The epigenetic modifier lysine methyltransferase 2C is frequently mutated in gastric remnant carcinoma

The Journal of Pathology: Clinical Research · 7 authors, 5 centres

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TL;DR

Whole-exome sequencing of 36 and targeted deep sequencing of 25 paired tumor-normal samples from patients with gastric remnant carcinoma (GRC) were performed to characterize the genomic landscape.

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Whole-exome sequencing of 36 and targeted deep sequencing of 25 paired tumor-normal samples from patients with gastric remnant carcinoma (GRC) were performed to characterize the genomic landscape. Recurrent mutations in epigenetic modifiers, notably KMT2C, were identified in 61.11% of cases. KMT2C-mutated tumors were associated with higher intratumoral CD3+ and CD8+ lymphocyte counts and PD-L1 expression. These findings provide a genomic profile for GRC and suggest KMT2C as a potential prognostic biomarker.

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cohort

SPECIALTY

oncology

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ORIGINAL PAPER

PMC10397379

The epigenetic modifier lysine methyltransferase 2C is frequently mutated in gastric remnant carcinoma

The Journal of Pathology: Clinical Research

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ABSTRACT

Abstract 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.

CITATION EXPORT

Bo Sun, Haojie Chen, Jiawen Lao et al.. The epigenetic modifier lysine methyltransferase 2C is frequently mutated in gastric remnant carcinoma. The Journal of Pathology: Clinical Research. (2023). https://doi.org/10.1002/cjp2.335

AUTHORS

7 · 5 CENTRES

Bo Sun, Haojie Chen, Jiawen Lao, Cong Tan, Yue Zhang, Zhen Shao, Dazhi Xu

1 Department of Gastric Surgery Fudan University Shanghai Cancer Center Shanghai PR China
2 Department of Oncology, Shanghai Medical College Fudan University Shanghai PR China
3 CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai PR China
4 Department of Gastric Surgery Sun Yat‐sen University Cancer Center Guangzhou PR China
5 Department of Pathology Fudan University Shanghai Cancer Center Shanghai PR China