Comparison of clinicopathological characteristics, metastatic sites, and prognosis of Ⅰ –Ⅲ stage MSS type colorectal cancer patients with different RAS/BRAF codon mutation_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Xiang ^1,2 , JIANG Weiqin ³ , HUA Hanju ³ , LIU Shuo ^1,2 , LIAO Tianyi ^1,2 ,  CAI Hui ^1,2,4

1. The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China;
2. General Surgery Department of Gansu Provincial People’s Hospital, Lanzhou 730099, P. R. China;
3. Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, P. R. China;
4. Key Laboratory of Molecular Diagnosis and Precision Medicine for Surgical Oncology in Gansu Province, Lanzhou 730000, P. R. China;

Corresponding author：

CAI Hui, Email: caialonteam@163.com

Keywords：

colorectal cancer; RAS/BRAF mutation; clinicopathological features; prognostic analysis

DOI：

10.7507/1007-9424.202312043

Video：

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Objective To investigate the correlation between different RAS/BRAF mutation sites and the clinicopathological characteristics, metastatic sites, and prognosis of patients with colorectal cancer. Methods A retrospective analysis was conducted on the clinicopathological data of 415 patients with stage Ⅰ –Ⅲ microsatellite stability (MSS) colorectal cancer who underwent radical surgery at the Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University, and the Department of General Surgery, Gansu Provincial People’s Hospital, from March 1, 2017, to October 1, 2022, and had next-generation sequencing data. According to the presence and sites of RAS/BRAF mutations, patients were divided into five groups: RAS/BRAF wild-type group, KRAS G12 codon mutation group, KRAS G13 codon mutation group, BRAF^V600E mutation group, and other RAS codon mutation group. The clinicopathological characteristics and prognostic differences between the four groups of RAS/BRAF mutant colorectal cancer patients and the RAS/BRAF wild-type colorectal cancer patients were compared. Results Among stage Ⅰ –Ⅲ MSS colorectal cancer patients, there were 166 cases (40.0%) of wild-type RAS/BRAF without mutation, 124 cases (29.9%) of KRAS G12 mutation, 55 cases (13.3%) of KRAS G13 mutation, 23 cases (5.5%) of BRAF^V600E mutation, and 47 cases (11.3%) of other RAS codon mutations. Clinicopathological characteristics analysis revealed that BRAF^V600E mutation was associated with mucinous adenocarcinoma (P=0.033). Compared with the wild-type group, KRAS G12 mutation could increase the probability of metachronous lung metastasis (P=0.003) and reduce the probability of metachronous liver metastasis (P=0.013); the KRAS G13 mutation and other RAS mutations could increase the probability of metachronous lung metastasis (P=0.004, P=0.006). Univariate and multivariate Cox proportional hazards regression analysis showed that among the RAS/BRAF codon mutations, only KRAS G13 mutation was an independent prognostic factor for poor prognosis in stage Ⅰ –Ⅲ colorectal cancer. Conclusions Different RAS/BRAF gene codon mutations are associated with distinct clinicopathological characteristics and organ metastatic sites in colorectal cancer. KRAS G13 codon mutation is an independent prognostic factor for poor prognosis in stage Ⅰ –Ⅲ colorectal cancer. It is recommended that routine detection of RAS/BRAF gene site mutations should be performed in stage Ⅰ –Ⅲ colorectal cancer patients to guide the follow-up management and help clinicians make rational clinical decisions after tumor recurrence.

Citation： ZHANG Xiang, JIANG Weiqin, HUA Hanju, LIU Shuo, LIAO Tianyi, CAI Hui. Comparison of clinicopathological characteristics, metastatic sites, and prognosis of Ⅰ –Ⅲ stage MSS type colorectal cancer patients with different RAS/BRAF codon mutation. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(6): 682-689. doi: 10.7507/1007-9424.202312043 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	郭慧娴, 周慧玲, 朱晓蔚, 等. 结直肠癌分子靶向治疗的研究进展. 癌症进展, 2022, 20(19): 1950-1953.
3.	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.
4.	岳育民, 陈曦, 王慧, 等. 结直肠癌肝转移切除术后患者RAS基因突变影响生存的整合分析. 中国普外基础与临床杂志, 2022, 29(12): 1583-1590.
5.	Cercek A, Braghiroli MI, Chou JF, et al. Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations. Clin Cancer Res, 2017, 23(16): 4753-4760.
6.	Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol, 2011, 6: 479-507.
7.	Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol, 2016, 34(2): 179-185.
8.	Huang L, Guo Z, Wang F, et al. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther, 2021, 6(1): 386. doi: 10.1038/s41392-021-00780-4.
9.	Macerola E, Proietti A, Poma AM, et al. Molecular alterations in relation to histopathological characteristics in a large series of pediatric papillary thyroid carcinoma from a single institution. Cancers (Basel), 2021, 13(13): 3123. doi: 10.3390/cancers13133123.
10.	Siraj AK, Bu R, Prabhakaran S, et al. A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma. Mol Cancer, 2014, 13: 168. doi: 10.1186/1476-4598-13-168.
11.	Riquelme E, Behrens C, Lin HY, et al. Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS Oncogene mutations. Cancer Research, 2016, 76(3): 675-685.
12.	Cook JH, Melloni GEM, Gulhan DC, et al. The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun 2021, 12(1): 1808. doi: 10.1038/ s41467-021-22125-z.
13.	Imamura Y, Morikawa T, Liao X, et al. Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1 075 BRAF Wild-Type colorectal cancers. Clinical Cancer Research, 2012, 18(17): 4753-4763.
14.	Modest DP, Ricard I, Heinemann V, et al. Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO Colorectal Cancer Study Group. Ann Oncol 2016, 27(9): 1746-1753.
15.	Yuan Y, Liu Y, Wu Y, et al. Clinical characteristics and prognostic value of the KRAS mutation in chinese colorectal cancer patients. Int J Biol Markers, 2021, 36(2): 33-39.
16.	Koulouridi A, Karagianni M, Messaritakis I, et al. Prognostic value of KRAS mutations in colorectal cancer patients. Cancers (Basel), 2022, 14(14): 3320. doi: 10.3390/cancers14143320.
17.	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 stageⅠ–Ⅳcolorectal cancer. Int J Cancer, 2019, 145(6): 1625-1634.
18.	Bao X, Zhang H, Wu W, et al. Analysis of the molecular nature associated with microsatellite status in colon cancer identifies clinical implications for immunotherapy. J Immunother Cancer r, 2020, 8(2): e001437. doi: 10.1136/jitc-2020-001437.
19.	Kim C G, Ahn J B, Jung M, et al. Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers. Br J Cancer, 2016, 115(1): 25-33.
20.	Provenzale D, Ness RM, Llor X, et al. NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2. 2020. J Natl Compr Canc Netw, 2020, 18(10): 1312-1320.
21.	Lai E, Pretta A, Impera V, et al. BRAF-mutant colorectal cancer, a Different Breed Evolving. Expert Rev Mol Diagn, 2018, 18(6): 499-512.
22.	叶胜兵, 李锐, 王小桐, 等. 1 889例结直肠癌MSI、K-ras、N-ras和B-raf基因状态以及临床病理特征分析. 诊断病理学杂志, 2023, 30(1): 1-5.
23.	Tie J, Lipton L, Desai J, et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res, 2011, 17(5): 1122-1130.
24.	Roth A D, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stageⅡand 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.
25.	Roth AD, Delorenzi M, Tejpar S, et al. Integrated analysis of molecular and clinical prognostic factors in stageⅡ/Ⅲ colon cancer. J Natl Cancer Inst, 2012, 104(21): 1635-1646.
26.	Ogino S, Meyerhardt JA, Irahara N, et al. KRAS mutation in stage Ⅲ colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res, 2009, 15(23): 7322-7329.
27.	Hutchins G, Southward K, Handley K, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol, 2011, 29(10): 1261-1270.
28.	Yoon HH, Tougeron D, Shi Q, et al. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stageⅢ colon cancers from an adjuvant chemotherapy trial (N0147 Alliance). Clin Cancer Res, 2014, 20(11): 3033-3043.
29.	Lee DW, Kim KJ, Han SW, et al. KRAS mutation is associated with worse prognosis in stageⅢ or high-risk stageⅡ colon cancer patients treated with adjuvant folfox. Ann surgical Oncol, 2015, 22(1): 187-194.
30.	马甘青, 张丹, 李路遥, 等. 转移性结直肠癌药物治疗研究进展. 中国普外基础与临床杂志, 2023, 30(7): 889-896.
31.	Tian J, Chen JH, Chao SX, et al. Combined PD-1, BRAF and MEK inhibition in BRAF^V600E colorectal cancer: a phase 2 trial. Nat Med, 2023, 29(2): 458-466.
32.	Ciardiello D, Maiorano BA, Martinelli E. Targeting KRAS^G12C in colorectal cancer: The beginning of a new era. ESMO Open, 2023, 8(1): 100745. doi: 10.1016/j.esmoop.2022.100745.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. 郭慧娴, 周慧玲, 朱晓蔚, 等. 结直肠癌分子靶向治疗的研究进展. 癌症进展, 2022, 20(19): 1950-1953.
3. 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.
4. 岳育民, 陈曦, 王慧, 等. 结直肠癌肝转移切除术后患者RAS基因突变影响生存的整合分析. 中国普外基础与临床杂志, 2022, 29(12): 1583-1590.
5. Cercek A, Braghiroli MI, Chou JF, et al. Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations. Clin Cancer Res, 2017, 23(16): 4753-4760.
6. Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol, 2011, 6: 479-507.
7. Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol, 2016, 34(2): 179-185.
8. Huang L, Guo Z, Wang F, et al. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther, 2021, 6(1): 386. doi: 10.1038/s41392-021-00780-4.
9. Macerola E, Proietti A, Poma AM, et al. Molecular alterations in relation to histopathological characteristics in a large series of pediatric papillary thyroid carcinoma from a single institution. Cancers (Basel), 2021, 13(13): 3123. doi: 10.3390/cancers13133123.
10. Siraj AK, Bu R, Prabhakaran S, et al. A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma. Mol Cancer, 2014, 13: 168. doi: 10.1186/1476-4598-13-168.
11. Riquelme E, Behrens C, Lin HY, et al. Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS Oncogene mutations. Cancer Research, 2016, 76(3): 675-685.
12. Cook JH, Melloni GEM, Gulhan DC, et al. The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun 2021, 12(1): 1808. doi: 10.1038/ s41467-021-22125-z.
13. Imamura Y, Morikawa T, Liao X, et al. Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1 075 BRAF Wild-Type colorectal cancers. Clinical Cancer Research, 2012, 18(17): 4753-4763.
14. Modest DP, Ricard I, Heinemann V, et al. Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO Colorectal Cancer Study Group. Ann Oncol 2016, 27(9): 1746-1753.
15. Yuan Y, Liu Y, Wu Y, et al. Clinical characteristics and prognostic value of the KRAS mutation in chinese colorectal cancer patients. Int J Biol Markers, 2021, 36(2): 33-39.
16. Koulouridi A, Karagianni M, Messaritakis I, et al. Prognostic value of KRAS mutations in colorectal cancer patients. Cancers (Basel), 2022, 14(14): 3320. doi: 10.3390/cancers14143320.
17. 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 stageⅠ–Ⅳcolorectal cancer. Int J Cancer, 2019, 145(6): 1625-1634.
18. Bao X, Zhang H, Wu W, et al. Analysis of the molecular nature associated with microsatellite status in colon cancer identifies clinical implications for immunotherapy. J Immunother Cancer r, 2020, 8(2): e001437. doi: 10.1136/jitc-2020-001437.
19. Kim C G, Ahn J B, Jung M, et al. Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers. Br J Cancer, 2016, 115(1): 25-33.
20. Provenzale D, Ness RM, Llor X, et al. NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2. 2020. J Natl Compr Canc Netw, 2020, 18(10): 1312-1320.
21. Lai E, Pretta A, Impera V, et al. BRAF-mutant colorectal cancer, a Different Breed Evolving. Expert Rev Mol Diagn, 2018, 18(6): 499-512.
22. 叶胜兵, 李锐, 王小桐, 等. 1 889例结直肠癌MSI、K-ras、N-ras和B-raf基因状态以及临床病理特征分析. 诊断病理学杂志, 2023, 30(1): 1-5.
23. Tie J, Lipton L, Desai J, et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res, 2011, 17(5): 1122-1130.
24. Roth A D, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stageⅡand 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.
25. Roth AD, Delorenzi M, Tejpar S, et al. Integrated analysis of molecular and clinical prognostic factors in stageⅡ/Ⅲ colon cancer. J Natl Cancer Inst, 2012, 104(21): 1635-1646.
26. Ogino S, Meyerhardt JA, Irahara N, et al. KRAS mutation in stage Ⅲ colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res, 2009, 15(23): 7322-7329.
27. Hutchins G, Southward K, Handley K, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol, 2011, 29(10): 1261-1270.
28. Yoon HH, Tougeron D, Shi Q, et al. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stageⅢ colon cancers from an adjuvant chemotherapy trial (N0147 Alliance). Clin Cancer Res, 2014, 20(11): 3033-3043.
29. Lee DW, Kim KJ, Han SW, et al. KRAS mutation is associated with worse prognosis in stageⅢ or high-risk stageⅡ colon cancer patients treated with adjuvant folfox. Ann surgical Oncol, 2015, 22(1): 187-194.
30. 马甘青, 张丹, 李路遥, 等. 转移性结直肠癌药物治疗研究进展. 中国普外基础与临床杂志, 2023, 30(7): 889-896.
31. Tian J, Chen JH, Chao SX, et al. Combined PD-1, BRAF and MEK inhibition in BRAF^V600E colorectal cancer: a phase 2 trial. Nat Med, 2023, 29(2): 458-466.
32. Ciardiello D, Maiorano BA, Martinelli E. Targeting KRAS^G12C in colorectal cancer: The beginning of a new era. ESMO Open, 2023, 8(1): 100745. doi: 10.1016/j.esmoop.2022.100745.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Comparison of clinicopathological characteristics, metastatic sites, and prognosis of Ⅰ –Ⅲ stage MSS type colorectal cancer patients with different RAS/BRAF codon mutation

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