Abstract 1479P
Background
Immune checkpoint inhibitors exhibited remarkable anti-tumor activity in dMMR/MSI-H gastric adenocarcinoma. Further investigation into the predictive biomarker of efficacious immunotherapy in this subset might benefit from detailed information of genomic landscape, which remains largely unknown.
Methods
Hybrid capture-based next-generation sequencing (NGS) including 733 cancer-related genes were performed in surgical-resected tumor tissue and matched whole blood sample from 175 patients with resectable gastric adenocarcinoma. Immunohistochemistry (IHC) for MMR proteins, polymerase chain reaction (PCR) test for 5 MSI loci, and NGS test for 100 MSI loci were implemented to comprehensively assess the dMMR/MSI-H status.
Results
IHC, PCR, and NGS testing identified 115 consistent-dMMR/MSI-H samples and 46 consistent-pMMR/MSS samples, of which the medians of tumor mutational burden were 65 and 17, respectively. dMMR/MSI-H was associated with early TNM stage (p=0.050), intestinal type of Lauren classification (p=0.058), lower expression of HER2 (p=0.034), and EBV negativity (p=0.008). As for genetic aberration, TP53 mutation was enriched in pMMR/MSS samples (p=0.021) and the mutations in ARID1A, ACVR2A, KMT2C, TGFBR2, KMT2D and RNF43 were dominant in dMMR/MSI-H samples (p<0.001) with mutational frequencies over 80%. Most dMMR/MSI-H samples carried mutations in chromatin remodeling (99%), WNT (99%), TGFβ (98%), PI3K-AKT-mTOR (91%), Hippo (90%), and NOTCH (90%) pathways, while relatively lower mutational rates were discovered in RTK (73%), Hedgehog (68%), cell cycle (63%), Ras-Raf-MEK-ERK/JNK (62%), and p53 (56%) pathways. Table: 1479P
| Consistent dMMR/MSI-H (n=115) | Consistent pMMR/MSS (n=46) | P value | ||
| Age | 0.22 | |||
| >65 | 54 (47.0%) | 16 (34.8%) | ||
| ≤65 | 61 (53.0%) | 30 (65.2%) | ||
| Sex | 0.15 | |||
| Male | 70 (60.9%) | 34 (73.9%) | ||
| Female | 45 (39.1%) | 12 (26.1%) | ||
| TNM stage | 0.050 | |||
| I | 29 (25.2%) | 7 (15.2%) | ||
| II | 48 (41.7%) | 13 (28.3%) | ||
| III | 37 (22.2%) | 25 (54.3%) | ||
| IV | 1 (0.9%) | 1 (2.2%) | ||
| Lauren | 0.058 | |||
| Intestinal | 59 (51.3%) | 15 (32.6%) | ||
| Diffuse | 19 (16.5%) | 14 (30.4%) | ||
| Mixed | 36 (31.3%) | 16 (34.8%) | ||
| N.A. | 1 (0.9%) | 1 (2.2%) | ||
| HER2 (IHC) | 0.034 | |||
| 0 | 51 (44.3%) | 19 (41.3%) | ||
| 1+ | 32 (27.8%) | 10 (21.7%) | ||
| 2+ | 30 (26.1%) | 7 (15.2%) | ||
| 3+ | 2 (1.7%) | 5 (10.9%) | ||
| N.A. | 0 (0.0%) | 5 (10.9%) | ||
| EBV (FISH) | 0.008 | |||
| Positive | 1 (0.9%) | 5 (10.9%) | ||
| Negative | 113 (98.3%) | 41 (89.1%) | ||
| N.A. | 1 (0.9%) | 0 (0.0%) | ||
| TMB | 65 (49-90) | 6.1 (3.4-9.2) | 6.9*10-38 |
Conclusions
Our results depicted the clinicopathological and genomic characteristics of dMMR/MSI-H resected gastric adenocarcinoma, providing a roadmap for patient stratification and biomarker investigation.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Peking University People’s Hospital.
Funding
Has not received any funding.
Disclosure
B. Zhang, Y. Xu: Full/Part-time employment: 3D Medicines Inc. All other authors have declared no conflicts of interest.