinoma (UTUC) and its prognostic value have not been investigated. Here, we immunohistochemically stained GATA3 and MMR proteins in 108 UTUC samples. GATA3 was positive in 74 cases, and its expression was significantly lower than in adjacent benign urothelium (P<0.001). Loss of GATA3 expression was statistically associated with adverse clinicopathologic parameters, such as advanced stage, lymphovascular invasion, neural invasion, lymph node metastasis, and extensive necrosis. Cancer-specific survival (CSS, P=0.028) and disease-free survival (DFS, P=0.024) were significantly shorter in patients with GATA3 negative tumors than in patients with GATA3 positive tumors. The absence of MMR proteins was observed in 8.3% of the cases, and focal staining was identified in 13.0%. When using “lax criteria” which resulted in counting cases as negative where MMR staining was in fact focally positive (<5%), we found that GATA3 was inversely associated with MSI (P=0.005). Moreover, GATA3/microsatellite stability (MS) tumors were correlated with advanced pT stage (P<0.001) and poor outcome (P=0.019 for CSS, P=0.016 for DFS) compared with GATA3+/MSI ones. The GATA3/MSI cases had unfavorable clinical outcomes compared with GATA3+/MSI cases (P=0.008 for CSS, P=0.023 for DFS). This finding raises a question as to whether GATA3 interacts with MSI through the TGF-β signaling pathway and regulates UTUC progression.

Keywords upper tract urothelial carcinoma      GATA binding protein 3      mismatch repair      microsatellite instability      prognosis     
Corresponding Authors: Huiying He   
Just Accepted Date: 11 March 2019   Online First Date: 22 April 2019    Issue Date: 16 December 2019
 Cite this article:   
Yue Wang,Jinxia Zhang,Yunfan Wang, et al. Expression status of GATA3 and mismatch repair proteins in upper tract urothelial carcinoma[J]. Front. Med., 2019, 13(6): 730-740.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0687-7
http://academic.hep.com.cn/fmd/EN/Y2019/V13/I6/730
Variable n % Variable n %
Patient age Lymph node metastasis
<65 40 37.0 No 98 90.7
≥65 68 63.0 Yes 10 9.3
Sex Concurrent CIS
Male 62 57.4 No 93 86.1
Female 46 42.6 Yes 15 13.9
Laterality Extensive necrosis
Left 49 45.4 No 91 84.3
Right 58 53.7 Yes 17 15.7
Both 1 0.9 Glomerular sclerosis
Tumor site No 73 67.6
Renal pelvis 42 38.9 Yes 35 32.4
Ureter 55 50.9 Solitary or Multifocal
Transitional zone 10 9.3 Solitary 93 86.1
Renal pelvis& Ureter 1 0.9 Multifocal 15 13.9
Tumor size Bladder cancer
<3.0 cm 60 55.6 No 71 75.6
≥3.0 cm 48 44.4 Simultaneous 5 5.3
Tumor grade Postoperative 16 17.0
Low grade 14 13.0 Preoperative 2 2.1
High grade 94 87.0 Median follow-up time (month) 28
Pathological stage Status
pTa 14 13.0 Survival 66 70.2
pT1 29 26.8 Death 28 29.8
NMI (pTa+ pT1) 43 39.8 Cancer-specific survival
pT2 27 25.0 <1 year 19
pT3 29 26.9 1?3 years 41 69.4% a
pT4 9 8.3 >3 years 34
MI (pT2+ pT3+ pT4) 65 60.2 Disease-free survival
Lympho-vascular involvement <1 year 36
No 87 80.6 1?3 years 31 67.5% b
Yes 21 19.4 >3 years 27
Neural invasion
No 99 91.7
Yes 9 8.3
Tab.1  Patient characteristics at diagnosis
n MMR P
focal+ + − vs. focal+/+ −/focal+ vs. +
GATA3 34 5 8 21 0.136 0.005*
GATA3+ 74 4 6 64
Tab.2  Correlation of GATA3 and MMR proteins in UTUC
Fig.1  Representative staining of GATA3 and MMR proteins in UTUC. (A) Representative H&E images of UTUC. (B) Representative H&E images of normal urothelium. (C) Representative examples of positive staining of GATA3 in UTUC. (D) Representative examples of negative staining of GATA3 in UTUC. (E−L) Representative examples of positive (left panel) and negative (right panel) staining of MSH2, MSH6, MLH1, PMS2 in UTUC, respectively. Magnification, 100×.
UTUC, total = 108 MI UTUC, total = 65
n GATA3+ P MSI P n GATA3+ P MSI P
Patient age
<65 40 29 0.528 2 0.480 23 12 0.608 1 1.000
≥65 68 45 7 42 25 3
Sex
Male 62 43 0.837 4 0.491 37 20 0.622 2 1.000
Female 46 31 5 28 17 2
Laterality
Left 49 35 0.358 2 0.244 31 18 0.693 1 0.637
Right 58 39 7 33 19 3
Both 1 0 0 1 0 0
Tumor site
Renal pelvis 42 28 0.048* 5 0.478 25 14 0.331 2 1.000
Ureter 55 42 3 31 20 2
Transitional zone 10 4 1 8 3 0
Renal pelvis & Ureter 1 0 0 1 0 0
Tumor size
<3.0 cm 60 44 0.298 3 0.182 36 22 0.463 2 1.000
≥3.0 cm 48 30 6 29 15 2
Tumor grade
Low grade 14 10 1.000 1 1.000 1 0 0.431 0 1.000
High grade 94 64 8 64 37 4
Pathological stage
NMI (pTa?pT1) 43 37 0.001* 5 0.479 - - - -
MI (pT2?pT4) 65 37 4 - -
LVI
No 87 64 0.035* 7 1.000 46 29 0.170 2 0.574
Yes 21 10 2 19 8 2
Neural invasion
No 99 72 0.004* 7 0.164 56 35 0.032* 2 0.089
Yes 9 2 2 9 2 2
Lymph node metastasis
No 98 71 0.010* 9 1.000 55 34 0.086 4 1.000
Yes 10 3 0 10 3 0
Concurrent CIS
No 93 62 0.381 7 0.609 55 30 0.495 2 0.109
Yes 15 12 2 10 7 2
Extensive necrosis
No 91 69 <0.001* 8 1.000 48 32 0.011* 3 1.000
Yes 17 5 1 17 5 1
Glomerular sclerosis
No 73 53 0.268 7 0.715 45 25 0.792 4 0.303
Yes 35 21 2 20 12 0
Solitary or Multifocal
Solitary 93 65 0.550 7 0.609 52 30 1.000 2 0.176
Multifocal 15 9 2 13 7 2
Bladder cancera
No 61 46 0.653 6 0.612 37 25 0.164 2 1.000
Simultaneous 5 4 0 4 3 0
Postoperative 16 10 0 7 2 0
Preoperative 2 2 0 2 2 0
Tab.3  Association of clinicopathologic characteristics with GATA3 expression and MSI
Cancer-specific survival Disease-free survival
Univariate Multivariate Univariate Multivariate
HR 95%CI P HR 95%CI P HR 95%CI P HR 95%CI P
All cases (n = 108)
GATA3 0.441 0.208?0.935 0.028* 0.684 0.308?1.517 0.350 0.448 0.210?0.955 0.024* 0.751 0.326?1.731 0.502
MSI 0.744 0.176?3.143 0.688 ? ? ? 0.697 0.165?2.943 0.623 ? ? ?
Tumor Grade 25.684 0.244?2.699E3 0.031* 2.395E5 ? 0.975 25.217 0.220?2.890E3 0.028* 3.748E5 ? 0.980
pT stage 9.463 2.245?39.891 <0.001* 4.126 0.921?18.492 0.064 9.007 2.135?37.988 <0.001* 4.328 0.973?19.251 0.054
LVI 2.379 1.089?5.200 0.024* 1.307 0.585?2.919 0.514 2.345 1.082?5.086 0.019* 1.201 0.531?2.720 0.660
Neural invasion 1.994 0.687?5.787 0.194 ? ? ? 1.785 0.617?5.165 0.252 ? ? ?
LN metastasis 4.734 1.751?12.802 0.001* 1.680 0.554?5.094 0.359 3.793 1.422?10.123 0.002* 1.349 0.457?3.984 0.587
Concurrent CIS 0.883 0.305?2.554 0.817 ? ? ? 0.882 0.306?2.545 0.806 ? ? ?
Extensive necrosis 6.288 2.864?13.804 <0.001* 2.986 1.229?7.256 0.016* 5.410 2.424?12.074 <0.001* 2.682 1.068?6.733 0.036*
MI UTUC (n = 65)
GATA3 0.607 0.280?1.317 0.206 ? ? ? 0.622 0.284?1.362 0.235 ? ? ?
MSI 1.181 0.278?5.022 0.822 ? ? ? 1.026 0.242?4.346 0.972 ? ? ?
Tumor Grade 21.096 0.001?8.890E5 0.395 ? ? ? 21.110 0.000?1.089E6 0.378 ? ? ?
LVI 1.550 0.695?3.454 0.277 ? ? ? 1.626 0.737?3.587 0.185 ? ? ?
Neural invasion 1.178 0.402?3.447 0.764 ? ? ? 1.075 0.369?3.137 0.885 ? ? ?
LN metastasis 2.848 1.046?7.756 0.032* 1.498 0.489?4.590 0.479 0.418 0.155?1.123 0.047* 1.372 0.463?4.070 0.568
Concurrent CIS 0.971 0.333?2.831 0.957 ? ? ? 0.939 0.323?2.727 0.900 ? ? ?
Extensive necrosis 3.757 1.683?8.383 0.001* 3.310 1.355?8.087 0.009* 3.316 1.463?7.519 0.001* 2.990 1.212?7.377 0.017*
Tab.4  Univariate and multivariate analysis of cancer-specific survival and disease-free survival in patients with UTUC
Fig.2  Cancer-specific survival (A) and disease-free survival (B) according to different groups of GATA3 and MMR protein expression status.
Fig.3  Cancer-specific survival (A) and disease-free survival (B) comparing GATA3+/MSI and GATA3/MS groups.
Fig.4  Cancer-specific survival (A) and disease-free survival (B) analysis comparing GATA3+/MSI and GATA3/MSI groups.
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