Prognostic impact of mutation profiling in Chinese patients with colorectal liver metastases.

Abstract

e15157 Background: To investigate mutation profiling in Chinese patients with colorectal liver metastases and explore new prognostic biomarkers. Methods: We investigated 197 patients who underwent surgery for colorectal liver metastases at Beijing Cancer Hospital between January 2015 and February 2017. Tumor DNA was isolated from FFPE tissues from liver metastatic lesions. Mutation spectrum was obtained by targeted deep sequencing of 620 selected genes. Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per 1Mbp and divided into quartiles. MSI status was tested with next-generation sequencing. Studies of impacts of mutation status on disease-free survival (DFS) and overall survival (OS) were performed with Kaplan-Meier analysis. Results: Mutation significance analysis confirmed enrichment in colorectal cancer driver gene mutations of TP53, APC, KRAS, SMAD4, SOX9, FBXW7 and PIK3CA in 72%, 61%, 29%, 14%, 10%, 10% and 9% of liver metastases, with no BRAF mutation found in any of these patients. Additionally, we observed frequent gene-level copy number variations, including amplifications of MYC, BRCA2, ERBB2, CCND2 and deletion of APC. Among 197 patients, only three showed MSI-high, who also exhibited high TMBs. Moreover, KRAS, MXRA5, and SETD2 mutations were significantly associated with shorter DFS ( KRAS mt vs wt: 8 months vs 11 months, p = 0.0086; MXRA5 mt vs wt: 6 months vs 11 months, p = 0.0178; SETD2 mt vs wt: 8 months vs 11 months, p = 0.0381), but KMT2A mutation associated with longer DFS (mt vs wt: 31.5 months vs 10 months, p = 0.0409). SPEN, GNAS, CTNNB1, SETD2 and FANCM mutations were significantly associated with poor OS ( SPEN mt vs wt: 23 months vs 30 months, p = 0.0047; GNAS mt vs wt: 24.5 months vs 30 months, p = 0.0386; CTNNB1 mt vs wt: 20 months vs 30 months, p = 0.0001; SETD2 mt vs wt: 20 months vs 30 months, p = 0.0026; FANCM mt vs wt: 13 months vs 30 months, p = 0.0007). Conclusions: Our study has found a novel panel of prognostic biomarkers in colorectal liver metastases. The clinical significance of mutations of MXRA5, SETD2, KMT2A, SPEN, GNAS, CTNNB1, FANCM needs to be confirmed on a larger scale.