Adorisio Riccardo, Ciardiello Davide, Rappa Alessandra, Gervaso Lorenzo, Pelizzari Gloria, Marinucci Laura, Fusco Nicola, Zampino Maria Giulia, Fazio Nicola, Venetis Konstantinos, Guerini-Rocco Elena
Division of Pathology, European Institute of Oncology, IRCCS, Milan, Italy.
Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy.
J Mol Diagn. 2025 Feb;27(2):130-138. doi: 10.1016/j.jmoldx.2024.11.007. Epub 2024 Dec 16.
Kirsten rat sarcoma viral oncogene homolog (KRAS) somatic mutations occur in 30% to 40% of patients with colorectal cancer (CRC). These were thought to equally affect prognosis and resistance to anti-epidermal growth factor receptor agents; however, recent data show the activity of KRAS-G12C and pan-RAS inhibitors. The effects of uncommon KRAS (uKRAS) variants are largely unexplored. The distribution and pathogenicity of uKRAS mutations and their relationship with patients' clinicopathologic features were assessed. A total of 2427 CRCs were profiled for KRAS using next-generation sequencing (NGS). The study and control groups included patients with uKRAS (<1% frequency in CRC data sets on cBioPortal) and canonical KRAS mutations, respectively. In silico protein structure modifications and prediction analyses were performed by using PyMOL, trRosetta, and PolyPhen-2. uKRAS mutations affected 35 cases (1.5%), with G13C (28.6%), G12R (20%), and V14I (8.6%) being most common. Missense mutations (D33E, G12W, G12F, Q22H, Q61L, and L19F) occurred in nine cases (25.7%). Duplications (G10dup and L52_G60dup) affected two cases. Pathogenicity analyses showed that G12W, Q22R, L56V, and A130I mutations are probably damaging, with scores between 0.928 and 1.000. No differences were seen in clinicopathologic features. uKRAS mutants had lower event-free survival but no difference in overall survival compared with controls. Although these data are hypothesis generating and need further confirmation, they highlight the importance of NGS-based profiling to identify CRC patients with uKRAS mutations as candidates for personalized therapy.
Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）体细胞突变发生在30%至40%的结直肠癌（CRC）患者中。这些突变曾被认为对预后和抗表皮生长因子受体药物的耐药性有同等影响；然而，最近的数据显示了KRAS - G12C和泛RAS抑制剂的活性。罕见KRAS（uKRAS）变体的影响在很大程度上尚未得到探索。评估了uKRAS突变的分布、致病性及其与患者临床病理特征的关系。使用下一代测序（NGS）对总共2427例CRC进行了KRAS分析。研究组和对照组分别包括uKRAS（在cBioPortal的CRC数据集中频率<1%）和典型KRAS突变的患者。使用PyMOL、trRosetta和PolyPhen - 2进行了计算机模拟蛋白质结构修饰和预测分析。uKRAS突变影响了35例（1.5%），其中G13C（28.6%）、G12R（20%）和V14I（8.6%）最为常见。错义突变（D33E、G12W、G12F、Q22H、Q61L和L19F）发生在9例（25.7%）中。重复（G10dup和L52_G60dup）影响了2例。致病性分析表明，G12W、Q22R、L56V和A130I突变可能具有损害性，评分在0.928至1.000之间。临床病理特征未见差异。与对照组相比，uKRAS突变体的无事件生存期较低，但总生存期无差异。尽管这些数据只是提出假设，需要进一步证实，但它们突出了基于NGS分析来识别具有uKRAS突变的CRC患者作为个性化治疗候选者的重要性。
