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Clinicopathological features of Egyptian colorectal cancer patients regarding somatic genetic mutations especially in KRAS gene and microsatellite instability status: a pilot study
Egyptian Journal of Medical Human Genetics Pub Date : 2019-11-19 , DOI: 10.1186/s43042-019-0028-z
Neemat M. Kassem , Gamal Emera , Hebatallah A. Kassem , Nashwa Medhat , Basant Nagdy , Mustafa Tareq , Rabab Abdel Moneim , Mohammed Abdulla , Wafaa H. El Metenawy

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths which contributes to a significant public health problem worldwide with 1.8 million new cases and almost 861,000 deaths in 2018 according to the World Health Organization. It exhibits 7.4% of all diagnosed cancer cases in the region of the Middle East and North Africa. Molecular changes that happen in CRCs are chromosomal instability, microsatellite instability (MSI), and CpG island methylator phenotype. The human RAS family (KRAS, NRAS, and HRAS) is the most frequently mutated oncogenes in human cancer appearing in 45% of colon cancers. Determining MSI status across CRCs offers the opportunity to identify patients who are likely to respond to targeted therapies such as anti-PD-1. Therefore, a method to efficiently determine MSI status for every cancer patient is needed. KRAS mutations were detected in 31.6% of CRC patients, namely in older patients (p = 0.003). Codons 12 and 13 constituted 5/6 (83.3%) and 1/6 (16.7%) of all KRAS mutations, respectively. We found three mutations G12D, G12C, and G13D which occur as a result of substitution at c.35G>A, c.34G>T, and c.38G>A and have been detected in 4/6 (66.6%), 1/6 (16.7%), and 1/6 (16.7%) patients, respectively. Eleven (57.9%) patients had microsatellite instability-high (MSI-H) CRC. A higher percentage of MSI-H CRC was detected in female patients (p = 0.048). Eight patients had both MSI-H CRC and wild KRAS mutation with no statistical significance was found between MSI status and KRAS mutation in these studied patients. In conclusion, considering that KRAS mutations confer resistance to EGFR inhibitors, patients who have CRC with KRAS mutation could receive more tailored management by defining MSI status. MSI-high patients have enhanced responsiveness to anti-PD-1 therapies. Thus, the question arises as to whether it is worth investigating this association in the routine clinical setting or not. Further studies with a larger number of patients are needed to assess the impact of MSI status on Egyptian CRC care.

中文翻译:

埃及结直肠癌患者关于体细胞基因突变的临床病理特征,尤其是 KRAS 基因和微卫星不稳定性状态:一项初步研究

根据世界卫生组织的数据,结直肠癌 (CRC) 是导致全球重大公共卫生问题的第三大癌症相关死亡原因,2018 年有 180 万新病例和近 861,000 人死亡。它占中东和北非地区所有确诊癌症病例的 7.4%。CRC 中发生的分子变化是染色体不稳定性、微卫星不稳定性 (MSI) 和 CpG 岛甲基化表型。人类 RAS 家族(KRAS、NRAS 和 HRAS)是人类癌症中最常见的突变癌基因,出现在 45% 的结肠癌中。确定跨 CRC 的 MSI 状态提供了识别可能对抗 PD-1 等靶向疗法有反应的患者的机会。所以,需要一种有效确定每位癌症患者 MSI 状态的方法。在 31.6% 的 CRC 患者中检测到 KRAS 突变,即在老年患者中(p = 0.003)。密码子 12 和 13 分别占所有 KRAS 突变的 5/6 (83.3%) 和 1/6 (16.7%)。我们发现了三个突变 G12D、G12C 和 G13D,它们是由 c.35G>A、c.34G>T 和 c.38G>A 处的取代而发生的,并且已在 4/6 (66.6%)、1 /6 (16.7%) 和 1/6 (16.7%) 患者,分别。11 名 (57.9%) 患者患有微卫星不稳定性高 (MSI-H) CRC。在女性患者中检测到更高百分比的 MSI-H CRC(p = 0.048)。8 名患者同时具有 MSI-H CRC 和野生 KRAS 突变,这些研究患者的 MSI 状态和 KRAS 突变之间没有发现统计学意义。综上所述,考虑到 KRAS 突变对 EGFR 抑制剂产生耐药性,患有 KRAS 突变的 CRC 患者可以通过定义 MSI 状态来接受更量身定制的管理。MSI 高的患者对抗 PD-1 疗法的反应增强。因此,问题在于是否值得在常规临床环境中研究这种关联。需要对更多患者进行进一步研究,以评估 MSI 状态对埃及 CRC 护理的影响。
更新日期:2019-11-19
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