[Relationship between KRAS gene mutation sites and clinical characteristics in colorectal cancer].

OBJECTIVES: Colorectal cancer is a common gastrointestinal malignancy worldwide. KRAS gene mutation is an important molecular feature of colorectal cancer, but the clinical significance of different mutation sites remains unclear. This study aims to investigate the distribution characteristics of specific KRAS gene mutation sites and analyze their associations with clinicopathological parameters and survival outcomes in patients with colorectal cancer, thereby providing a basis for precise stratified diagnosis and treatment.

METHODS: A total of 550 patients with colorectal cancer who underwent surgical treatment at the Affiliated Cancer Hospital of Zhengzhou University from May 2018 to January 2020 were retrospectively included, and tumor tissue specimens were retained from all patients. Polymerase chain reaction (PCR) was first used to screen all specimens for KRAS gene mutations, and the overall mutation rate was calculated. High-throughput sequencing was then performed on 210 of these specimens using the Illumina Nova sequencing platform to determine the specific mutation types at codons 12 and 13 of exon 2 of the KRAS gene. Clinicopathological data, including age, sex, tumor stage, lymph node metastasis status, and primary lesion diameter, were collected. Survival data were obtained through outpatient follow-up and telephone follow-up, with the follow-up cutoff date of December 29, 2023. Univariate and multivariate Cox proportional hazards regression models were used to identify independent risk factors affecting prognosis. Variables were included based on a univariate analysis threshold of P<0.10 and clinically recognized key variables, such as tumor stage and lymph node metastasis.

RESULTS: Among the 550 specimens, KRAS gene mutations were detected in 232 cases, with an overall mutation rate of 42.18%. Among the 210 specimens subjected to high-throughput sequencing, mutations were detected in 155 cases, with a mutation rate of 73.81%. Seven mutation types were identified. G12D was the most common mutation site (19.52%), followed by G12V (12.86%), G13D (12.86%), G12S (10.95%), G12A (8.57%), G12C (8.10%), and double mutations, including G12D+G12V and G12V+G13D, each accounting for 0.48%. Analysis of associations with clinical features showed that the proportion of patients with lymph node metastasis at initial diagnosis was 73.17% (30/41) among patients with the G12D mutation, which was significantly higher than that in patients with wild-type KRAS [38.18% (21/55), P<0.05]. However, the proportion of patients with a primary lesion diameter ≥4 cm was 36.59% in the G12D mutation group, which did not differ significantly from that in the wild-type group (25.45%, P>0.05). The proportions of patients with a primary lesion diameter ≥4 cm were 66.67%, 76.47%, 78.26%, and 66.67% among patients with G12A, G12C, G12S, and G13D mutations, respectively, all of which were significantly higher than that in the wild-type group (all P<0.05). However, the proportions of lymph node metastasis in these mutation groups did not differ significantly from that in the wild-type group (P>0.05). Cox proportional hazards regression analysis demonstrated that tumor stage Ⅲ-Ⅳ (HR=1.820, 95% CI 1.194 to 2.774, P=0.005), G12C mutation (HR=2.014, 95% CI 1.321 to 3.069, P=0.001), G12D mutation (HR=1.857, 95% CI 1.218 to 2.930, P=0.004), and G12V mutation (HR=1.751, 95% CI 1.149 to 2.669, P=0.009) were independent risk factors for death in patients with colorectal cancer.

CONCLUSIONS: Different KRAS gene mutation sites are specifically associated with clinical features of colorectal cancer. The G12D mutation is associated with a high risk of lymph node metastasis, whereas G12A, G12C, G12S, and G13D mutations are associated with increased primary tumor size. G12C, G12D, and G12V mutations are independent prognostic risk factors and may serve as potential molecular markers for risk stratification and individualized treatment.