Annals of Coloproctology

Original Articles

Prognostic Impact of Microsatellite Instability in Colorectal Cancer Presenting With Mucinous, Signet-Ring, and Poorly Differentiated Cells: Sang Hun Jung, So Hyun Kim, Jae Hwang Kim; Ann Coloproctol. 2016;32(2):58-65. Published online April 30, 2016; DOI: https://doi.org/10.3393/ac.2016.32.2.58

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Purpose

Mucinous cells (MUCs), signet-ring cells (SRCs), and poorly differentiated cells (PDCs) are uncommon histologic types and have been associated with advanced tumor stage and poor prognosis. However, MUCs, SRCs, and PDCs are commonly observed in cancers with high microsatellite instability (MSI), which have favorable outcomes compared with cancers with microsatellite stability (MSS). The purpose of this study was to evaluate the prognostic impact of high-MSI in patients with sporadic colorectal cancer presenting with MUCs, SRCs, and/or PDCs.

Methods

Between January 2006 and December 2012, 176 with proven microsatellite status who also presented with MUCs, SRCs, and PDCs were selected for this study and were divided into 2 groups, high-MSI and MSS; their outcomes were analyzed.

Results

Of the 176 patients, 56 and 120, respectively, had high-MSI and MSS cancers. High-MSI cancers had larger tumors, proximal tumor location, and a lower TNM stage. The recurrence rate was lower in the high-MSI group (13.7% vs. 35.4%, P = 0.006). Common patterns of distant metastasis for MUC, SRC, PDC cancers were peritoneal spread (46.9%) and hematogenous metastasis (46.4%). The 5-year CSS rates were 88.2% and 61.2% for patients with high-MSI and MSS cancers, respectively (P < 0.0001). In the multivariate analysis, except for stage-IV cancer, MSI status was an independent risk factor for cancer-specific survival (MSS: hazard ratio, 4.34; 95% confidence interval, 1.68-11.21).

Conclusion

In patients with colorectal cancer presenting with MUCs, SRCs, and/or PDCs, those with high-MSI cancers had better outcomes.

Citations

Citations to this article as recorded by

Dipeptidase-1–knockout mice develop invasive tumors with features of microsatellite-unstable colorectal cancer
Sarah E. Glass, Matthew E. Bechard, Zheng Cao, Radhika Aramandla, Ping Zhao, Samuel T. Ellis, Emily H. Green, Elizabeth G. Fisher, Ryan T. Smith, Chelsie K. Sievers, Maria Johnson Irudayam, Frank Revetta, M. Kay Washington, Gregory D. Ayers, Cody N. Heise
JCI Insight.2025;[Epub] CrossRef
Clinicopathological features and evaluation of microsatellite stability of colorectal carcinoma with cribriform comedo pattern
Tuğba Günler, Pinar Karabağli, Hicret Tiyek, Özge Keskin, Muslu K. Körez
Indian Journal of Pathology and Microbiology.2024; 67(2): 275. CrossRef
Correlation of clinical, pathologic, and genetic parameters with intratumoral immune milieu in mucinous adenocarcinoma of the colon
Azfar Neyaz, Amaya Pankaj, Andrew Crabbe, Steffen Rickelt, Lieve Leijssen, Anne Dinaux, Martin Taylor, Stuti G. Shroff, Rory Crotty, M. Lisa Zhang, Omer H. Yilmaz, Osman Yılmaz, Deepa T. Patil, Aparna R. Parikh, David T. Ting, David Berger, Vikram Deshpan
Modern Pathology.2022; 35(11): 1723. CrossRef
The Molecular Associations of Signet-Ring Cell Carcinoma in Colorectum: Meta-Analysis and System Review
Xueting Liu, Litao Huang, Menghan Liu, Zhu Wang
Medicina.2022; 58(7): 836. CrossRef
Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis
James W. T. Toh, Kevin Phan, Faizur Reza, Pierre Chapuis, Kevin J. Spring
International Journal of Colorectal Disease.2021; 36(8): 1573. CrossRef
Tumour infiltrating lymphocyte status is superior to histological grade, DNA mismatch repair and BRAF mutation for prognosis of colorectal adenocarcinomas with mucinous differentiation
David S. Williams, Dmitri Mouradov, Marsali R. Newman, Elham Amini, David K. Nickless, Catherine G. Fang, Michelle Palmieri, Anuratha Sakthianandeswaren, Shan Li, Robyn L. Ward, Nicholas J. Hawkins, Iain Skinner, Ian Jones, Peter Gibbs, Oliver M. Sieber
Modern Pathology.2020; 33(7): 1420. CrossRef
Prognostic value of KRAS mutation status in colorectal cancer patients: a population-based competing risk analysis
Dongjun Dai, Yanmei Wang, Liyuan Zhu, Hongchuan Jin, Xian Wang
PeerJ.2020; 8: e9149. CrossRef
Implication of Microsatellite Instability in Chinese Cohort of Human Cancers

Meiying Cui, Pan Li, Ying Mao, Lan Zhang, Peiyi Xia, Enjie Liu, Weiwei Wang, Jianying Zhang, Guozhong Jiang, Wencai Li
Cancer Management and Research.2020; Volume 12: 10287. CrossRef
Outcomes for Metastatic Colorectal Cancer Based on Microsatellite Instability: Results from the South Australian Metastatic Colorectal Cancer Registry
Li Chia Chong, Amanda Rose Townsend, Joanne Young, Amitesh Roy, Cynthia Piantadosi, Jennifer E. Hardingham, David Roder, Christos Karapetis, Robert Padbury, Guy Maddern, James Moore, Timothy Jay Price
Targeted Oncology.2019; 14(1): 85. CrossRef
Signet ring cell colorectal cancer: genomic insights into a rare subpopulation of colorectal adenocarcinoma
Krittiya Korphaisarn, Van Morris, Jenifer S. Davis, Michael J. Overman, David R. Fogelman, Bryan K. Kee, Arvind Dasari, Kanwal P. S. Raghav, Imad Shureiqi, Metha Trupti, Robert A. Wolff, Cathy Eng, David G. Menter, Stanley Hamilton, Scott Kopetz
British Journal of Cancer.2019; 121(6): 505. CrossRef
SILAC-Based Quantification of TGFBR2-Regulated Protein Expression in Extracellular Vesicles of Microsatellite Unstable Colorectal Cancers
Fabia Fricke, Malwina Michalak, Uwe Warnken, Ingrid Hausser, Martina Schnölzer, Jürgen Kopitz, Johannes Gebert
International Journal of Molecular Sciences.2019; 20(17): 4162. CrossRef
Is microsatellite instability-high really a favorable prognostic factor for advanced colorectal cancer? A meta-analysis
Bingyan Wang, Fei Li, Xin Zhou, Yanpeng Ma, Wei Fu
World Journal of Surgical Oncology.2019;[Epub] CrossRef
Cáncer de colon en Colombia, fenotipo molecular: tamizaje para síndromes con agregación familiar
Mabel Elena Bohórquez L, Ángel Alexandro Criollo R, Luis Carvajal Carmona, María Magdalena Echeverry de Polanco
Revista de la Asociación Colombiana de Ciencias Biológicas.2019; : 87. CrossRef
Evaluation of Long-Term Outcomes of Microsatellite Instability Status in an Asian Cohort of Sporadic Colorectal Cancers
Winson Jianhong Tan, Julie Liana Hamzah, Sanchalika Acharyya, Fung Joon Foo, Kiat Hon Lim, Iain Bee Huat Tan, Choong Leong Tang, Min Hoe Chew
Journal of Gastrointestinal Cancer.2018; 49(3): 311. CrossRef
What are the Clinicopathological Features and Outcomes of Sporadic Colorectal Cancer (CRC) in an Ethiopian Cohort with focus on young-onset CRC?
Dominic Worku
Journal of Cancer Prevention & Current Research.2017;[Epub] CrossRef
Mismatch Repair Proteins and Microsatellite Instability in Colorectal Carcinoma (MLH1, MSH2, MSH6 and PMS2): Histopathological and Immunohistochemical Study
Nour El Hoda S. Ismael, Samar A. El Sheikh, Suzan M. Talaat, Eman M. Salem
Open Access Macedonian Journal of Medical Sciences.2017; 5(1): 9. CrossRef
Impact of Microsatellite Instability in Signet-Ring Cell and Mucinous Components in Patients With Colorectal Carcinoma
Ik Yong Kim
Annals of Coloproctology.2016; 32(2): 45. CrossRef

Is Microsatellite Instability Really a Good Prognostic Factor of Colorectal Cancer?: Ui Sup Shin, Sang Sik Cho, Sun Mi Moon, Sun Hoo Park, Sun Hee Jee, Eun-Joo Jung, Dae-Yong Hwang; Ann Coloproctol. 2014;30(1):28-34. Published online February 28, 2014; DOI: https://doi.org/10.3393/ac.2014.30.1.28

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Abstract PDF

Purpose

The aim of this study was to investigate the clinicopathologic features of and the prognosis for colorectal cancers (CRCs) with microsatellite instabilities (MSIs).

Methods

Between 2006 and 2009, genotyping was performed on 245 patients with stage II/III CRCs to establish the MSI status. The clinicopathologic differences and the prognostic value of MSI were analyzed. The median follow-up period was 38 months (range, 7-68 months).

Results

Of the total 245 patients, 20 (8.2%) had MSI-high (H) and 225 (91.8%) had MSI-low (L) or stable (S) CRCs. Adjuvant chemotherapies were performed on 101 stage II (87.8%) and 107 stage III patients (82.3%). Patients with MSI-H CRCs more frequently had a family history of colon cancer (10% vs. 2.7%, P = 0.003), more frequently had a cancer located at the proximal colon (90.0% vs. 19.1%, P < 0.0001), and more often showed a mucinous phenotype or poor differentiation (35.0% vs. 7.1%, P = 0.001). Despite less frequent lymph node metastasis (25% vs. 55.6%, P = 0.01), the number of retrieved lymph nodes was higher (26.3 ± 13.1 vs. 20.7 ± 1.2, P = 0.04) in the MSI-H group. The overall survival and the disease-free survival (DFS) did not differ with respect to MSI status. However, in the stage II subgroup, the DFS for patients with MSI-H CRCs was significantly worse (72.2% vs. 90.7%, P = 0.03). The multivariate analysis performed on this subgroup revealed that MSI-H was an independent poor prognostic factor (adjusted hazard ratio, 4.0; 95% confidence interval, 1.0-15.6, P = 0.046).

Conclusion

MSI-H CRCs had distinct clinicopathologic features, and MSI-H was an independent poor prognostic factor in stage II CRCs. Considering the majority of stage II patients were administrated adjuvant chemotherapy, the efficacy of adjuvant chemotherapy for treating MSI CRCs might be different from that for treating MSI-L/S tumors.

Citations

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Reassessing the Prognostic Value of Lymph Node Metastasis in Deficient Mismatch Repair Colorectal Cancer
Zilan Ye, Dakui Luo, Fan Chen, Jiayu Chen, Zezhi Shan, Junyong Weng, Yu Zhang, Qingguo Li, Xinxiang Li
Current Oncology.2025; 32(5): 254. CrossRef
Prognostic significance of negative lymph node count in microsatellite instability-high colorectal cancer
Xuan Dai, Zhujiang Dai, Jihong Fu, Zhonglin Liang, Peng Du, Tingyu Wu
World Journal of Surgical Oncology.2024;[Epub] CrossRef
Oncological characteristics, treatments and prognostic outcomes in MMR-deficient colorectal cancer
Wen-Xuan Fan, Fei Su, Yan Zhang, Xiao-Ling Zhang, Yun-Yi Du, Yang-Jun Gao, Wei-Ling Li, Wen-Qing Hu, Jun Zhao
Biomarker Research.2024;[Epub] CrossRef
Exploring the value of multiple preprocessors and classifiers in constructing models for predicting microsatellite instability status in colorectal cancer
Yi Ma, Zhihao Shi, Ying Wei, Feng Shi, Guochu Qin, Zhengyang Zhou
Scientific Reports.2024;[Epub] CrossRef
The prognostic significance of microsatellite instability in colorectal cancer: a Swedish multi-center study
Petri Rantanen, Anne Keränen, Shabane Barot, Sam Ghazi, Annelie Liljegren, Caroline Nordenvall, Annika Lindblom, Ulrik Lindforss
International Journal of Colorectal Disease.2023;[Epub] CrossRef
Preoperative albumin–bilirubin score as a prognostic indicator in patients with stage III colon cancer
Hyun Gu Lee, Seok-Byung Lim, Jong Lyul Lee, Chan Wook Kim, Yong Sik Yoon, In Ja Park, Jin Cheon Kim
Scientific Reports.2022;[Epub] CrossRef
Radiomics features based on internal and marginal areas of the tumor for the preoperative prediction of microsatellite instability status in colorectal cancer
Yi Ma, Changsong Lin, Song Liu, Ying Wei, Changfeng Ji, Feng Shi, Fan Lin, Zhengyang Zhou
Frontiers in Oncology.2022;[Epub] CrossRef
Anatomical Distribution of Colon Cancer: A Retrospective 10-Year Study to Evaluate Rightward Shift in Two Referral Hospitals in Iran
Ahmad R Mafi, Shima Azimi Oliaei, Ramin Heshmat, Hossein Yahyazadeh, Ali G Motlagh
International Journal of Cancer Management.2022;[Epub] CrossRef
Current status on microsatellite instability, prognosis and adjuvant therapy in colon cancer: A nationwide survey of medical oncologists, colorectal surgeons and gastrointestinal pathologists
James W. T. Toh, Hema Mahajan, Pierre Chapuis, Kevin Spring
Cancer Reports.2021;[Epub] CrossRef
Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis
James W. T. Toh, Kevin Phan, Faizur Reza, Pierre Chapuis, Kevin J. Spring
International Journal of Colorectal Disease.2021; 36(8): 1573. CrossRef
Computed Tomography-Based Radiomics Model to Preoperatively Predict Microsatellite Instability Status in Colorectal Cancer: A Multicenter Study
Zhi Li, Qi Zhong, Liang Zhang, Minhong Wang, Wenbo Xiao, Feng Cui, Fang Yu, Chencui Huang, Zhan Feng
Frontiers in Oncology.2021;[Epub] CrossRef
Colon cancer patients with mismatch repair deficiency are more likely to present as acute surgical cases
Ioannis Gkekas, Jan Novotny, Tuomas Kaprio, Ines Beilmann-Lehtonen, Pavel Fabian, Sofia Edin, Karin Strigård, Tomas Svoboda, Jaana Hagström, Lucie Barsova, Tomas Jirasek, Caj Haglund, Richard Palmqvist, Ulf Gunnarsson
European Journal of Cancer.2021; 157: 1. CrossRef
Pathological Features and Prognostication in Colorectal Cancer
Kabytto Chen, Geoffrey Collins, Henry Wang, James Wei Tatt Toh
Current Oncology.2021; 28(6): 5356. CrossRef
Prognostic and predictive role of DNA mismatch repair status in stage II‐III colorectal cancer: A systematic review and meta‐analysis
Zhujun Deng, Yun Qin, Jing Wang, Gang Wang, Xiaoqiang Lang, Juan Jiang, Kang Xie, Wengeng Zhang, Heng Xu, Yang Shu, Yan Zhang
Clinical Genetics.2020; 97(1): 25. CrossRef
Implication of Microsatellite Instability in Chinese Cohort of Human Cancers

Meiying Cui, Pan Li, Ying Mao, Lan Zhang, Peiyi Xia, Enjie Liu, Weiwei Wang, Jianying Zhang, Guozhong Jiang, Wencai Li
Cancer Management and Research.2020; Volume 12: 10287. CrossRef
Small RNA expression from viruses, bacteria and human miRNAs in colon cancer tissue and its association with microsatellite instability and tumor location
Robin Mjelle, Wenche Sjursen, Liv Thommesen, Pål Sætrom, Eva Hofsli
BMC Cancer.2019;[Epub] CrossRef
Evaluation of Long-Term Outcomes of Microsatellite Instability Status in an Asian Cohort of Sporadic Colorectal Cancers
Winson Jianhong Tan, Julie Liana Hamzah, Sanchalika Acharyya, Fung Joon Foo, Kiat Hon Lim, Iain Bee Huat Tan, Choong Leong Tang, Min Hoe Chew
Journal of Gastrointestinal Cancer.2018; 49(3): 311. CrossRef
Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system
Jeong Mo Bae, Jung Ho Kim, Yoonjin Kwak, Dae-Won Lee, Yongjun Cha, Xianyu Wen, Tae Hun Lee, Nam-Yun Cho, Seung-Yong Jeong, Kyu Joo Park, Sae Won Han, Hye Seung Lee, Tae-You Kim, Gyeong Hoon Kang
British Journal of Cancer.2017; 116(8): 1012. CrossRef
Investigation of correlation between mutational status in key EGFR signaling genes and prognosis of stage II colorectal cancer
Li Li, Bei-Bei Ni, Qing-Hua Zhong, Yan-Hui Liu, Ming-Hui Zhang, Ke-Ping Zhang, Dai-Ci Chen, Lei Wang
Future Oncology.2017; 13(17): 1473. CrossRef
Comparison of oncological outcomes of right-sided colon cancer versus left-sided colon cancer after curative resection
Dae Ro Lim, Jung Kul Kuk, Taehyung Kim, Eung Jin Shin
Medicine.2017; 96(42): e8241. CrossRef
Downregulation of acetyl-CoA synthetase 2 is a metabolic hallmark of tumor progression and aggressiveness in colorectal carcinoma
Jeong Mo Bae, Jung Ho Kim, Hyeon Jeong Oh, Hye Eun Park, Tae Hun Lee, Nam-Yun Cho, Gyeong Hoon Kang
Modern Pathology.2017; 30(2): 267. CrossRef
Prognostic relevance of microsatellite instability in pT3N0M0 colon cancer: a population-based study
Francesco Iachetta, Federica Domati, Luca Reggiani-Bonetti, Valeria Barresi, Giulia Magnani, Luigi Marcheselli, Claudia Cirilli, Monica Pedroni
Internal and Emergency Medicine.2016; 11(1): 41. CrossRef
Clinical, histological, and molecular risk factors for cancer recurrence in patients with stage II colon cancer
Yann Touchefeu, Marie Provost-Dewitte, Thierry Lecomte, Alain Morel, Isabelle Valo, Jean-François Mosnier, Céline Bossard, Juliette Eugène, Emilie Duchalais, Jérôme Chetritt, Serge Guyetant, Stéphane Bézieau, Hélène Senellart, Morgane Caulet, Estelle Cauc
European Journal of Gastroenterology & Hepatology.2016; 28(12): 1394. CrossRef
Microsatellite instability is associated with reduced disease specific survival in stage III colon cancer
H.M. Mohan, E. Ryan, I. Balasubramanian, R. Kennelly, R. Geraghty, F. Sclafani, D. Fennelly, R. McDermott, E.J. Ryan, D. O'Donoghue, J.M.P. Hyland, S.T. Martin, P.R. O'Connell, D. Gibbons, Des Winter, K. Sheahan
European Journal of Surgical Oncology (EJSO).2016; 42(11): 1680. CrossRef
Different treatment strategies and molecular features between right-sided and left-sided colon cancers
Hong Shen
World Journal of Gastroenterology.2015; 21(21): 6470. CrossRef
Is a Microsatellite Instability Still Useful for Tailored Treatment in Stage II and III Colon Cancer?
Nam Kyu Kim
Annals of Coloproctology.2014; 30(1): 5. CrossRef

Knowledge of and Practice Patterns for Hereditary Colorectal Cancer Syndromes in Korean Surgical Residents: Jangho Park, Soo Young Lee, Duck-Woo Kim, Sung-Bum Kang, Seung-Yong Jeong, Kyu Joo Park; Ann Coloproctol. 2013;29(5):186-191. Published online October 31, 2013; DOI: https://doi.org/10.3393/ac.2013.29.5.186

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Abstract PDF

Purpose

Obtaining a detailed family history through detailed pedigree is essential in recognizing hereditary colorectal cancer (CRC) syndromes. This study was performed to assess the current knowledge and practice patterns of surgery residents regarding familial risk of CRC.

Methods

A questionnaire survey was performed to evaluate the knowledge and the level of recognition for analyses of family histories and hereditary CRC syndromes in 62 residents of the Department of Surgery, Seoul National University Hospital. The questionnaire consisted of 22 questions regarding practice patterns for, knowledge of, and resident education about hereditary CRC syndromes.

Results

Two-thirds of the residents answered that family history should be investigated at the first interview, but only 37% of them actually obtained pedigree detailed family history at the very beginning in actual clinical practice. Three-quarters of the residents answered that the quality of family history they obtained was poor. Most of them could diagnose hereditary nonpolyposis colorectal cancer and recommend an appropriate colonoscopy surveillance schedule; however, only 19% knew that cancer surveillance guidelines differed according to the family history. Most of our residents lacked knowledge of cancer genetics, such as causative genes, and diagnostic methods, including microsatellite instability test, and indicated a desire and need for more education regarding hereditary cancer and genetic testing during residency.

Conclusion

This study demonstrated that surgical residents' knowledge of hereditary cancer was not sufficient and that the quality of the family histories obtained in current practice has to be improved. More information regarding hereditary cancer should be considered in education programs for surgery residents.

Citations

Citations to this article as recorded by

Transition of care in pediatric hereditary polyposis: the why, how and to whom
Thomas M. Attard, Ajay Bansal, Caitlin E. Lawson, Nicole Stoecklein, Michele H. Maddux
Expert Review of Gastroenterology & Hepatology.2025; 19(5): 527. CrossRef
Efficacy, functional outcome and post‑operative complications of total abdominal colectomy with ileorectal anastomosis vs. segmental colectomy in hereditary non‑polyposis colorectal cancer
Jie Sun, Mingjie Dong, Xiaoping Xiao
Experimental and Therapeutic Medicine.2018;[Epub] CrossRef
Clinicopathological Features and Type of Surgery for Lynch Syndrome: Changes during the Past Two Decades
Il Tae Son, Duck-Woo Kim, Seung-Yong Jeong, Young-Kyoung Shin, Myong Hoon Ihn, Heung-Kwon Oh, Sung-Bum Kang, Kyu Joo Park, Jae Hwan Oh, Ja-Lok Ku, Jae-Gahb Park
Cancer Research and Treatment.2016; 48(2): 605. CrossRef

Microsatellite Instability-low Colorectal Carcinomas: Are They Comparable with Microsatellite Stable Cancer?.: Paek, Ok Joo , Oh, Seung Yeop , Kim, Young Bae , Suh, Kwang Wook; J Korean Soc Coloproctol. 2010;26(2):145-151.; DOI: https://doi.org/10.3393/jksc.2010.26.2.145

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Abstract PDF

PURPOSE
Microsatellite instability-high (MSI-H) colorectal cancer (CRC) displays a well-described distinct phenotype, but the true biological significance of MSI-low (L) is still uncertain. To clarify the significance of this MSI-L, we studied the differences between patients with CRC with MSI-H, MSI-L, and microsatellite stability (MSS).
METHODS
A total of 723 consecutive patients (429 males and 294 females) who had undergone resections between September 2002 and August 2007 were studied. We analyzed the clinicopathological features, the MSI statuses, and the prognoses of the 723 CRC patients.
RESULTS
MSI-H was observed in 54 (7.5%), MSI-L in 27 (3.7%), and MSS in 642 (88.8%) of the 723 colorectal cancer patients. MSI-L and MSS CRC share similar clinicopathological features. A univariate analysis showed no significant differences in overall survival between MSI-L, MSS, and MSI-H. In the multivariate Cox regression analysis, MSI-L was significantly (P=0.036) associated with poorer prognosis compared with MSS tumors, after adjustment for factors previous shown to be associated with the survival based on potentially relevant variables.
CONCLUSION
In conclusion, the current study showed no difference in the clinicopathological features of MSI-L versus MSS CRCs. However, in the multivariate analysis, patients with MSI-L CRCs had significantly poorer overall survival. Finally, these findings support the existence of MSI-L CRCs as a distinct category. Thus, further studies are required to explore possible reasons for the adverse prognosis associated with MSI-L cancers.

Citations

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MSI‐L/EMAST is a predictive biomarker for metastasis in colorectal cancer patients
Amir Torshizi Esfahani, Seyed Yoosef Seyedna, Ehsan Nazemalhosseini Mojarad, Ahmad Majd, Hamid Asadzadeh Aghdaei
Journal of Cellular Physiology.2019; 234(8): 13128. CrossRef

Review

Genomic Instability in Colorectal Cancer; from Bench to Bed.: Lee, Kang Young; J Korean Soc Coloproctol. 2009;25(2):129-138.; DOI: https://doi.org/10.3393/jksc.2009.25.2.129

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Abstract PDF: Colorectal cancer is a disease developed by the accumulation of genomic alteration. Two genomic instability pathways, chromosomal instability pathway and microsatellite instability pathway, are known as the main pathways of the development of colorectal cancer. These are almost always mutually exclusive and tumors developed through each pathways show distinct clinicopathologic features. For the reason, molecular markers which represent each genomic instability pathways have been a candidate for translational research to find out prognostic or predictive factors. Loss of heterozygosity and aneuploidy are the hallmark of chromosomal instability and regarded as poor prognostic markers, whereas tumors with high frequency of microsatellite instability show better prognosis than microsatellite stable tumor. As a predictive factor of response from chemotherapy, loss of heterozygosity seems to be associated with a survival benefit from 5-FU adjuvant therapy. MSI-H has been reported as a predictive factor for poor response to 5-FU adjuvant chemotherapy. However, these molecular markers are not accepted to use in the clinic yet, since some of this kind of studies reported contradictory results. Further study will be needed to make more concrete evidences for these markers and to identify new molecular markers for routine use in the clinic.

Original Articles

Clinicopathologic Features of Sporadic Colorectal Cancer with MLH1/MSH2 Loss of Expression - Reduced Likelihood of Metastases.: Park, Ji Won , Chang, Hee Jin , Jung, Kyung Hae , Kim, Dae Yong , Sohn, Dae Kyung , Han, Kyung Soo , Hong, Chang Won , Lim, Seok Byung , Choi, Hyo Seong , Jeong, Seung Yong , Lee, Sang Jeon; J Korean Soc Coloproctol. 2008;24(3):175-183.; DOI: https://doi.org/10.3393/jksc.2008.24.3.175

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Abstract PDF

PURPOSE
This study was designed to determine the frequency of MMR defective sporadic colorectal cancer (CRC) by using immunohistochemistry and to investigate the correlation between the MMR status and the metastatic potential.
METHODS
The study included 249 patients with sporadic colorectal cancer who underwent surgical resection. The MMR status was determined by using an immunohistochemical analysis of MLH1 and MSH2 expression. RESULTS: Twenty seven (10.8%) carcinomas showed abnormal MMR protein expression (18 MLH1 negative and 9 MSH2 negative) and were classified as MMR defective tumors whereas 222 tumors demonstrated normal MLH1/MSH2 immunoreactivity (MMR intact tumor). MMR defective tumors developed at significantly higher frequencies in a proximal site (59.3% vs. 27.5%, P=0.001) and tended to be larger in size (6.3+/-2.4 cm vs. 5.1+/-2.1 cm, P=0.026). They showed significantly lower overall stage, N stage, and M stage at the time of diagnosis (P=0.002, P=0.014, P=0.010, respectively). In patients who had MMR defective tumors, lymphocytic infiltration (40.7% vs. 8.7%, P<0.001) and poor differentiation (22.2% vs. 11.7%, P=0.012) were more frequently observed. Less frequently MMR defective tumors displayed lymphatic invasion (40.7% vs. 67.1%, P=0.007) and infiltrative borders (22.2% vs. 51.8%, P=0.004). The MMR defect was strongly associated with a decreased likelihood of lymph node (odds ratio: 0.34, 95% CI: 0.13~0.95) and distant organ metastases at diagnosis (odds ratio: 0.09, 95% CI: 0.01~0.94), independent of the clinicopathologic features. CONCLUSIONS: mmunohistochemical analysis revealed that 10.8% of sporadic CRC cases showed no staining for MLH1 or MSH2. Lymphatic invasion and distant metastases were found at lower rates in these MMR defective tumors.

Citations

Citations to this article as recorded by

Characterization of RNA editome in primary and metastatic lung adenocarcinomas
Lihua Peng, Leo J Lee, Heng Xiong, Hong Su, Junhua Rao, Dakai Xiao, Jianxing He, Kui Wu, Dongbing Liu
Oncotarget.2017; 8(7): 11517. CrossRef
Prognostic Impact of Microsatellite Instability in Colorectal Cancer Presenting With Mucinous, Signet-Ring, and Poorly Differentiated Cells
Sang Hun Jung, So Hyun Kim, Jae Hwang Kim
Annals of Coloproctology.2016; 32(2): 58. CrossRef
Microsatellite instability testing in Korean patients with colorectal cancer
Jung Ryul Oh, Duck-Woo Kim, Hye Seung Lee, Hee Eun Lee, Sung Min Lee, Je-Ho Jang, Sung-Bum Kang, Ja-Lok Ku, Seung-Yong Jeong, Jae-Gahb Park
Familial Cancer.2012; 11(3): 459. CrossRef

Efficacy of hMLH1/hMSH2 Immunohistochemical Staining as Representative Index for Microsatellite Instability Status in Sporadic Colorectal Cancer.: Jung, Sang Hun , Kim, Hee Cheol , Kim, Jung Sun , Choi, Jene , Yu, Chang Sik , Kim, Jin Cheon; J Korean Soc Coloproctol. 2006;22(3):184-191.

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Abstract PDF: PURPOSE
Sporadic colorectal cancer with micosatellite instability (MSI) is supposed to have a distinct molecular profile, distinct clinocopathologic feature, and a distinct prognosis. However, the test for MSI is still expensive, and a big machine is needed for routine screening. This study was performed to examine the clinicopathologic of characteristics of MSI sporadic colorectal cancer and the efficacy of immunohistochemical staining for hMLH1 and hMSH2.
METHODS
Five hundred sixty nine colorectal adenocarinomas resected from September 2003 to August 2004 at Asan Medical Center were prospectively collected. FAP (familial adenomatous polyposis), HNPCC (hereditary non-polyposis colo-rectal cancer), and incomplete tests of immunohistochemical staining or MSI were excluded. The MSI status was determined by using PCR (polymerase chain reaction). A first round of immunohistochemical staining for hMLH1/hMSH2 was performed, and a second round was performed for cases showing a disparity between the two exams. The clinicopathologic variables regarding the MSI status were analyzed, and the sensitivity and the specificity of immunohistochemical staining were evaluated.
RESULTS
Sporadic colorectal cancers with MSI-H were 8.4% (n=48) and were associated with age (< or = 60 years), colorectal cancer familial history, synchronous colorectal cancer, right side tumor location, and poorly differentiated or mucinous cell type. However, age, synchronous colorectal cancer, and right side tumor location were associated an the multivariate analysis. In the first round of immunohistochemical staining, no expression of hMLH1 and/or hMSH2 was obserred in 71 cases (12.5%), and the sensitivity and the specificity were 50.0% and 91.9%, respectively. After repetitive immunohistochemical staining for the 71 cases showing disagreement with the to MSI status, the sensitivity and the specificity of the second round of immunohistochemical staining were 53.3% and 97.6%, respectively.
CONCLUSIONS
Sporadic colorectal cancer with MSI appears to have distinct characteristics. However, immunohistochemical staining for hMLH1 and hMSH2 is not accurate enough to be used instead of MSI.

Relationship between Microsatellite Instability and Dihydropyrimidine Dehydrogenase Expression as a Predictor of Response to 5-Fluorouracil Chemotherapy for Colorectal Cancer.: Rhyou, Jai Hyun , Lee, Suk Hwan , Lee, Woo In , Lee, Ryung Ah , Kim, Kwang Ho , Chung, Soon Sup , Park, Eung Bum; J Korean Soc Coloproctol. 2005;21(3):157-166.

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Abstract PDF: PURPOSE
Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in 5-FU catabolism, so the enzymatic activity of DPD reflects the 5-FU response. Moreover, recent studies have revealed that microsatellite instability (MSI) status correlates well with the prognosis and the 5-FU chemosensitivity in colorectal cancer (CRC). This study aimed to determine whether DPD mRNA expression is related with the MSI status of primary CRC as a prognostic predictor.
METHODS
Tumor samples and adjacent normal colonic mucosal tissues were collected from 59 patients. DPD mRNA expression was calculated by using the real-time RT-PCR method. The MSI status was examined by using multiplex fluorescent PCR with five reference markers. The results of DPD mRNA expression and MSI status were compared with the clinicopathologic variables and with each other.
RESULTS
The mean age of the 59 patients was 59 (range: 36~81) years. In 55 patients (93.2%), the colorectal cancers were histologically well or moderately differentiated. Forty-nine of the tumors (49, 83.1%) were located distal to the splenic flexure, and 46 patients (78%) had TNM stage II (n=17) or stage III (n=29) cancer. The DPD mRNA expression level was informative in all 59 cases. The median expression level was 2.5 (range: 0~67.33). There was no correlation between the DPD mRNA expression level and age, gender, location, or TNM stage. MSI status was informative in 43 cases (72.9%). Thirty-six cases (36, 83.7%) were microsatellite-stable (MSS), 4 cases (9.3%) showed low-level microsatellite instability (MSI-L), and 3 cases (7.0%) showed high-level microsatellite instability (MSI-H). Proximal CRC showed a higher proportion of MSI-H than distal CRC (25% vs. 2.9%, P=0.03). We could not find any correlation between the DPD mRNA expression level and the MSI status in tumor tissues (r=0.29, P=0.09).
CONCLUSIONS
The expression level of DPD mRNA raried among the tumors studied. The relatively low frequency of MSI in distal CRC prohibits the use of MSI status as a predictor of 5-FU chemosensitivity. We suggest that a well-designed large-scale study would be helpful to confirm the relation between DPD mRNA expression and MSI status as a predictor of 5-FU chemosensitivity in CRC patients.

COX-2 and iNOS Expression and Microvessel Density by Microsatellite Instability in Colorectal Cancer.: Jin, So Young , Kim, Jin Won , Jang, Yong Seog , Kim, Jae Joon , Hong, Sung Ho , Cho, Choo Yon; J Korean Soc Coloproctol. 2005;21(1):27-35.

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Abstract PDF: PURPOSE
We tried to identify the overall incidence of microsatellite instability (MSI) and the utility of mismatch repair (MMR) protein expression in sporadic colorectal cancers in Korean. We also investigate the role of angiogenesis in colorectal cancers by MSI status.
METHODS
A total 85 resected colorectal cancers were submitted for MSI study using PCR methods with 5 markers and immunohistochemistry (IHS) for hMLH1 and hMSH2. Expression of COX-2 and iNOS and microvessel density by IHS were correlated with various clinicopathologic prognostic factors.
RESULTS
Among 85 cases of sporadic colorectal cancers, MSI was observed in 11 cases (12.9%) including 10 MSI-H and 1 MSI-L cases. Patients with MSI (+) showed female prevalence (1.75 : 1), low Dukes stage, mucinous histologic type, and Crohn-like lymphoid reaction than those with MSS. Overall sensitivity of hMLH1 and/or hMSH2 expression was 98.6% and specificity was 72.7%. iNOS expression was significantly correlated with COX-2 expression in tumor cells (P=0.006), however, they were not correlated with MSI status. High microvessel density was correlated with hMLH1 expression (P=0.025), COX-2 expression (P= 0.05), and Crohn-like lymphoid reaction (P=0.041).
CONCLUSIONS
IHS for MMR proteins is a valuable substitute of MSI status and COX-2 related neoangiogenesis is thought to be related to inhibition of microsatellite unstable colorectal cancer progression via decreased microvessel density.

Clinicopathological Correlation of hMLH1 and hMSH2 Protein Expressions in Stage III Colon Cancer.: Cho, Young Kyu , Yu, Chang Sik , Namgung, Hwan , Kim, Hee Chul , Kim, Jung Seon , Lee, Je Hwan , Kim, Tae Won , Kim, Jin C; J Korean Soc Coloproctol. 2004;20(4):218-224.

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Abstract PDF: PURPOSE
Functional loss of mismatch repair has been reported to be the reason for resistance to several chemotherapeutic drugs. The expressions of hMLH1 and hMSH2 were examined to assess whether they correlated with the biological behavior and the chemotherapeutic responsiveness in paflents with sporadic colon cancers.
METHODS
Ninety-one patients with stage III primary colon cancer were included from the tumor registry of the Asan Medical Center, Seoul, Korea. All patients underwent a curative operation and postoperative chemotherapy with 5- fluorouracil and leucovorin for 6 cycles between 1993 and 1997. Immunohistochemical staining for hMLH1 and hMSH2 was performed using archival paraffin blocks. A positive expression was determined when unequivocal nuclear staining was identified in more than 10% of the cancer cells. The survival and the clinicopathologic variables regarding hMLH1 and hMSH2 expressions were assessed using the log-rank test and the Cox proportional regression method.
RESULTS
Either hMLH1 or hMSH2 expression was lost in nine cases (9.9%). hMLH1 and hMSH2 expressions were significantly correlated with tumor invasion (P=0.012) and tumor differentiation (P=0.017). The disease-free survival did not differ with respect to hMLH1 and hMSH2 expressions. The number of metastatic lymph nodes and the preoperative serum CEA level were independent predictors of disease-free survival on a multivariate analysis.
CONCLUSIONS
The loss of hMLH1 or hMSH2 expresscon appears to be involved in the differentiation of and the invasion by colon cancer. However, nether hMLH1 nor hMSH2 expression was correlated withthe 5-fluorouracil responsiveness.

Review

Mechanism of Genomic Instability and Its Clinical Applications.: Lee, Suk Hwan; J Korean Soc Coloproctol. 2004;20(1):64-73.

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Abstract PDF: Multiple genetic alterations are common prerequisite for carcinogenesis including colorectal cancers (CRCs). Recently, mutations within microsatellites have been described as a result of defective DNA mismatch repair (MMR) mechanisms, resulting in the phenomenon of microsatellite instability (MSI). This has been implicated in the etiology of hereditary non-polyposis colorectal cancer (HNPCC) and significant portions of sporadic colorectal cancers. However, the mechanisms underlying the MSI are different from hereditary CRCs and sporadic CRCs. While the germline mutation of MMR genes is responsible for HNPCC, the hypermethylation of MLH1 gene promoter regions, an epigenetic, not inherited alteration is responsible for most sporadic CRCs showing MSI. MSI tumors exhibit characteristic clinco- pathologic features, i.e, tumors are preferentially located to proximal to splenic flexure, poorly differentiated, mucinous cell type, frequently showing peritumoral lymphocytic infiltration, and, of importance, showing better survival in stage- matched cases. In this article, the results of recent investigations about MSI and its clinical applications are comprehensively reviewed. Knowledge of these biochemical mechanisms are likely to lead to more effective diagnosis and therapy of CRCs in the future

Original Articles

Clinicopathological Characteristics of Sporadic Colorectal Cancer with DNA Microsatellite Instability.: Kim, Nam Kyu , Kim, Hoguen , Park, Jae Kun , Lee, Kang Yong , Sohn, Seung Kook , Min, Jin Sik; J Korean Soc Coloproctol. 2003;19(1):13-19.

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Abstract PDF: PURPOSE
Sporadic colorectal cancers, with DNA microsatellite instability (MSI), have been characterized by a predilection area of proximal colon, younger age onset, exophytic growth and larger tumor size. MSI colorectal cancers have recently been had a good survival rate. The aim of this study is to determine the MSI status in sporadic colorectal cancers, and compare their clinical and pathological characteristics with those of MSS (Microsatellite Stable) cancers.
METHODS
Between March 1995 and December 1997, deep frozen fresh tissue of 107 eligible colorectal cancer patients, who underwent surgical resections, were used for analysis. Hereditary nonpolyposis colorectal cancer, and familial adenomatous polyposis, patients were excluded. All the patients were registered on a colorectal cancer database, and followed up completely with regular visits for a potential recurrence. Genomic DNA was prepared by the SDS-proteinase K and phenol chloroform extraction methods. The DNA was amplified by PCR at five microsatellite loci (BAT26, BAT25, D2S123, D5S346, and D17S250) to evaluate the MSI. The PCR products were separated in 6% polyacrylamide gels, containing 5.6 M urea, followed by autoradiography. The MSI was defined as being over 2 marker positive, and the MSS as 1 marker positive, all marker negatives were classed as MSS. The survival rates were calculated by the Kaplan- Meier methods.
RESULTS
MSI was noted at 16/107 (15%), with mean ages for the patients of 51.8 vs. 58.6 years old for MSI and MSS, respectively. For the patients under 40 years old 5 (31.3%) vs. 6 (6.6%) had MSI and MSS, respectively (P<0.01). The cancer was located in the right colon in 12 of each of the MSI and MSS (P<0.01). There were no MSI rectal cancer tumors. The average tumor sizes were 7.6 3.6 cm vs. 5.3 2.2 cm (P<0.01) for MSI and MSS, respectively, but there were no correlations with the frequency of associated polyps, recurrence and distant metastasis between MSI and MSS. The cells were well differentiated (12.5% vs. 17.6%), moderately differentiated (68.8% vs. 76.9%), poorly differentiated (6.2% vs. 3.3%), and mucinous type (12.5% vs. 2.2%), with MSI and MSS, respectively. The overall survival rates were 93.8% vs. 73.8% for MSI and MSS (P=0.07), respectively.
CONCLUSIONS
Sporadic colorectal cancer, with DNA microsatellite instability (MSI), was located predominantly in the proximal colon, in the younger age onset, and larger size of tumor. The survival rate of the patients with MSI tumors were good, but with no statistical significance.

hMLH1/hMSH2 Protein Expression in Sporadic Colorectal Carcinoma and Its Clinicopathological Significance.: Kang, Jae Hee , Lee, Kil Yeon , Lee, Kee Hyung , Yoon, Choong , Oh, Soo Myung , Lee, Joo Hee; J Korean Soc Coloproctol. 2001;17(1):38-46.

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Abstract PDF: PURPOSE
DNA replication errors (RERs) in repeated nucleotide sequences (microsatellite instability) is caused by defective mismatch repair (MMR) genes. Ninety percent of colorectal carcinomas in hereditary nonpolyposis colorectal cancer (HNPCC) patients and 10-15% of sporadic colorectal cancers show microsatellite instability. In the majority of colorectal cancers with microsatellite instability, the defective MMR gene is hMLH1 or hMSH2. The author examined immunohistochemical expression of hMLH1 and hMSH2 in 75 cases of colorectal carcinomas excluding HNPCC, based on Amsterdam criteria for investigating clinicopathological characteristics and prognosis in hMLH1/hMSH2 negative cases.
METHODS
Formalin fixed, paraffin blocks obtained from tumors of 75 cases of colorectal cancers were stained with two monoclonal antibodies (hMLH1 and hMSH2). The correlation between hMLH1/hMSH2 negativity, and clinicopathological feature and prognosis were statistically analysed.
RESULTS
Twelve cases (16.0%) showed hMLH1/hMSH2 negativity. Negative expression of hMLH1/hMSH2 was associated with early onset (under age 50), proximal location, multiplicity, mucinous histologic type and poor differentiation. There was a significant survival advantage in patients with hMLH1/hMSH2 negative colorectal carcinoma.
CONCLUSIONS
This study shows that hMLH1/hMSH2 negative colorectal carcinomas have the same clinicopathological characteristics of colorectal carcinomas with microsatellite instability. The immunohistochemical test for hMLH1/hMSH2 protein can be a simple screening method routinely applicable. The result of this test is available for establishing guidelines for management, and an independent prognostic factor for sporadic colorectal cancers.

Microsatellite Instability and hMSH2 Gene Mutations in Sporadic Colorectal Cancers.: Jeon, Hae Myung , Oh, Seung Tack , Kim, Jeong Soo , Chang, Suk Kyun , Kim, Jae Sung; J Korean Soc Coloproctol. 1998;14(1):41-49.

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Abstract PDF: Microsatellites are short nucleotide repeat sequences present throughout the human genome. Alterations of microsatellites, comprising extra or missing copies of these se quences, have been termed microsatellite instability(MSI, genetic instability, replication errors, RER(+) phenotype). To date, at least four genes involved in DNA mismatch repair, hMSH2, hMLH1, hPMS1 and hPMS2, are thought to account for the observation of microsatellite instability in tumor from Hereditary nonpolyposis colorectal cancer (HNPCC) patients. The genetic defect responsible for the MIN+ phenotype in sporadic colorectal cancer, however, has yet to be clearly delineated. The purpose of this study was to determine the presence of MSI in sporadic cancer and to correlate its occurrence with clinicopathological parameters, we have studied six microsatellite loci by use of polymerase chain reaction amplification and denaturing polyacrylamide gel electrophoresis. We found that 20%(9 of 46 cases) sporadic colorectal cancers showed RER at two or several loci(RER+). Microsatellite instability was associated with location of the tumor in the proximal colon 66%(6 of 9 cases) and with poorly differentiated tumor phenotype 56%(5 of 9 cases). In order to better understand the role of somatic alterations within hMSH2 in the process of colorectal tumorigenesis, we examined the most conserved regions(codon 598~789) of this gene in nine patients with MIN spotadic colorectal cancer. 6 patient of RER(+) colorectal ca. patients had a polymorphism which was a T to C base change in the intron sequence at -6 position of the splice acceptor site at the 5'end of exon 13. This particular sequence variation is a polymorphism rather than a mutation which increase cancer susceptability. These data suggest that the genetic instability is detect ed in some colorectal cancers and play an important role in the pathogenesis of sporadic colorectal cancer.

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