Cancer Research and Treatment

Original Article

Identifying Anti-Cancer Effects and Exploring the Mechanism of an MPS1/TTK Inhibitor in Gastric Cancer: Eunseo Kim, Woo Sun Kwon, Tae Soo Kim, Jihyun Hwang, Sunghwan Kim, Sun Young Rha; Received August 14, 2024 Accepted December 10, 2024 Published online December 12, 2024; DOI: https://doi.org/10.4143/crt.2024.780 [Accepted]

Abstract PDF: Purpose
To identify the anti-cancer effect and investigate the underlying mechanism of MPS1/TTK (Monopolar spindle 1; also known as threonine tyrosine kinase) inhibitor in gastric cancer (GC) cell lines.
Materials and Methods
This study used compound-9, a highly selective MPS1/TTK inhibitor, to evaluate its anticancer effects on GC cell lines. Cell viability assay was performed to determine sensitivity to the inhibitor. Cell cycle analysis and apoptosis assays were performed using Flow cytometry to evaluate the effects of the inhibitor. Protein-expression levels were analyzed through western blotting after the inhibitor treatment.
Results
The EBV and MSI-H groups tended to be sensitive to the inhibitor, while the GS-likely group tended to be moderate-to-resistant. In contrast, the CIN-likely group was extremely sensitive or resistant. Within the CIN group, TP53^WT cell lines were sensitive, whereas TP53^MUT cell lines were sensitive or resistant. Upon treatment of the inhibitor, the TP53^WT-sensitive cell line underwent cell death more rapidly compared to the TP53^MUT-sensitive cell line. In contrast, the TP53^MUT-sensitive cell experienced higher levels of aneuploidy or polyploidy and underwent cell death at later time point than the TP53^WT-sensitive cell line. The TP53^MUT-resistant line can tolerate aneuploidy or polyploidy and exhibits drug resistance.
Conclusion
Our study explores the potential of an MPS1/TTK inhibitor, compound-9, as a targeted therapy in gastric cancer cells and investigates its mechanism of action.

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Review Article

Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency: Yoo-Na Kim, Doga C. Gulhan, Hu Jin, Dominik Glodzik, Peter J. Park; Cancer Res Treat. 2024;56(4):975-990. Published online July 17, 2024; DOI: https://doi.org/10.4143/crt.2024.154

Abstract PDF PubReader ePub: Accurate detection of homologous recombination deficiency (HRD) in cancer patients is paramount in clinical applications, as HRD confers sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. With the advances in genome sequencing technology, mutational profiling on a genome-wide scale has become readily accessible, and our knowledge of the genomic consequences of HRD has been greatly expanded and refined. Here, we review the recent advances in HRD detection methods. We examine the copy number and structural alterations that often accompany the genome instability that results from HRD, describe the advantages of mutational signature-based methods that do not rely on specific gene mutations, and review some of the existing algorithms used for HRD detection. We also discuss the choice of sequencing platforms (panel, exome, or whole-genome) and catalog the HRD detection assays used in key PARP inhibitor trials.

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Original Articles

Gastrointestinal cancer

Effector Function Characteristics of Exhausted CD8+ T-Cell in Microsatellite Stable and Unstable Gastric Cancer: Dong-Seok Han, Yoonjin Kwak, Seungho Lee, Soo Kyung Nam, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Nak-Jung Kwon, Hye Seung Lee, Han-Kwang Yang; Cancer Res Treat. 2024;56(4):1146-1163. Published online April 12, 2024; DOI: https://doi.org/10.4143/crt.2024.317

Abstract PDF PubReader ePub

Purpose
Gastric cancer exhibits molecular heterogeneity, with the microsatellite instability–high (MSI-H) subtype drawing attention for its distinct features. Despite a higher survival rate, MSI-H gastric cancer lack significant benefits from conventional chemotherapy. The immune checkpoint inhibitors, presents a potential avenue, but a deeper understanding of the tumor immune microenvironment of MSI-H gastric cancer is essential.
Materials and Methods
We explored the molecular characteristics of CD8+ T-cell subtypes in three MSI-H and three microsatellite stable (MSS) gastric cancer samples using single-cell RNA sequencing and spatial transcriptome analysis.
Results
In MSI-H gastric cancer, significantly higher proportions of effector memory T cell (Tem), exhausted T cell (Tex), proliferative exhausted T cell (pTex), and proliferative T cell were observed, while MSS gastric cancer exhibited significantly higher proportions of mucosal-associated invariant T cell and natural killer T cell. In MSI-H gastric cancer, Tex and pTex exhibited a significant upregulation of the exhaustion marker LAG3, as well as elevated expression of effector function markers such as IFNG, GZMB, GZMH, and GZMK, compared to those in MSS gastric cancer. The interferon γ (IFN-γ) signaling pathway of Tex and pTex was retained compared to those of MSS gastric cancer. The spatial transcriptome analysis demonstrates the IFN-γ signaling pathway between neighboring Tex and malignant cell, showcasing a significantly elevated interaction in MSI-H gastric cancer.
Conclusion
Our study reveals novel finding indicating that IFN-γ signaling pathway is retained in Tex and pTex of MSI-H gastric cancer, offering a comprehensive perspective for future investigations into immunotherapy for gastric cancer.

Citations

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Simvastatin induces ferroptosis and activates anti-tumor immunity to sensitize anti-PD-1 immunotherapy in microsatellite stable gastric cancer
Yumei Ning, Shilin Fang, Runan Zhang, Jun Fang, Kun Lin, Yang Ding, Haihang Nie, Jingkai Zhou, Qiu Zhao, Hengning Ke, Haizhou Wang, Fan Wang
International Immunopharmacology.2024; 142: 113244. CrossRef

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Histopathologic and Molecular Biomarkers of PD-1/PD-L1 Inhibitor Treatment Response among Patients with Microsatellite Instability‒High Colon Cancer: Jaewon Hyung, Eun Jeong Cho, Jihun Kim, Jwa Hoon Kim, Jeong Eun Kim, Yong Sang Hong, Tae Won Kim, Chang Ohk Sung, Sun Young Kim; Cancer Res Treat. 2022;54(4):1175-1190. Published online January 12, 2022; DOI: https://doi.org/10.4143/crt.2021.1133

Abstract PDF Supplementary Material PubReader ePub

Purpose
Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability‒high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC.
Materials and Methods
MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning–based classification model was built to predict treatment response among MSI-H CRCs patients.
Results
A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, PRAME had the highest fold change in the responder group. Higher expression of PRAME was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response.
Conclusion
We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification.

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The Relationship of PRAME Expression with Clinicopathologic Parameters and Immunologic Markers in Melanomas: In Silico Analysis
Yasemin Cakir, Banu Lebe
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Norah A. Alturki
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Gynecologic cancer

Frequency of Mismatch Repair Deficiency/High Microsatellite Instability and Its Role as a Predictive Biomarker of Response to Immune Checkpoint Inhibitors in Gynecologic Cancers: Joseph J. Noh, Min Kyu Kim, Min Chul Choi, Jeong-Won Lee, Hyun Park, Sang Geun Jung, Won Duk Joo, Seung Hun Song, Chan Lee; Cancer Res Treat. 2022;54(4):1200-1208. Published online December 13, 2021; DOI: https://doi.org/10.4143/crt.2021.828

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study was to investigate the frequency of mismatch repair deficiency/high microsatellite instability (MMRd/MSI-H) in gynecologic malignancies and the efficacy of immune checkpoint inhibitors (ICIs) in patients with recurrent gynecologic cancers according to MMR/MSI status.
Materials and Methods
We conducted a multi-center retrospective review on the patients who were diagnosed with gynecologic cancers between 2015 and 2020. Their clinicopathologic information, results of immunohistochemistry staining for MLH1/MSH2/MSH6/PMS2 and MSI analysis, tumor response to treatment with ICIs were investigated.
Results
Among 1,093 patients included in the analysis, MMRd/MSI-H was most frequent in endometrial/uterine cancers (34.8%, 164/471), followed by ovarian, tubal, and peritoneal cancers (12.8%, 54/422) and cervical cancer (11.3%, 21/186). When assessed by histology without regard for cancer types, the frequency of MMRd/MSI-H was 11.0% (38/345) in high-grade serous adenocarcinoma, 38.6% (117/303) in endometrioid adenocarcinoma, and 30.2% (16/53) in carcinosarcoma. A total of 114 patients were treated with ICIs at least once. The objective response rate (ORR) was 21.6% (8/37) in cervical cancer, 4.7% (2/43) in ovarian cancer, and 25.8% (8/31) in endometrial/uterine cancers. Univariate regression analysis identified MMRd/MSI-H as the only significant factor associated with the ORR (28.9% [11/38] vs. 11.8% [9/76]; odds ratio, 3.033; 95% confidence interval, 1.129–8.144; p=0.028).
Conclusion
The frequency of MMRd/MSI-H is moderate to high in gynecologic cancers in the Korean population. MMRd/MSI-H could be effective predictive biomarkers in gynecologic cancers of any type.

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Yu Miyama, Tomomi Kato, Masayasu Sato, Akira Yabuno, Kosei Hasegawa, Masanori Yasuda
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Shanhui Liang, Huijuan Ge, Shuling Zhou, Jie Tang, Yanzi Gu, Xiaohua Wu, Jin Li
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Immunotherapy in MMR-d/MSI-H recurrent/metastatic endometrial cancer
Renata Pacholczak-Madej, Michele Bartoletti, Lucia Musacchio, Mirosława Püsküllüoglu, Paweł Blecharz, Domenica Lorusso
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Expression patterns of mismatch repair proteins in cervical cancer uncover independent prognostic value of MSH-2
Madeleine Charlotte van den Berg, Hege F Berg, Tomasz Stokowy, Erling A Hoivik, Kathrine Woie, Hilde Engerud, Akinyemi I Ojesina, Ingfrid Salvesen Haldorsen, Jone Trovik, Bjørn I Bertelsen, Camilla Krakstad, Mari Kyllesø Halle, Janie Foote
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Na Li, Zixuan Wan, Dongyan Lu, Ruilian Chen, Xiaowei Ye
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Guillaume Mestrallet, Matthew Brown, Cansu Cimen Bozkus, Nina Bhardwaj
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Gastrointestinal cancer

Adjuvant Chemotherapy in Microsatellite Instability–High Gastric Cancer: Jin Won Kim, Sung-Yup Cho, Jeesoo Chae, Ji-Won Kim, Tae-Yong Kim, Keun-Wook Lee, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im; Cancer Res Treat. 2020;52(4):1178-1187. Published online June 11, 2020; DOI: https://doi.org/10.4143/crt.2020.313

Abstract PDF Supplementary Material PubReader ePub

Purpose
Microsatellite instability (MSI) status may affect the efficacy of adjuvant chemotherapy in gastric cancer. In this study, the clinical characteristics of MSI-high (MSI-H) gastric cancer and the predictive value of MSI-H for adjuvant chemotherapy in large cohorts of gastric cancer patients were evaluated. Material and Methods This study consisted of two cohorts. Cohort 1 included gastric cancer patients who received curative resection with pathologic stage IB-IIIC. Cohort 2 included patients with MSI-H gastric cancer who received curative resection with pathologic stage II/III. MSI was examined using two mononucleotide markers and three dinucleotide markers.
Results
Of 359 patients (cohort 1), 41 patients (11.4%) had MSI-H. MSI-H tumors were more frequently identified in older patients (p < 0.001), other histology than poorly cohesive, signet ring cell type (p=0.005), intestinal type (p=0.028), lower third tumor location (p=0.005), and absent perineural invasion (p=0.027). MSI-H status has a tendency of better disease-free survival (DFS) and overall survival (OS) in multivariable analyses (hazard ratio [HR], 0.4; p=0.059 and HR, 0.4; p=0.063, respectively). In the analysis of 162 MSI-H patients (cohort 2), adjuvant chemotherapy showed a significant benefit with respect to longer DFS and OS (p=0.047 and p=0.043, respectively). In multivariable analysis, adjuvant chemotherapy improved DFS (HR, 0.4; p=0.040).
Conclusion
MSI-H gastric cancer had distinct clinicopathologic findings. Even in MSI-H gastric cancer of retrospective cohort, adjuvant chemotherapy could show a survival benefit, which was in contrast to previous prospective studies and should be investigated in a further prospective trial.

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Management of Microsatellite Instability High (MSI-H) Gastroesophageal Adenocarcinoma
Katherine I. Zhou, Brent A. Hanks, John H. Strickler
Journal of Gastrointestinal Cancer.2024; 55(2): 483. CrossRef
The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023
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Satya Das, Taymeyah Al-Toubah, Jonathan Strosberg
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A Multi-cohort Study of the Prognostic Significance of Microsatellite Instability or Mismatch Repair Status after Recurrence of Resectable Gastric Cancer: Ji Yeong An, Yoon Young Choi, Jeeyun Lee, Woo Jin Hyung, Kyoung-Mee Kim, Sung Hoon Noh, Min-Gew Choi, Jae-Ho Cheong; Cancer Res Treat. 2020;52(4):1153-1161. Published online May 4, 2020; DOI: https://doi.org/10.4143/crt.2020.173

Abstract PDF Supplementary Material PubReader ePub

Purpose
High microsatellite instability (MSI) is related to good prognosis in gastric cancer. We aimed to identify the prognostic factors of patients with recurrent gastric cancer and investigate the role of MSI as a prognostic and predictive biomarker of survival after tumor recurrence.
Materials and Methods
This retrospective cohort study enrolled patients treated for stage II/III gastric cancer who developed tumor recurrence and in whom the MSI status or mismatch repair (MMR) status of the tumor was known. MSI status and the expression of MMR proteins were evaluated using polymerase chain reaction and immunohistochemical analysis, respectively.
Results
Of the 790 patients included, 64 (8.1%) had high MSI status or MMR deficiency. The tumor-node-metastasis stage, type of recurrence, Lauren classification, chemotherapy after recurrence, and interval to recurrence were independently associated with survival after tumor recurrence. The MSI/MMR status and receiving adjuvant chemotherapy were not associated with survival after recurrence. In a subgroup analysis of patients with high MSI or MMR-deficient gastric cancer, those who did not receive adjuvant chemotherapy had better treatment response to chemotherapy after recurrence than those who received adjuvant chemotherapy.
Conclusion
Patients with high MSI/MMR-deficient gastric cancer should be spared from adjuvant chemotherapy after surgery, but aggressive chemotherapy after recurrence should be considered. Higher tumor-node-metastasis stage, Lauren classification, interval to recurrence, and type of recurrence are associated with survival after tumor recurrence and should thus be considered when establishing a treatment plan and designing clinical trials targeting recurrent gastric cancer.

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HIGD1B, as a novel prognostic biomarker, is involved in regulating the tumor microenvironment and immune cell infiltration; its overexpression leads to poor prognosis in gastric cancer patients
Shibo Wang, Siyi Zhang, Xiaoxuan Li, Xiangxue Li, Shufen Zhao, Jing Guo, Shasha Wang, Rui Wang, Mengqi Zhang, Wensheng Qiu
Frontiers in Immunology.2024;[Epub] CrossRef
Proteomic signatures of infiltrative gastric cancer by proteomic and bioinformatic analysis
Li-Hua Zhang, Hui-Qin Zhuo, Jing-Jing Hou, Yang Zhou, Jia Cheng, Jian-Chun Cai
World Journal of Gastrointestinal Oncology.2022; 14(11): 2097. CrossRef
The distinct clinical trajectory, metastatic sites, and immunobiology of microsatellite-instability-high cancers
Shuting Han, Aik Yong Chok, Daniel Yang Yao Peh, Joshua Zhi-Ming Ho, Emile Kwong Wei Tan, Si-Lin Koo, Iain Bee-Huat Tan, Johnny Chin-Ann Ong
Frontiers in Genetics.2022;[Epub] CrossRef
Mismatch Repair Status Characterization in Oncologic Pathology: Taking Stock of the Real-World Possibilities
Roberto Piciotti, Konstantinos Venetis, Elham Sajjadi, Nicola Fusco
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The Impact of Mismatch Repair Status on Prognosis of Patients With Gastric Cancer: A Multicenter Analysis
Wen-Long Guan, Yue Ma, Yue-Hong Cui, Tian-Shu Liu, Yan-Qiao Zhang, Zhi-Wei Zhou, Jian-Ying Xu, Li-Qiong Yang, Jia-Yu Li, Yu-Ting Sun, Rui-Hua Xu, Feng-Hua Wang, Miao-Zhen Qiu
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Establishment of a 5-gene risk model related to regulatory T cells for predicting gastric cancer prognosis
Gang Hu, Ningjie Sun, Jiansong Jiang, Xiansheng Chen
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A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair–Deficient/Microsatellite Instability–High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer: Jwa Hoon Kim, Sun Young Kim, Ji Yeon Baek, Yong Jun Cha, Joong Bae Ahn, Han Sang Kim, Keun-Wook Lee, Ji-Won Kim, Tae-You Kim, Won Jin Chang, Joon Oh Park, Jihun Kim, Jeong Eun Kim, Yong Sang Hong, Yeul Hong Kim, Tae Won Kim; Cancer Res Treat. 2020;52(4):1135-1144. Published online April 24, 2020; DOI: https://doi.org/10.4143/crt.2020.218

Abstract PDF Supplementary Material PubReader ePub

Purpose
We evaluated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations.
Materials and Methods
In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1.
Results
The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in 4 and 2 patients, respectively, with no treatment-related deaths.
Conclusion
Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.

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TGF-β Suppresses COX-2 Expression by Tristetraprolin-Mediated RNA Destabilization in A549 Human Lung Cancer Cells: Soyeong Kang, Ahrum Min, Seock-Ah Im, Sang-Hyun Song, Sang Gyun Kim, Hyun-Ah Kim, Hee-Jun Kim, Do-Youn Oh, Hyun-Soon Jong, Tae-You Kim, Yung-Jue Bang; Cancer Res Treat. 2015;47(1):101-109. Published online October 22, 2014; DOI: https://doi.org/10.4143/crt.2013.192

Abstract PDF PubReader ePub

Purpose
Overexpression of cyclooxygenase 2 (COX-2) is thought to promote survival of transformed cells. Transforming growth factor β (TGF-β) exerts anti-proliferative effects on a broad range of epithelial cells. In the current study, we investigated whether TGF-β can regulate COX-2 expression in A549 human lung adenocarcinoma cells, which are TGF-β-responsive and overexpress COX-2.
Materials and Methods
Western blotting, Northern blotting, and mRNA stability assays were performed to demonstrate that COX-2 protein and mRNA expression were suppressed by TGF-β. We also evaluated the effects of tristetraprolin (TTP) on COX-2 mRNA using RNA interference.
Results
We demonstrated that COX-2 mRNA and protein expression were both significantly suppressed by TGF-β. An actinomycin D chase experiment demonstrated that COX-2 mRNA was more rapidly degraded in the presence of TGF-β, suggesting that TGF-β–induced inhibition of COX-2 expression is achieved via decreased mRNA stability. We also found that TGF-β rapidly and transiently induced the expression of TTP, a well-known mRNA destabilizing factor, before suppression of COX-2 mRNA expression was observed. Using RNA interference, we confirmed that increased TTP levels play a pivotal role in the destabilization of COX-2 mRNA by TGF-β. Furthermore, we showed that Smad3 is essential to TTP-dependent down-regulation of COX-2 expression in response to TGF-β.
Conclusion
The results of this study show that TGF-β down-regulated COX-2 expression via mRNA destabilization mediated by Smad3/TTP in A549 cells.

Citations

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Diwen Zhang, Zhigang Zhou, Ruixia Yang, Sujun Zhang, Bin Zhang, Yanxuan Tan, Lingyao Chen, Tao Li, Jian Tu
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Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells
Miso Lee, Kyung-Hun Lee, Ahrum Min, Jeongeun Kim, Seongyeong Kim, Hyemin Jang, Jee Min Lim, So Hyeon Kim, Dong-Hyeon Ha, Won Jae Jeong, Koung Jin Suh, Yae-Won Yang, Tae Yong Kim, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im
Cancer Research and Treatment.2019; 51(2): 451. CrossRef
Transforming Growth Factor β Activation Primes Canonical Wnt Signaling Through Down‐Regulation of Axin‐2
Justin Gillespie, Rebecca L. Ross, Clarissa Corinaldesi, Filomena Esteves, Emma Derrett‐Smith, Michael F. McDermott, Gina M. Doody, Christopher P. Denton, Paul Emery, Francesco Del Galdo
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Cyclin E overexpression confers resistance to the CDK4/6 specific inhibitor palbociclib in gastric cancer cells
Ahrum Min, Jung Eun Kim, Yu-Jin Kim, Jee Min Lim, Seongyeong Kim, Jin Won Kim, Kyung-Hun Lee, Tae-Yong Kim, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im
Cancer Letters.2018; 430: 123. CrossRef
Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro
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Tristetraprolin activation by resveratrol inhibits the proliferation and metastasis of colorectal cancer cells
Se-Ra Lee, Hua Jin, Won-Tae Kim, Won-Jung Kim, Sung Zoo Kim, Sun-Hee Leem, Soo Mi Kim
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Molecular Cancer Therapeutics.2018; 17(12): 2507. CrossRef
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Hee‐Jun Kim, Ahrum Min, Seock‐Ah Im, Hyemin Jang, Kyung Hun Lee, Alan Lau, Miso Lee, Seongyeong Kim, Yaewon Yang, Jungeun Kim, Tae Yong Kim, Do‐Youn Oh, Jeffrey Brown, Mark J. O'Connor, Yung‐Jue Bang
International Journal of Cancer.2017; 140(1): 109. CrossRef
Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis
Seongyeong Kim, Ahrum Min, Kyung-Hun Lee, Yaewon Yang, Tae-Yong Kim, Jee Min Lim, So Jung Park, Hyun-Jin Nam, Jung Eun Kim, Sang-Hyun Song, Sae-Won Han, Do-Youn Oh, Jee Hyun Kim, Tae-You Kim, David Hangauer, Johnson Yiu-Nam Lau, Kyongok Im, Dong Soon Lee,
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Low tristetraprolin expression promotes cell proliferation and predicts poor patients outcome in pancreatic cancer
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Clinico-pathologic Parameters for Prediction of Microsatellite Instability in Colorectal Cancer: Sang-Bong Jung, Han-IL Lee, Hoon-Kyu Oh, Im-Hee Shin, Chang-Ho Jeon; Cancer Res Treat. 2012;44(3):179-186. Published online September 30, 2012; DOI: https://doi.org/10.4143/crt.2012.44.3.179

Abstract PDF PubReader ePub

PURPOSE
Although the incidence of microsatellite instability (MSI) accounts for 10-15% of cases of colorectal cancer, its clinical application for all colorectal cancers has widened. We attempted to identify clinical and pathological parameters that may be helpful in selection of patients with MSI-high (MSI-H).
MATERIALS AND METHODS
A total of 120 resected colorectal cancers were enrolled retrospectively for this MSI study. Polymerase chain reaction (PCR) and denaturing high performance liquid chromatography and/or real time PCR methods with five markers and immunohistochemistry (IHC) for MLH1 and MSH2 were performed for analysis of cancer and blood specimens. Clinico-pathologic parameters, including IHC, were investigated in order to determine their usefulness as predictive factors of MSI.
RESULTS
Among 120 cases of colorectal cancer, MSI was observed in 15 cases (12.5%), including 11 cases of MSI-H and four cases of MSI-low. Patients with MSI were younger, less than 50 years old, had a family history of cancer, Rt. sided colon cancer and/or synchronous multiple colorectal cancer, mucinous histologic type, and serum carcinoembryonic antigen group in the normal range. Results of multivariate analysis showed Bethesda guidelines, Rt. sided and/or synchronous multiple colorectal cancer, and negative expression of IHC for MLH1, which was consistently associated with MSI-H. MSI-H colorectal tumors have met at least one of these three parameters and their sensitivity and specificity were 100% and 72.5%, respectively.
CONCLUSION
Bethesda guidelines, tumor location, and negative expression of MLH1 protein are important parameters for selection of patients with colorectal cancers for MSI testing. MSI testing is recommended for patients showing any of these three parameters.

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Ping Li, Jia-Xun Cai, Fei Han, Jie Wang, Jia-Jie Zhou, Kai-Wen Shen, Liu-Hua Wang
World Journal of Gastrointestinal Oncology.2020; 12(4): 492. CrossRef
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Ji Li, Yabin Zou, Bin Wang, Xiangwei Meng, Xun Sun
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I S Reynolds, S J Furney, E W Kay, D A McNamara, J H M Prehn, J P Burke
British Journal of Surgery.2019; 106(6): 682. CrossRef
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Johan Rimbert, Gaëlle Tachon, Audelaure Junca, Claire Villalva, Lucie Karayan-Tapon, David Tougeron
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Xiangyan Zhang, Wenwen Ran, Jie Wu, Hong Li, Huamin Liu, Lili Wang, Yujing Xiao, Xiaonan Wang, Yujun Li, Xiaoming Xing
PeerJ.2018; 6: e4341. CrossRef
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Guo-Jun Tong, Gui-Yang Zhang, Jian Liu, Zhao-Zheng Zheng, Yan Chen, Ping-Ping Niu, Xu-Ting Xu
World Journal of Clinical Oncology.2018; 9(7): 148. CrossRef
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Quentin Thiebault, Gautier Defossez, Lucie Karayan-Tapon, Pierre Ingrand, Christine Silvain, David Tougeron
BMC Cancer.2017;[Epub] CrossRef
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Moritz Jesinghaus, Nicole Pfarr, Matthias Kloor, Volker Endris, Luca Tavernar, Alexander Muckenhuber, Magnus von Knebel Doeberitz, Roland Penzel, Wilko Weichert, Albrecht Stenzinger
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Won Kyung Kang, Jin Kwon Lee, Seong Taek Oh, Sung Hak Lee, Chan Kwon Jung
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Ju-Xiang Ye
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Hermann Brenner, Matthias Kloor, Christian Peter Pox
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Journal of the American College of Surgeons.2013; 217(2): 181. CrossRef

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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

Abstract PDF PubReader ePub

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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Iina Niittymäki, Alexandra Gylfe, Leena Laine, Marko Laakso, Heli J. Lehtonen, Johanna Kondelin, Jaana Tolvanen, Kari Nousiainen, Jeroen Pouwels, Heikki Järvinen, Kyösti Nuorva, Jukka-Pekka Mecklin, Markus Mäkinen, Ari Ristimäki, Torben F. Ørntoft, Sampsa
Carcinogenesis.2011; 32(3): 305. CrossRef
Physiological Relevance of Cell Cycle Kinases
Marcos Malumbres
Physiological Reviews.2011; 91(3): 973. CrossRef

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Clinicopathological Features of Replication Error-positive Tumors in Single or Multiple Gastric Carcinomas: Gyeong Hoon Kang, So Dug Lim, Bong Hee Kim, Jae Jeong Jang, Hwoon Yong Jung, Jae Y Ro; J Korean Cancer Assoc. 1999;31(2):230-239.

Abstract PDF: PURPOSE
Replication error (RER) is an important mechanism in the gastric carcinogenesis and known to contribute to the pathogenesis of multiple gastric carcinomas (GCs). A proportion of sporadic GCs are RER-positive and RER-positive GCs have been reported to have distinct clinicopathological features. The purpose of the present study included whether there are characteristic clinicopathological features of RER-positive GCs and whether there is a difference of RER frequency between single and multiple GC in age-matched patients.
MATERIALS AND METHODS
We analyzed 96 cases of single GC and 19 cases of multiple GC for the RER status using 7 microsatellite loci to assess their clinicopathological features.
RESULT
Ten cases (10%) of 96 single GCs and five cases (26.3%) of 19 multiple GCs were RER-positive. However, comparison of RER frequency between single and multiple GCs in patients older than 60 years revealed no significant difference. Jn single GCs, RER-positive tumors showed a proclivity toward older age, antral location, and elevated gross type (Borrmann 2 or EGC IIa or I). Multiple GCs with RER showed a female-sex preponderance. Clinicopathological features of RER-positive tumors were similar in both single and multiple GCs.
CONCLUSION
The present study revealed that RER-positive tumors had distinct clinico- pathological features and there was no significant difference of RER frequency between single and multiple GC in elderly patients. Our data suggests that RER contributes to the pathogenesis of GC, either single or multiple, in aged patients.

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Microsatellite Instability Correlate with a Prognosis in Breast Cancer: Hwa Young Lee, Chengshi Quan, Soo Jung Gong, Joon Oh Park, Joong Bae Ahn, Kwang Yong Shim, Sun Young Rha, Nae Choon Yoo, Woo Ick Yang, Joo Hang Kim, Jae Kyung Roh, Kyong Sik Lee, Byung Soo Kim, Hyun Cheol Chung; J Korean Cancer Assoc. 1998;30(5):914-920.

Abstract PDF: PURPOSE
Microsatellite instability in patients with defects in the mismatch repair system resulting in RER has a high risk of accumulating mutations in oncogene and tumor suppressor gene. In this study, we evaluated the incidence of microsatellite instability in breast cancer by comparing PCR-amplified sequences from frozen samples of normal and tumor tissue fram affected patients. We also investigated whether RER was associated with TGF-beta RII mutation.
MATERIALS AND METHODS
Fifty surgically resected breast cancer specimens from Jan. 1996 to June, 1997 were used for study. Microsatellite instability(referred to as replication error, RER) at three loci with BAT 26, BAT 40, TA10 was analyzed by polymerase chain reaction and the results were compared with clinicopathologic characteristics.
RESULTS
Of the 50 breast cancer patients, 14(28%) were RER(+) at one or more microsatellite loci, and 4(8%) showed TGF-beta RII mutation. Microsatellite instability was significantly correlated with lymph node involvement(especially in case of 4 or more lymph nodes involvement). But we could not find any correlation between RER and other prognostic factors including tumor size, tumor grade, hormone receptor status and pathology. One of fourteen tumors with RER(+) showed TGF-beta RII mutstion. There was no signiticant correlation between RER(+) and TGF-beta type II receptor gene mutation.
CONCLUSION
The findings suggest that microsatellite instability would be useful prognostic factor in unilateral breast cancer patients, and the role of targeting to gene mutation will be explored in future studies.

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Microsatellite Instability in Korean Hepatocellular Carcinoma using Fluorescent - PCR: Young Suk Park, Hee Jung Wnag, Moon Ju Oh, Eun Ha Kim, Kyung Ok Lee, Myung Wook Kim, Young Gyu Chai; J Korean Cancer Assoc. 1998;30(3):544-552.

Abstract PDF: PURPOSE
Hepatocellular carcinoma (HCC) is one of the most common cancers in many parts of the world, however the molecular mechanisms underlying liver cell transformation remain obscure. The instability of microsatellite sequences dispersed in the genome has been linked to a deficiency in cellular mismatch repair. This phenotype has been frequently observed in various human neoplasms and is regarded as a major factor in tumorigenesis. To investigate cumulative genetic changes related with apoptosis during development and progression of HCC, we examined DNAs isolated from 12 Korean HCCs and their adjacent non-tumorous parts to look for evidence of microsatellite instability (MSI).
MATERIALS AND METHODS
Twelve microsatellite loci (D6S271, D6S426, D13S153, D13S263, D17S849, D17S938, D17S945, D18S474, D18S64, D19S420, D.19S418 and D19S210) were amplified by PCR from 12 Korean HCCs, and analyzed using an automated DNA analyzer.
RESULTS
The high percentages of the MSI were found for the loci of D6S426 (33.3%) and D17S945 (25.0%). The related genes with high frequency of MSI were noted in the wafl (41.7%) and p53 (25.0%). From this study, fifty eight percent of HCCs (7/12) showed MSI with at least one marker.
CONCLUSION
This results suggest that the analysis of MSI in HCC might be useful for identifying genes whose loss of function contributes to the development of liver cancer. Furthennore, this method may give a more rapid and accurate sizing of the PCR products of microsatellite; making the routine assessment of MSI possible in many clinical fields.

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Stability of Cisplatin and Etoposide in Normal Solution: Sang Cheul Oh, Young Mi Kim, Young Inn You, Song Ja Jo, Byung Soo Kim, Sang Won Shin, Yeul Hong Kim, Jun Suk Kim; J Korean Cancer Assoc. 1997;29(4):700-705.

Abstract PDF: PURPOSE
The cisplatin and etoposide had been reported to be an effective anti-tumor drug for small cell lung cancer, ovarian cancer, breast cancer and so on. The aim of this study was to evaluate the stability of cisplatin and etoposide in aqueous solution.
MATERIALS AND METHODS
Cisplatin 200 microgram/ml was prepared in 0.9% sodium chloride and stored in either glass bottle or polyvinyl chloride (pvc) bag and protected from light or exposed to fluorescent light. Etoposide solution was prepared in 0.9% sodium chloride, and contained in glass bottle. Precipitating concentration was achieved using 200 microgram/ml, 400microgram/ml, 600 microgram/ml, and 1000 microgram/ml of etoposide solution. Samples were stored at room temperature and visually inspected and assayed for etoposide and cisplatin content by high-performance liquid chromatography after 15 minutes, 2, 4, 8, 12, 16 and 24 hours of storage.
RESULT
1) Cisplatin concentration decreased less than 10% from initial concentration for 24 hours of storage, both in glass bottle and pvc bag. Stability of cisplatin 200 microgram/ml in both container were not different. and Condition of light exposure did not have significant effect on stability of cisplatin 200 microgram/ml in glass bottle. 2) The etoposide 200 microgram/ml was not precipitated and stable for 24 hours, but we could find the precipitates of etoposide with the concentration of 400 microgram/ml or higher for 24 hours.
CONCLUSION
Cisplatin 200 microgram/ml and etoposide 200 microgram/ml in 0.9% sodium chloride were stable at room temperature under room fluorescent light for 24 hours.

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