Advanced Search
YU Jinchuan, XIAO Xuexue, HE Weiying, YANG Yanan, YUE Junqiu. Clinicopathological Characteristics of Colorectal Cancer Patients with Different Mismatch Repair Statuses and Their Correlation with KRAS/NRAS/BRAF Gene Mutations[J]. Cancer Research on Prevention and Treatment, 2024, 51(11): 937-944. DOI: 10.3971/j.issn.1000-8578.2024.24.0156
Citation: YU Jinchuan, XIAO Xuexue, HE Weiying, YANG Yanan, YUE Junqiu. Clinicopathological Characteristics of Colorectal Cancer Patients with Different Mismatch Repair Statuses and Their Correlation with KRAS/NRAS/BRAF Gene Mutations[J]. Cancer Research on Prevention and Treatment, 2024, 51(11): 937-944. DOI: 10.3971/j.issn.1000-8578.2024.24.0156

Clinicopathological Characteristics of Colorectal Cancer Patients with Different Mismatch Repair Statuses and Their Correlation with KRAS/NRAS/BRAF Gene Mutations

Funding: Health Research Fund of Hubei Province (No. WJ2019H124); Jingjian-Tongshu Microsatellite Instability Research Fund Project, 2020 (No. JJTS2020-017); Biomedical Center Special Research Fund Project of Hubei Cancer Hospital (No. 2022SWZX24)
More Information
  • Corresponding author:

    YUE Junqiu, E-mail: yuejunqiu@hotmail.com

  • Received Date: February 28, 2024
  • Revised Date: August 17, 2024
  • Objective 

    To investigate the clinicopathological characteristics of colorectal cancer patients with different mismatch repair (MMR) statuses and their correlation with KRAS/NRAF/BRAF (KNB) gene mutations.

    Methods 

    The clinicopathological data of 477 patients with colorectal cancer were collected, and MMR, microsatellite instability (MSI), and KNB status were detected via immunohistochemistry (IHC), PCR–capillary electrophoresis, and next-generation sequencing (NGS), respectively. The clinicopathological features of patients with different MMR statuses and correlations with KNB mutations were analyzed.

    Results 

    Compared with the patients in the pMMR group, the patients in the classical dMMR group were younger, included more females, and exhibited more tumors in the right colon, mostly mucinous adenocarcinoma and poorly differentiated tumors (all P<0.05). The tumors in the nonclassical dMMR group were commonly found in the right colon and were prone to special histologic types (all P<0.05). MLH1-PMS2 codeletion, BRAF mutation, and KRAS G13 codon mutation were common in patients in both the classical and the nonclassical dMMR groups (both P<0.05). The results of MMR IHC (100%) were highly consistent with those of MSI PCR (99.1%). Patients in the classical dMMR group with KRAS mutations were younger, included more males, and were prone to specific histologic types, but distant metastasis was rare (all P<0.05). Conversely, lymph node metastasis was rare in patients in the nonclassical dMMR group with KRAS mutations (P=0.005). The mutation rate of the MSH6 gene was relatively high in the nonclassical dMMR group (P=0.002), and all patients presented complete deletion of MLH1-PMS2 combined with nonclassical expression of MSH6 (100%). Five patients with medullary carcinoma components had complete deletions of MLH1-PMS2. Among the five patients, three had combined nonclassical expression of MSH2/MSH6. Two of the three patients carried the MSH6 gene c.3261 locus mutation.

    Conclusion 

    The clinicopathologic features of patients with classical/nonclassical dMMR colorectal cancer differ from those of patients with pMMR, and MMR IHC could be used to predict effectively the MSI status. The clinicopathologic features differ between classical and nonclassical dMMR colorectal cancer patients with KRAS mutations, but both groups present codeletion of MLH1-PMS2, BRAF mutation, and KRAS G13 codon mutation. In patients with nonclassical dMMR, complete deletion of MLH1-PMS2 combined with nonclassical expression of MSH6 is common. Mutations in the MSH6 gene may play a key role in the development of colorectal cancer with medullary carcinoma components.

  • Competing interests: The authors declare that they have no competing interests.

  • [1]
    Cervantes A, Martinelli E. Updated treatment recommendation for third-line treatment in advanced colorectal cancer from the ESMO Metastatic Colorectal Cancer Living Guideline[J]. Ann Oncol, 2024, 35(2): 241-243. doi: 10.1016/j.annonc.2023.10.129
    [2]
    Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up[J]. Ann Oncol, 2023, 34(1): 10-32. doi: 10.1016/j.annonc.2022.10.003
    [3]
    Benson AB, Venook AP, Al-Hawary MM, et al. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw, 2021, 19(3): 329-359. doi: 10.6004/jnccn.2021.0012
    [4]
    Sinicrope FA, Sargent DJ. Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications[J]. Clin Cancer Res, 2012, 18(6): 1506-1512. doi: 10.1158/1078-0432.CCR-11-1469
    [5]
    Guillotin D, Martin SA. Exploiting DNA mismatch repair deficiency as a therapeutic strategy[J]. Exp Cell Res, 2014, 329(1): 110-115. doi: 10.1016/j.yexcr.2014.07.004
    [6]
    Boland CR, Goel A. Microsatellite instability in colorectal cancer [J]. Gastroenterology, 2010, 138(6): 2073-2087. e3.
    [7]
    Oneda E, Zaniboni A. Adjuvant treatment of colon cancer with microsatellite instability - the state of the art[J]. Crit Rev Oncol Hematol, 2022, 169: 103537. doi: 10.1016/j.critrevonc.2021.103537
    [8]
    Reitsam NG, Maerkl B, Dintner S, et al. Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes[J]. Front Oncol, 2022, 12: 1019798. doi: 10.3389/fonc.2022.1019798
    [9]
    Zito Marino F, Amato M, Ronchi A, et al. Microsatellite Status Detection in Gastrointestinal Cancers: PCR/NGS Is Mandatory in Negative/Patchy MMR Immunohistochemistry[J]. Cancers(Basel), 2022, 14(9): 2204.
    [10]
    Chen L, Chen G, Zheng X, et al. Expression status of four mismatch repair proteins in patients with colorectal cancer: clinical significance in 1238 cases[J]. Int J Clin Exp Pathol, 2019, 12(10): 3685-3699.
    [11]
    Salem ME, Battaglin F, Goldberg RM, et al. Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer[J]. Oncologist, 2020, 25(5): 404-413. doi: 10.1634/theoncologist.2019-0552
    [12]
    Hissong E, Crowe EP, Yantiss RK, et al. Assessing colorectal cancer mismatch repair status in the modern era: a survey of current practices and re-evaluation of the role of microsatellite instability testing[J]. Mod Pathol, 2018, 31(11): 1756-1766. doi: 10.1038/s41379-018-0094-7
    [13]
    Li X, Zhang S, Zeng J, et al. Heterogeneous expression of mismatch repair proteins and interpretation of immunohistochemical results in colorectal cancer and endometrial cancer[J]. Pathol Res Pract, 2023, 248: 154647. doi: 10.1016/j.prp.2023.154647
    [14]
    Shia J, Zhang L, Shike M, et al. Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency[J]. Mod Pathol, 2013, 26(1): 131-138. doi: 10.1038/modpathol.2012.138
    [15]
    Evrard C, Tachon G, Randrian V, et al. Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer[J]. Cancers (Basel), 2019, 11(10): 1567. doi: 10.3390/cancers11101567
    [16]
    Guyot D'asnières De Salins A, Tachon G, Cohen R, et al. Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer[J]. ESMO Open, 2021, 6(3): 100120. doi: 10.1016/j.esmoop.2021.100120
    [17]
    Taieb J, Svrcek M, Cohen R, et al. Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment[J]. Eur J Cancer, 2022, 175: 136-157. doi: 10.1016/j.ejca.2022.07.020
    [18]
    Meng M, Zhong K, Jiang T, et al. The current understanding on the impact of KRAS on colorectal cancer[J]. Biomed Pharmacother, 2021, 140: 111717. doi: 10.1016/j.biopha.2021.111717
    [19]
    Zhou Y, Kuang Y, Wang C, et al. Impact of KRAS mutation on the tumor microenvironment in colorectal cancer[J]. Int J Biol Sci, 2024, 20(5): 1947-1964. doi: 10.7150/ijbs.88779
    [20]
    Punt CJ, Koopman M, Vermeulen L. From tumour heterogeneity to advances in precision treatment of colorectal cancer[J]. Nat Rev Clin Oncol, 2017, 14(4): 235-246. doi: 10.1038/nrclinonc.2016.171
    [21]
    Palomba G, Doneddu V, Cossu A, et al. Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study[J]. J Transl Med, 2016, 14(1): 292. doi: 10.1186/s12967-016-1053-z
    [22]
    Wang Y, Liu H, Hou Y, et al. Performance validation of an amplicon-based targeted next-generation sequencing assay and mutation profiling of 648 Chinese colorectal cancer patients[J]. Virchows Arch, 2018, 472(6): 959-968. doi: 10.1007/s00428-018-2359-4
    [23]
    Taieb J, Le Malicot K, Shi Q, et al. Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage Ⅲ Colon Cancer[J]. J Natl Cancer Inst, 2017, 109(5): djw272. doi: 10.1093/jnci/djw272
    [24]
    Oliveira C, Westra JL, Arango D, et al. Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status[J]. Hum Mol Genet, 2004, 13(19): 2303-2311. doi: 10.1093/hmg/ddh238
    [25]
    Chen W, Pearlman R, Hampel H, et al. MSH6 immunohistochemical heterogeneity in colorectal cancer: comparative sequencing from different tumor areas[J]. Hum Pathol, 2020, 96: 104-111. doi: 10.1016/j.humpath.2019.11.003
    [26]
    Farchoukh L, Kuan SF, Dudley B, et al. MLH1-deficient Colorectal Carcinoma With Wild-type BRAF and MLH1 Promoter Hypermethylation Harbor KRAS Mutations and Arise From Conventional Adenomas[J]. Am J Surg Pathol, 2016, 40(10): 1390-1399. doi: 10.1097/PAS.0000000000000695
    [27]
    O'brien MJ, Yang S, Mack C, et al. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points[J]. Am J Surg Pathol, 2006, 30(12): 1491-1501. doi: 10.1097/01.pas.0000213313.36306.85
  • Related Articles

    [1]SUN Wenjia, YUE Junqiu, WANG Manxiang. Clinicopathological Characteristics and Therapeutic Effect of Patients with Non-small Cell Lung Cancer and Uncommon EGFR Mutations[J]. Cancer Research on Prevention and Treatment, 2023, 50(12): 1221-1226. DOI: 10.3971/j.issn.1000-8578.2023.23.0431
    [2]CAO Xinhua, HAN Lifei, LYU Jianxin, HU Haolin, ZHANG Ya'nan. Association Between Family History of Malignant Neoplasms and Clinicopathological Features of Breast Cancer Patients[J]. Cancer Research on Prevention and Treatment, 2020, 47(10): 752-755. DOI: 10.3971/j.issn.1000-8578.2020.20.0027
    [3]RAO Xionghui, LUO Hongliang, HUANG Jun, ZHU Zhengming. Prognostic and Clinicopathological Significance of PD-L1 Expression for Colorectal Cancer: A Meta-analysis[J]. Cancer Research on Prevention and Treatment, 2019, 46(11): 1013-1021. DOI: 10.3971/j.issn.1000-8578.2019.19.0363
    [4]SONG Jinling, LI Zhongwu, WEI Maomao, ZHOU Ni'na, YANG Zhi, WANG Xuejuan. Relation Between Metabolic Parameters of 18F-FDG PET/CT and Clinicopathological Features of Colorectal Cancer Patients[J]. Cancer Research on Prevention and Treatment, 2019, 46(11): 1006-1012. DOI: 10.3971/j.issn.1000-8578.2019.19.0665
    [5]YANG Hanjie, LIU Geliang, LIU Bo. Correlation of FoxO3 Gene with Clinicopathological Features and Prognosis of Bladder Cancer Patients[J]. Cancer Research on Prevention and Treatment, 2019, 46(1): 58-62. DOI: 10.3971/j.issn.1000-8578.2019.18.0806
    [6]HU Ming, HUANG Xiaohong, ZUO Weiwei, ZHAO Jing. Clinicopathological and Prognostic Value of Circulating Tumor Cells in Peripheral Blood in Head and Neck Cancer Patients:A Meta-analysis[J]. Cancer Research on Prevention and Treatment, 2018, 45(11): 883-889. DOI: 10.3971/j.issn.1000-8578.2018.18.0407
    [7]XU Haitao, ZHANG Lianguo, LIU Jianwei, LIU Hongjian, ZHANG Qingguang. Relationship of Macrophage Migration Inhibitory Factor Expression with Clinicopathologic Features and Prognosis of Cardiac Carcinoma Patients[J]. Cancer Research on Prevention and Treatment, 2016, 43(9): 779-782. DOI: 10.3971/j.issn.1000-8578.2016.09.010
    [8]AN Songlin, RONG Weiqi, WANG Liming, WU Fan, FENG Li, TIAN Fei, WU Jianxiong. Clinicopathologic Features and Surgical Treatment of Abdominal Inflammatory Myofibroblastic Tumor[J]. Cancer Research on Prevention and Treatment, 2016, 43(5): 396-399. DOI: 10.3971/j.issn.1000-8578.2016.05.016
    [9]HAN Xiaona, SUN Zhenqiang, TANG Yong, WANG Haijiang, QU Yanli, TANG Xushan. Relationship Between Preoperative Fibrinogen Level and Clinicopathological Characteristics of Colon Cancer[J]. Cancer Research on Prevention and Treatment, 2014, 41(12): 1326-1329. DOI: 10.3971/j.issn.1000-8578.2014.12.016
    [10]FU Wen-rong, ZHANG Qin, CHENG Zheng-jiang. Correlation between survivin Expression and Clinicopathological Factors in Colorectal Cancers[J]. Cancer Research on Prevention and Treatment, 2008, 35(10): 719-722. DOI: 10.3971/j.issn.1000-8578.2866
  • Cited by

    Periodical cited type(2)

    1. 杨帆,王浓燕,方蒙,章莹姣,胡海燕,方鹏. 基于m5C修饰相关基因的肺腺癌预后模型的建立与验证. 肿瘤防治研究. 2025(03): 208-216 . 本站查看
    2. 曹祥辉,曹佳庆,杜新华. 基于TCGA数据库构建胃癌免疫相关基因的预后风险模型. 黑龙江中医药. 2023(01): 106-108 .

    Other cited types(1)

Catalog

    Figures(1)  /  Tables(6)

    Article views (670) PDF downloads (149) Cited by(3)

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return