表观遗传修饰因子赖氨酸甲基转移酶 2C 在残胃癌中频繁突变

Gastric remnant carcinoma (GRC), which occurs in the stomach after partial gastrectomy, is a rare and aggressive form of gastric adenocarcinoma (GAC). Comprehensive profiling of genomic mutations in GRC could provide the basis for elucidating the origin and characteristics of this cancer.

Herein, whole-exome sequencing (WES) was performed on 36 matched tumor-normal samples from patients with GRC and identified recurrent mutations in epigenetic modifiers, notably KMT2C, ARID1A, NSD1, and KMT2D, in 61. 11% of cases. Mutational signature analysis revealed a low frequency of microsatellite instability (MSI) in GRC, which was further identified by MSIsensor, MSI-polymerase chain reaction, and immunohistochemistry analysis.

Comparative analysis demonstrated that GRC had a distinct mutation spectrum compared to that of GAC in The Cancer Genome Atlas samples, with a significantly higher mutation rate of KMT2C. Targeted deep sequencing (Target-seq) of an additional 25 paired tumor-normal samples verified the high mutation frequency (48%) of KMT2C in GRC. KMT2C mutations correlated with poor overall survival in both WES and Target-seq cohorts and were independent prognosticators in GRC.

In addition, KMT2C mutations were positively correlated with favorable outcomes in immune checkpoint inhibitor-treated pan-cancer patients and associated with higher intratumoral CD3 + , CD8 + tumor-infiltrating lymphocyte counts, and PD-L1 expression in GRC samples (p = 0. 018, 0. 092, 0. 047, 0. 010, and 0. 034, respectively).

Our dataset provides a platform for information and knowledge mining of the genomic characteristics of GRC and helps to frame new therapeutic approaches for this disease.