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Gastrointestinal cancer
FGFR4 Gly388Arg Polymorphism Affects the Progression of Gastric Cancer by Activating STAT3 Pathway to Induce Epithelial to Mesenchymal Transition
Yanwei Ye, Jie Li, Dongbao Jiang, Jingjing Li, Chuangfeng Xiao, Yingze Li, Chao Han, Chunlin Zhao
Cancer Res Treat. 2020;52(4):1162-1177.   Published online May 25, 2020
DOI: https://doi.org/10.4143/crt.2020.138
AbstractAbstract PDFPubReaderePub
Purpose
Fibroblast growth factor receptor 4 (FGFR4) plays a critical role in cancer progression involving in tumor proliferation, invasion, and metastasis. This study clarified the role of FGFR4-Arg388 variant in gastric cancer (GC), and more importantly highlighted the possibility of this single nucleotide polymorphism (SNP) as potential therapeutic targets.
Materials and Methods
FGFR4 polymorphism was characterized in advanced GC patients to perform statistical analysis. FGFR4-dependent signal pathways involving cell proliferation, invasion, migration, and resistance to oxaliplatin (OXA) in accordance with the SNP were also assessed in transfected GC cell lines.
Results
Among 102 GC patients, the FGFR4-Arg388 patients showed significantly higher tumor stage (p=0.047) and worse overall survival (p=0.033) than the Gly388 patients. Immunohistochemical results showed that FGFR4-Arg388 patients were more likely to have higher vimentin (p=0.025) and p-STAT3 (p=0.009) expression compared with FGFR4-Gly388 patients. In transfected GC cells, the overexpression of FGFR4-Arg388 variant increased proliferation and invasion of GC cells, increasing resistance of GC cells to OXA compared with cells overexpressing the Gly388 allele.
Conclusion
The exploration mechanism may be through FGFR4-Arg388/STAT3/epithelial to mesenchymal transition axis regulating pivotal oncogenic properties of GC cells. The FGFR4-Arg388 variant may be a biomarker and a candidate target for adjuvant treatment of GC.

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  • Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers
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  • FGFR4 Gly388Arg Polymorphism Reveals a Poor Prognosis, Especially in Asian Cancer Patients: A Meta-Analysis
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    Cancers.2021; 13(22): 5796.     CrossRef
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PD-L1 Testing in Gastric Cancer by the Combined Positive Score of the 22C3 PharmDx and SP263 Assay with Clinically Relevant Cut-offs
Yujun Park, Jiwon Koh, Hee Young Na, Yoonjin Kwak, Keun-Wook Lee, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Hye Seung Lee
Cancer Res Treat. 2020;52(3):661-670.   Published online January 10, 2020
DOI: https://doi.org/10.4143/crt.2019.718
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
We provide a comparison between 22C3 pharmDx and SP263 assay, for evaluating programmed death ligand 1 (PD-L1) expression in advanced gastric cancer (GC) patients.
Materials and Methods
The PD-L1 immunohistochemistry by 22C3 pharmDx and SP263 assays was performed in the center of the tumor (CT) and invasive margin (IM) in 379 GC tissues using tissue microarrays and interpreted as combined positive score (CPS) and tumor proportion score (TPS). Of the total samples, 55 samples were independently reviewed by five pathologists.
Results
The two assays showed a high correlation in both the CPS and TPS. At a CPS ≥ 1 cut-off, 219 (57.8%) and 231 (60.9%) GCs were positive for PD-L1 with the 22C3 and SP263 assays, and at ≥ 10 cut-off, 37 (9.8%) and 36 (9.5%) GCs were positive, respectively. The overall percent agreement (OPA) was greater than 90% with CPS ≥ 1 and ≥ 10 cut-offs, and TPS ≥ 1% and ≥ 10% cut-offs. There was higher OPA between the two assays with a CPS cut-off ≥ 10 (99.2%) than ≥ 1 (94.7%). The percent agreement between the CT and IM was higher with a CPS cut-off ≥ 10 (92.9%) than ≥ 1 (77.6%). Patient with positive expression at CPS ≥ 5 cut-off had a significantly better outcomes in both assays. Interobserver variability among five pathologists was higher than the assay variability.
Conclusion
Two assays for PD-L1 expression in GC showed high agreement. These results provide guidance for selecting eligible patients with GC for pembrolizumab treatment.

Citations

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    Hans-Ulrich Schildhaus, Wilko Weichert
    Der Pathologe.2021; 42(4): 380.     CrossRef
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    Enrico Munari, Francesca R. Mariotti, Linda Quatrini, Pietro Bertoglio, Nicola Tumino, Paola Vacca, Albino Eccher, Francesco Ciompi, Matteo Brunelli, Guido Martignoni, Giuseppe Bogina, Lorenzo Moretta
    International Journal of Molecular Sciences.2021; 22(10): 5123.     CrossRef
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    Soomin Ahn, Kyoung-Mee Kim
    Modern Pathology.2021; 34(9): 1719.     CrossRef
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    Tamara Z. Dabbagh, Maher A. Sughayer
    Applied Immunohistochemistry & Molecular Morphology.2021; 29(6): 462.     CrossRef
  • Expression of the immune checkpoint receptors PD-1, LAG3, and TIM3 in the immune context of stage II and III gastric cancer by using single and chromogenic multiplex immunohistochemistry
    Yujun Park, An Na Seo, Jiwon Koh, Soo Kyoung Nam, Yoonjin Kwak, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Hye Seung Lee
    OncoImmunology.2021;[Epub]     CrossRef
  • Appropriate PD-L1 Cutoff Value for Gastric Cancer Immunotherapy: A Systematic Review and Meta-Analysis
    Tong Xie, Zhening Zhang, Xiaotian Zhang, Changsong Qi, Lin Shen, Zhi Peng
    Frontiers in Oncology.2021;[Epub]     CrossRef
  • Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer
    Hye Jung Hwang, Soo Kyung Nam, Hyunjin Park, Yujun Park, Jiwon Koh, Hee Young Na, Yoonjin Kwak, Woo Ho Kim, Hye Seung Lee
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Body Mass Index and Risk of Gastric Cancer in Asian Adults: A Meta-Epidemiological Meta-Analysis of Population-Based Cohort Studies
Jong-Myon Bae
Cancer Res Treat. 2020;52(2):369-373.   Published online August 12, 2019
DOI: https://doi.org/10.4143/crt.2019.241
AbstractAbstract PDFPubReaderePub
Purpose
A previous meta-analysis (MA) published in 2009 reported that excess body weight was associated with an increased risk of gastric cancer in non-Asians, but not in Asians. The aim was to conduct a meta-epidemiological MA (MEMA) to evaluate association between excess body weight and the risk of gastric cancer in Asian adults with using the proposed classification of weight by body mass index (BMI) in Asian adults.
Materials and Methods
The selection criteria were population-based prospective cohort studies that measured BMI of cohort participants and evaluated a risk of gastric cancer. Overweight group (OW) and obesity group (OB) were defined as 23.0-24.9 and ≥ 25.0, respectively. A group only showing results for BMI over 23.0 was defined as overweight and obesity group (OWB). Random effect model was applied if I2 value was over 50%.
Results
After four new studies were added through citation discovery tools, seven cohort studies with 21 datasets were selected finally for MEMA. The I2 value of OW, OB, and OWB were 76.1%, 83.5%, and 97.1%, respectively. Only OWB in men had a I2 value below 50% (22.5%) and showed a statistical significance with inverse association (summary relative risk, 0.79; 95% confidence interval, 0.77 to 0.81).
Conclusion
This MEMA supported the hypothesis that OW might be a protective factor in gastric cancer risk in Asian adults. It will be necessary to conduct additional cohort studies with lengthening follow-up periods and re-analyzing the effect of overweight and obesity classified by the Asian criteria.

Citations

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  • Can patients with mild non-neoplastic lesions diagnosed at baseline screening be safely exempt from surveillance: evidence from multicenter community-based cohorts
    Siyi He, Zhiyi Zhang, Guohui Song, Zhenhai Wang, Chunyun Dai, Shipeng Yan, Kun Jiang, Bingbing Song, He Li, Maomao Cao, Dianqin Sun, Fan Yang, Xinxin Yan, Shaoli Zhang, Yi Teng, Qianru Li, Changfa Xia, Wanqing Chen
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    Hyeong Ho Jo
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    Xiang Feng, Jinhua Zhu, Zhaolai Hua, Shenghua Yao, Hongjun Yin, Qiuping Shi, Jinyi Zhou
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    Zhaoping Zang, Yi Shao, Rena Nakyeyune, Yi Shen, Chen Niu, Lingyan Zhu, Xiaoli Ruan, Tong Wei, Ping Wei, Fen Liu
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    Junhao Chen, Kaimin Ke, Zhenghuan Liu, Luchen Yang, Linchun Wang, Jing Zhou, Qiang Dong
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    Narges Azizi, Moein Zangiabadian, Golnoosh Seifi, Afshan Davari, Elham Yekekhani, Seyed Amir Ahmad Safavi-Naini, Nathan A. Berger, Mohammad Javad Nasiri, Mohammad-Reza Sohrabi
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Increased Risk of Osteoporosis in Gastric Cancer Survivors Compared to General Population Control: A Study with Representative Korean Population
Su-Min Jeong, Dong Wook Shin, Ji Eun Lee, Sang-Man Jin, Sung Kim
Cancer Res Treat. 2019;51(2):530-537.   Published online June 27, 2018
DOI: https://doi.org/10.4143/crt.2018.164
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Although several studies have suggested that osteoporosis is common in survivors of gastric cancer (GC), no study to date has directly assessed the risk for osteoporosis in GC survivors compared to matched controls. Thus, we aimed to investigate the relative risk for osteoporosis in survivors of GC compared to general population.
Materials and Methods
We used the Korea National Health and Nutrition Examination Survey data (2008-2011). Patients with a history of GC (n=94) were defined as case among 8,142 individuals over 50 years old who were evaluated by dual-energy X-ray absorptiometry. Controls (n=470) were matched to cases by age and sex in a 1:5 ratio. Osteopenia (–2.5 < T-score < –1.0) and osteoporosis (T-score ≤ –2.5) were defined.
Results
The prevalence of osteoporosis in GC survivors was 30.2%, which was significantly greater than that of controls (19.7%). In total, GC survivors had a 3.7-fold increased risk for osteoporosis compared to controls (p=0.021). In addition, the risk for osteoporosis of the total proximal femur total (TF) and femur neck (FN) was significantly increased among GC survivors compared to controls (adjusted relative risk, 4.64; 95% confidence interval, 1.16 to 18.6 in TF and adjusted relative risk, 3.58; 95% confidence interval, 1.19 to 10.8 in FN). Furthermore, we found sub-optimal daily calcium intake and mean serum levels of 25-hydroxy-vitamin D in both groups.
Conclusion
GC survivors are at significantly increased risk for osteoporosis, especially in the femur. Clinically, our finding supports the importance of screening bone health and adequate nutrient supplementation in survivors of GC.

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Mutational Analysis of TTK Gene in Gastric and Colorectal Cancers with Microsatellite Instability
Chang Hyeok Ahn, Yoo Ri Kim, Sung Soo Kim, Nam Jin Yoo, Sug Hyung Lee
Cancer Res Treat. 2009;41(4):224-228.   Published online December 31, 2009
DOI: https://doi.org/10.4143/crt.2009.41.4.224
AbstractAbstract PDFPubReaderePub
Purpose

The TTK gene plays a crucial role in regulation of the mitotic checkpoint. The TTK gene has an A9 mononucleotide repeat in the coding sequences, which harbors mutations in gastric (GC) and colorectal cancers (CRC) with microsatellite instability (MSI). However, there are three more repeats (the A7s) in the coding sequences that have not been analyzed. The aim of this study was to explore whether the three A7s as well as the A9 are altered in GC and CRC, and to find any association of TTK mutation with clinocopathologic characteristics of GC and CRC.

Materials and Methods

We analyzed exon 5 (A7 and A7) and exon 22 (A9 and A7) which have repeat sequences in 30 GC with high MSI (MSI-H), 15 GC with low MSI (MSI-L), 35 CRC with MSI-H, and 15 CRC with MSI-L, by single-strand conformation polymorphism (SSCP) and DNA sequencing assays.

Results

Overall, we detected 23 frameshift mutations in the repeat sequences of TTK in the GC with MSI-H (11/30; 36.7%) and the CRC with MSI-H (12/35; 34.3%), but not in the cancers with MSI-L. The mutations were observed in both A9 and A7 of exon 22, but in neither of the two A7s of exon 5. The mutations consisted of c.2560delA, c.2560dupA, c.2571delA and c.[2560delA(+)2571delA]. All of the mutations were frameshift mutations and would result in premature stops of TTK protein synthesis. There was no significant difference in clinopathologic parameters of the cancers with the mutations.

Conclusion

Our data indicate that frameshift mutations of TTK are common in both GC and CRC with MSI-H, and that the mutations occur not only in the A9 repeat but also in the A7 repeat. The data suggest that frameshift mutations of TTK might alter cell cycle control in the affected cells and contribute to pathogenesis of cancers with MSI-H.

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