Clinicopathological Features and Prognostic Value of KRAS/NRAS/BRAF Mutations in Colorectal Cancer Patients of Central China

Summary

The incidence of colorectal cancer (CRC) is increasing in China, with high mortality. Here, we aimed to evaluate the latest clinicopathological features and prognostic value of the KRAS/NRAS/BRAF mutation status in CRC patients in Central China. The clinical data of 1549 CRC patients with stage I-IV disease diagnosed at Union Hospital, Tongji Medical College of Huazhong University of Science and Technology from 2015 to 2017 were collected and analyzed retrospectively. KRAS/NRAS/BRAF mutations were detected by real-time quantitative polymerase chain reaction (q-PCR) in 410 CRC patients, with mutation frequencies of KRAS, NRAS and BRAF of 47.56%, 2.93% and 4.15%, respectively. The gene mutation status and clinicopathological characteristics of 410 patients with CRC who underwent qPCR were analyzed. The KRAS and BRAF gene mutations were related to the pathological differentiation and number of metastatic lymph nodes. The BRAF gene mutation was also associated with cancer thrombosis in blood vessels. Cox regression analysis showed that there was no statistically significant difference in the overall survival (OS) between patients with KRAS, NRAS mutants and wild-type CRC patients, while the BRAF gene mutation was negatively correlated with the OS rate of CRC patients. It is suggested that the BRAF gene mutation may be an independent risk factor for the prognosis of CRC.

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References

  1. 1

    Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin, 2017,67(1):7–30

    Article  Google Scholar 

  2. 2

    Santos C, Azuara D, Vieitez JM, et al. Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial. Ann Oncol, 2019,30(5):796–803

    CAS  Article  Google Scholar 

  3. 3

    Mizukami T, Izawa N, Nakajima TE, et al. Targeting EGFR and RAS/RAF Signaling in the Treatment of Metastatic Colorectal Cancer: From Current Treatment Strategies to Future Perspectives. Drugs, 2019,79(6): 633–645

    CAS  Article  Google Scholar 

  4. 4

    Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. Acta Oncol, 2014,53(7):852–864

    CAS  Article  Google Scholar 

  5. 5

    Zhang X, Liu G, Ding L, et al. HOXA3 promotes tumor growth of human colon cancer through activating EGFR/Ras/Raf/MEK/ERK signaling pathway. J Cell Biochem, 2018,119(3):2864–2874

    CAS  Article  Google Scholar 

  6. 6

    Worthley DL, Whitehall VL, Spring KJ, et al. Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol, 2007,13(28):3784–3791

    CAS  Article  Google Scholar 

  7. 7

    Vaughn CP, Zobell SD, Furtado LV, et al. Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer, 2011,50(5):307–312

    CAS  Article  Google Scholar 

  8. 8

    Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol, 2018,15(11): 709–720

    CAS  Article  Google Scholar 

  9. 9

    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature, 2002,417(6892): 949–954

    CAS  Article  Google Scholar 

  10. 10

    Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med, 2013,369(11):1023–1034

    CAS  Article  Google Scholar 

  11. 11

    Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol, 2010,28(3):466–474

    CAS  Article  Google Scholar 

  12. 12

    Russo AL, Borger DR, Szymonifka J, et al. Mutational analysis and clinical correlation of metastatic colorectal cancer. Cancer, 2014,120(10):1482–1490

    CAS  Article  Google Scholar 

  13. 13

    Di Bartolomeo M, Pietrantonio F, Perrone F, et al. Lack of KRAS, NRAS, BRAF and TP53 mutations improves outcome of elderly metastatic colorectal cancer patients treated with cetuximab, oxaliplatin and UFT. Target Oncol, 2014,9(2):155–162

    CAS  Article  Google Scholar 

  14. 14

    Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol, 2014,15(10): 1065–1075

    CAS  Article  Google Scholar 

  15. 15

    De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol, 2010,11(8):753–762

    CAS  Article  Google Scholar 

  16. 16

    Provenzale D, Jasperson K, Ahnen DJ, et al. Colorectal Cancer Screening, Version 1.2015. J Natl Compr Canc Netw, 2015,13(8):959–968; quiz 68

    Article  Google Scholar 

  17. 17

    Zlobec I, Bihl MP, Schwarb H, et al. Clinicopathological and protein characterization of BRAF- and K-RAS-mutated colorectal cancer and implications for prognosis. Int J Cancer, 2010,127(2):367–380

    CAS  PubMed  Google Scholar 

  18. 18

    Naguib A, Mitrou PN, Gay LJ, et al. Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study. BMC Cancer, 2010,10:99

    Article  Google Scholar 

  19. 19

    Mannan A, Hahn-Stromberg V. K-ras mutations are correlated to lymph node metastasis and tumor stage, but not to the growth pattern of colon carcinoma. Apmis, 2012,120(6):459–468

    CAS  Article  Google Scholar 

  20. 20

    Shen Y, Wang J, Han X, et al. Effectors of epidermal growth factor receptor pathway: the genetic profiling of KRAS, BRAF, PIK3CA, NRAS mutations in colorectal cancer characteristics and personalized medicine. PLoS One, 2013,8(12):e81628

    Article  Google Scholar 

  21. 21

    Guo TA, Wu YC, Tan C, et al. Clinicopathologic features and prognostic value of KRAS, NRAS and BRAF mutations and DNA mismatch repair status: A single-center retrospective study of 1,834 Chinese patients with Stage I-IV colorectal cancer. Int J Cancer, 2019,145(6):1625–1634

    CAS  Article  Google Scholar 

  22. 22

    Fu X, Huang Y, Fan X, et al. Demographic trends and KRAS/BRAF(V600E) mutations in colorectal cancer patients of South China: A single-site report. Int J Cancer, 2019,144(9):2109–2117

    CAS  PubMed  Google Scholar 

  23. 23

    Imamura Y, Lochhead P, Yamauchi M, et al. Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review. Mol Cancer, 2014,13:135

    Article  Google Scholar 

  24. 24

    Martinetti D, Costanzo R, Kadare S, et al. KRAS and BRAF mutational status in colon cancer from Albanian patients. Diagn Pathol, 2014,9:187

    Article  Google Scholar 

  25. 25

    Wickenden JA, Jin H, Johnson M, et al. Colorectal cancer cells with the BRAF(V600E) mutation are addicted to the ERK1/2 pathway for growth factor-independent survival and repression of BIM. Oncogene, 2008,27(57):7150–7161

    CAS  Article  Google Scholar 

  26. 26

    Tan YH, Liu Y, Eu KW, et al. Detection of BRAF V600E mutation by pyrosequencing. Pathology, 2008,40(3): 295–298

    CAS  Article  Google Scholar 

  27. 27

    Wangefjord S, Sundstrom M, Zendehrokh N, et al. Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study. Biol Sex Differ, 2013,4(1):17

    Article  Google Scholar 

  28. 28

    Li C, Lee KC, Schneider EB, et al. BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. J Clin Endocrinol Metab, 2012,97(12):4559–4570

    CAS  Article  Google Scholar 

  29. 29

    Chen D, Huang JF, Liu K, et al. BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis. PLoS One, 2014,9(3):e90607

    Article  Google Scholar 

  30. 30

    Ye JX, Liu Y, Qin Y, et al. KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients. World J Gastroenterol, 2015,21(5):1595–1605

    CAS  Article  Google Scholar 

  31. 31

    Liou JM, Wu MS, Shun CT, et al. Mutations in BRAF correlate with poor survival of colorectal cancers in Chinese population. Int J Colorectal Dis, 2011,26(11): 1387–1395

    Article  Google Scholar 

  32. 32

    Ahn TS, Jeong D, Son MW, et al. The BRAF mutation is associated with the prognosis in colorectal cancer. J Cancer Res Clin Oncol, 2014,140(11):1863–1871

    CAS  Article  Google Scholar 

  33. 33

    Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med, 2009,361(1): 98–99

    CAS  Article  Google Scholar 

  34. 34

    Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol, 2009,27(35):5924–5930

    CAS  Article  Google Scholar 

  35. 35

    Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol, 2009,27(35):5931–5937

    CAS  Article  Google Scholar 

  36. 36

    Safaee Ardekani G, Jafarnejad SM, Tan L, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One, 2012,7(10):e47054

    Article  Google Scholar 

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Correspondence to Hong-li Liu or Xiu Nie.

Additional information

This study was supported by the National Natural Science Foundation of China (No. 81472707) and Chinese South Western Oncology Group (CSWOG-CCET005).

Conflict of Interest Statement

The authors declare no potential conflicts of interest.

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Chang, Xn., Shang, Fm., Jiang, Hy. et al. Clinicopathological Features and Prognostic Value of KRAS/NRAS/BRAF Mutations in Colorectal Cancer Patients of Central China. CURR MED SCI 41, 118–126 (2021). https://doi.org/10.1007/s11596-021-2326-1

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Key words

  • colorectal cancer
  • KRAS mutation
  • NRAS mutation
  • BRAF mutation
  • prognosis