Abstract 746: Genomic alteration of Chinese dMMR/MSI-H gastric cancer
Authors: Wei Jia , Wang Jian , Fan Xiangshan , Wang Yue , Fu Yao , Wang Kai , Wu Nandie , Liu Qin , Yang Yang , Wang Weifeng , Liu Baorui 
Published: August 2019

Background: Gastric cancer is a high incidence malignancy often diagnosed at an advanced stage with limited therapeutic options and poor prognosis. A small fraction of gastric cancer with dMMR/MSI-H has extraordinary response to the immune checkpoint inhibitor treatment attributing to the immunogenicity generated by the elevated tumor mutation burden. At the meantime, the extensive genomic variants also cause profound impact on many other cancer related genes. Thus the understanding of dMMR/MSI-H gastric cancer genomic profiling is urgent for exploring clinical strategy to this cohort.

Methods: Formalin Fixed Paraffin Embedded (FFPE) samples of 30 Chinese gastric cancer patients were collected for 450 gene panel based next-generation sequencing (NGS) assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. Microsatellite instability (MSI) status and tumor mutational burden (TMB) were also calculated by NGS algorithm.

Results: There were 15 males (50%) and 15 females (50%) diagnosed as gastric cancer with a median age of 67 years old. The TMB value of this cohort ranged from 29 to 118 muts/Mb, with the median value of 58 muts/Mb. The most frequent genomic alterations in Chinese MSI-H gastric cancer patients were revealed as KMT2D (50%), RNF43 (50%), CIC (50%), PIK3CA (50%), KMT2C (43%), ACVR2A (40%), TP53 (30%), ATM (33%), and ERBB3 (33%). Truncation has been found the most frequent gene alteration among these top mutations due to the deficiency of mismatch repair system caused reading frame shift. Epigenetic modifier genes with functions of chromatin remodeling and histone methylation have been found extensively mutated in MSI-H gastric cancer. Among eighteen (60%=18/30) patients carrying truncations in ARID1A whose coding protein participates in chromatin remodeling, seven of them possess loss-of-function biallelic truncations. Moderate frequency of mutation also occur at other genes in chromatin remodeling such as ARID1B (23%), PBRM1 (17%) and SMARCA4 (26%). About 77% patients in this cohort carry at least one truncation in genes belonging to the histone lysine methyltransferase 2 (KMT2) family such as KMT2A, KMT2C and KMT2D. Mutations of B2M gene which are commonly associated with resistance to immune checkpoint inhibitor have been found in 23% MSI-H gastric cancer. About 66% of the patients in this cohort carrying mutations in FBXW7, PIK3CA, PTEN, STK11 and TSC may benefit from the mTOR inhibitors.

Conclusions: In general, dMMR/MSI-H gastric cancers possess elevated and dispersive TMB value. Epigenetic modifier genes involving in chromatin remodeling and histone methylation mutate frequently in MSI-H gastric cancer. About 66% of the patients in this cohort may benefit from the mTOR inhibitors.

Citation Format: Jia Wei, Jian Wang, Xiangshan Fan, Yue Wang, Yao Fu, Kai Wang, Nandie Wu, Qin Liu, Yang Yang, Weifeng Wang, Baorui Liu. Genomic alteration of Chinese dMMR/MSI-H gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 746.