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Abstract：
OBJECTIVE: The present study aimed to evaluate the frequencies of KRAS, NRAS, and BRAF mutations and their possible associations with clinicopathological features in 249 Moroccan patients with colorectal cancer (CRC).
METHODS: A retrospective investigation of a cohort of formalin-fixed paraffin-embedded tissues of 249 patients with CRC was screened for KRAS/NRAS/BRAF mutations using Idylla™ technology and pyrosequencing.
RESULTS: KRAS, NRAS, and BRAF mutations were revealed in 46.6% (116/249), 5.6% (14/249), and 2.4% (6/249) of patients. KRAS exon 2 mutations were identified in 87.9% of patients (102/116). KRAS G12D and G12 C were the most frequent, at 32.8% and 12.93%, respectively. Among the patients with KRAS exon 2 wild-type (wt), 27.6% (32/116) harbored additional KRAS mutations. Concurrent KRAS mutations were identified in 9.5% (11/116); including six in codon 146 (A146P/T/V), three in codon 61 (Q61H/L/R), one in codon 12 (G12 A and Q61H), and one in codon 13 (G13D and Q61 L). Among the NRAS exon 2 wt patients, 64.3% (9/14) harbored additional NRAS mutations. Concurrent NRAS mutations were identified in 28.6% (4/14) of NRAS-mutant patients. Since 3.2% wt KRAS were identified with NRAS mutations, concomitant KRAS and NRAS mutations were identified in 2.4% (6/249) of patients. KRAS mutations were higher in the >50-year-old age-group (P = .031), and the tumor location was revealed to be significantly associated with KRAS mutations (P = .028) predominantly in left colon (27.5%) and colon (42.2%) locations. NRAS mutations were most prevalent in the left colon (42.8%) and in well-differentiated tumors (64.2%).
CONCLUSIONS: Detection of KRAS mutations, particularly the G12 C subtype, may be significant for patients with CRC and has possible therapeutic implications. However, rare KRAS concomitant mutations in CRC patients suggest that each individual may present distinct therapeutic responses. KRAS testing alongside the identification of other affected genes in the same patient will make the treatments even more personalized by contributing more accurately to the clinical decision process. Overall, early diagnosis using novel molecular techniques may improve the management of CRC by providing the most efficient therapies for Moroccan patients.
METHODS: A retrospective investigation of a cohort of formalin-fixed paraffin-embedded tissues of 249 patients with CRC was screened for KRAS/NRAS/BRAF mutations using Idylla™ technology and pyrosequencing.
RESULTS: KRAS, NRAS, and BRAF mutations were revealed in 46.6% (116/249), 5.6% (14/249), and 2.4% (6/249) of patients. KRAS exon 2 mutations were identified in 87.9% of patients (102/116). KRAS G12D and G12 C were the most frequent, at 32.8% and 12.93%, respectively. Among the patients with KRAS exon 2 wild-type (wt), 27.6% (32/116) harbored additional KRAS mutations. Concurrent KRAS mutations were identified in 9.5% (11/116); including six in codon 146 (A146P/T/V), three in codon 61 (Q61H/L/R), one in codon 12 (G12 A and Q61H), and one in codon 13 (G13D and Q61 L). Among the NRAS exon 2 wt patients, 64.3% (9/14) harbored additional NRAS mutations. Concurrent NRAS mutations were identified in 28.6% (4/14) of NRAS-mutant patients. Since 3.2% wt KRAS were identified with NRAS mutations, concomitant KRAS and NRAS mutations were identified in 2.4% (6/249) of patients. KRAS mutations were higher in the >50-year-old age-group (P = .031), and the tumor location was revealed to be significantly associated with KRAS mutations (P = .028) predominantly in left colon (27.5%) and colon (42.2%) locations. NRAS mutations were most prevalent in the left colon (42.8%) and in well-differentiated tumors (64.2%).
CONCLUSIONS: Detection of KRAS mutations, particularly the G12 C subtype, may be significant for patients with CRC and has possible therapeutic implications. However, rare KRAS concomitant mutations in CRC patients suggest that each individual may present distinct therapeutic responses. KRAS testing alongside the identification of other affected genes in the same patient will make the treatments even more personalized by contributing more accurately to the clinical decision process. Overall, early diagnosis using novel molecular techniques may improve the management of CRC by providing the most efficient therapies for Moroccan patients.
摘要：
目的：本研究旨在评估KRAS的频率，NRAS,和BRAF突变及其与249例摩洛哥结直肠癌（CRC）患者临床病理特征的可能关联。
方法：对249例CRC患者的一组福尔马林固定石蜡包埋组织进行回顾性调查，使用Idylla™技术和焦磷酸测序法筛选KRAS/NRAS/BRAF突变。
结果：KRAS，NRAS,和BRAF突变显示在46.6%(116/249),5.6%（14/249），2.4%(6/249)的患者。在87.9%的患者中发现了KRAS外显子2突变(102/116)。KRASG12D和G12C是最常见的，分别为32.8%和12.93%，分别。在KRAS外显子2野生型（wt）的患者中，27.6%(32/116)有额外的KRAS突变。在9.5%（11/116）中发现了并发KRAS突变；包括密码子146（A146P/T/V）中的6个，三密码子61（Q61H/L/R），密码子12中的一个（G12A和Q61H），和一个在密码子13(G13D和Q61L)中。在NRAS外显子2wt患者中，64.3%(9/14)有额外的NRAS突变。在28.6%(4/14)的NRAS突变患者中发现并发NRAS突变。由于3.2%wt的KRAS被鉴定为NRAS突变，2.4%(6/249)的患者发现KRAS和NRAS同时发生突变.KRAS突变在>50岁年龄组中更高（P=0.031），并且发现肿瘤位置与KRAS突变（P=0.028）显着相关，主要在左结肠（27.5％）和结肠（42.2％）位置。NRAS突变在左结肠(42.8%)和高分化肿瘤(64.2%)中最为普遍。
结论：检测KRAS突变，特别是G12C亚型，可能对CRC患者具有重要意义，并可能具有治疗意义。然而,CRC患者中罕见的KRAS伴随突变提示每个个体可能呈现不同的治疗反应.KRAS测试以及同一患者中其他受影响基因的识别将通过更准确地促进临床决策过程，使治疗更加个性化。总的来说,通过为摩洛哥患者提供最有效的治疗方法,使用新型分子技术进行早期诊断可以改善CRC的治疗.
方法：对249例CRC患者的一组福尔马林固定石蜡包埋组织进行回顾性调查，使用Idylla™技术和焦磷酸测序法筛选KRAS/NRAS/BRAF突变。
结果：KRAS，NRAS,和BRAF突变显示在46.6%(116/249),5.6%（14/249），2.4%(6/249)的患者。在87.9%的患者中发现了KRAS外显子2突变(102/116)。KRASG12D和G12C是最常见的，分别为32.8%和12.93%，分别。在KRAS外显子2野生型（wt）的患者中，27.6%(32/116)有额外的KRAS突变。在9.5%（11/116）中发现了并发KRAS突变；包括密码子146（A146P/T/V）中的6个，三密码子61（Q61H/L/R），密码子12中的一个（G12A和Q61H），和一个在密码子13(G13D和Q61L)中。在NRAS外显子2wt患者中，64.3%(9/14)有额外的NRAS突变。在28.6%(4/14)的NRAS突变患者中发现并发NRAS突变。由于3.2%wt的KRAS被鉴定为NRAS突变，2.4%(6/249)的患者发现KRAS和NRAS同时发生突变.KRAS突变在>50岁年龄组中更高（P=0.031），并且发现肿瘤位置与KRAS突变（P=0.028）显着相关，主要在左结肠（27.5％）和结肠（42.2％）位置。NRAS突变在左结肠(42.8%)和高分化肿瘤(64.2%)中最为普遍。
结论：检测KRAS突变，特别是G12C亚型，可能对CRC患者具有重要意义，并可能具有治疗意义。然而,CRC患者中罕见的KRAS伴随突变提示每个个体可能呈现不同的治疗反应.KRAS测试以及同一患者中其他受影响基因的识别将通过更准确地促进临床决策过程，使治疗更加个性化。总的来说,通过为摩洛哥患者提供最有效的治疗方法,使用新型分子技术进行早期诊断可以改善CRC的治疗.
