Abstract
KRAS variants are associated with tumor progression; however, the prevalence of KRAS variant subtypes and their association with survival and recurrence in patients with intrahepatic cholangiocarcinoma (ICC) after curative resection are largely unknown. To explore the prognostic association of KRAS variant subtypes with survival and recurrence in patients with ICC. In this cohort study, patients who underwent curative resection for ICC from January 2009 through December 2016 at a single hospital in China were recruited, and whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify KRAS variants. Kaplan-Meier and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Data were analyzed from April 2020 to January 2021. Hepatectomy in patients with ICC. The association of KRAS variant subtypes with OS and DFS. Of 1024 included patients with ICC, 621 (60.6%) were male, and the mean (SD) age was 59.2 (10.2) years. A total of 14 different subtypes of KRAS somatic variants affecting 127 patients (12.4%) were identified. G12D was the most frequent allele in this cohort, accounting for 55 of 127 identified KRAS variants (43.3%), followed by G12V (25 [19.7%]), G12C (9 [7.1%]), and G13D (8 [6.3%]). Compared with patients with wild-type KRAS, patients with variant KRAS were more likely to have high levels of carbohydrate antigen 19-9 (92 of 127 [72.4%] vs 546 of 897 [60.9%]; P = .01) and γ-glutamyltransferase (72 of 127 [56.7%] vs 420 of 897 [46.8%]; P = .04). Multivariable analysis revealed that G12 KRAS variants but not non-G12 KRAS variants were independently associated with worse OS (hazard ratio [HR], 1.69; 95% CI, 1.31-2.18; P < .001) and DFS (HR, 1.47; 95% CI, 1.16-1.88; P = .002). Among the patients with G12 KRAS variants, the G12V KRAS variant was the strongest prognostic determinant for the worst OS (HR, 3.05; 95% CI, 1.94-4.79; P < .001) and DFS (HR, 1.79; 95% CI, 1.13-2.85; P = .01). In this cohort study, the distribution of KRAS variant subtypes was characterized in a large cohort of patients with ICC from China. The presence of G12 KRAS variants but not non-G12 KRAS variants was associated with worse survival and increased risk of recurrence. Patients with the G12V variant exhibited the worst outcomes in the whole cohort.
Highlights
Clinical Characteristics The clinical characteristics of the patients with wild-type KRAS and variant KRAS genotypes are presented in eTable 3 in the Supplement
A, Kaplan-Meier survival analysis showing overall survival based on wild-type KRAS and variant KRAS
In addition to being associated with prognosis after curative resection among patients with intrahepatic cholangiocarcinoma (ICC), we found that G12 KRAS variants but not non-G12 KRAS variants were associated with lymphatic metastasis, especially G12V KRAS variants, which were enriched in patients with lymphatic metastasis (9 [6.3%] vs 16 [1.8%]; P = .005)
Summary
Patients and Follow-up We enrolled a total of 1024 patients with primary ICC who received curative resection from January 2009 to December 2016 in the Department of Liver Surgical Oncology of Zhongshan Hospital, Fudan University, Shanghai, China, and tissue samples from tumors and matched noncancerous livers were continually collected. Patients receiving palliative procedures or prior interventions (such as transhepatic artery embolization, chemotherapy, or radiotherapy) or with other primary malignancies and inflammatory diseases during the follow-up were excluded from the study. Before surgical operation and tissue sample collection, we obtained oral and written informed consent from each participant, with information such as the use of tissue sample and clinical characteristics for scientific research, which was granted by the Research Ethics Committee of Zhongshan Hospital. The Research Ethics Committee of Zhongshan Hospital granted ethical
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