3521 - Large-scale analysis of CDH1 mutations define a distinctive molecular subset in gastric cancer (GC)

Background

Though molecular classifications have been well studied, targeted therapies for GC are still limited. CDH1 mutations are characteristics of genomically stable GC and associated with poor prognosis. Herein, to understand the specific mutation profile and enriched pathways in CDH1-mutated (MT) GC could help to discover novel drug targets.

Methods

GC (N = 1596) were analyzed by next-generation sequencing (NGS) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutation, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Gene fusions were evaluated using Archer (N = 253) or Whole Transcriptome Sequencing (WTS, N = 96).

Results

The overall mutation frequency of CDH1 was 9.7%. A significant association of CDH1 mutations with cancer types (GC, 12% vs gastroesophageal junction adenocarcinoma, 2%), sex (female, 13% vs male, 8%), Lauren subtypes (diffuse, 27% vs intestinal, 1%) and younger age (58 vs 62) were observed (p < 0.05). The most frequently mutated genes in CDH1-MT GC were ARID1A (55%), TP53 (44%), KMT2D (8%), RNF43 (7%), PIK3CA (6%). Compared to CDH1-wild type (WT) GC, mutations in ARID1A (55% vs 39%), WRN (3% vs 1%), POT1 (2% vs 0.1%), CDK12 (2% vs 0.6%) and FANCC (1.4% vs 0.2%) were significantly higher, while TP53 (44% vs 64%) and APC (2% vs 6%) were significantly lower in CDH1-MT GC (p < 0.05); Amplifications of KRAS and HER2 were significantly lower, while CRKL and IGF1R amplifications were significantly higher in CDH1-MT GC, compared to CDH1-WT GC (p < 0.05). For immune-related markers, CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score>0) (57% vs. 73%, p < 0.05). No significant difference of TMB and MSI-H were overserved between CDH1-MT/WT GC. RNA sequencing showed similar frequency of ARHGAP26 fusion (6% vs 7%) in CDH1-MT vs WT tumors.

Conclusions

This is the largest study to explore the distinct genomic landscape in CDH1-MT GC. It indicates CDH1-MT GC patients could potentially benefit from agents targeting WRN, POT1, CDK12 and IGF1R, while immunotherapy may be of lower efficacy in this cohort based on lower CPS score. Efficiency of these therapeutic targets and enriched pathways in CDH1-MT GC warrant further investigation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.