Abstract 1952P
Background
MDM2 is a key negative regulator of tumor suppressor p53. MDM2 gene amplification has been reported as a potential marker for hyperprogression under checkpoint inhibitors (ICI). We aimed to characterize the molecular and gene expression profile of MDM2 amplified (a-MDM2) GI cancers.
Methods
23632 samples were included: 11692 colorectal, 3830 gastric/esophageal, 3960 pancreatic, 1860 biliary cancers (BC), 2330 other GI. Samples were analyzed using NextGen DNA seq for gene mutation (mut) and amplification (copy number > 6), in situ hybridization, whole transcriptome RNA seq and immunohistochemistry (Caris Life Sciences). EBseq was used to identify differentially expressed genes based on MDM2 expression levels (above vs below median) with control for FDR (Q < 0.2). Pathway and functional enrichment analysis was performed using Reactome.
Results
A-MDM2 frequency was highest in small bowel cancers (4.5%, 28/627), gastric/esophageal (3.3%, 125/3830), and BC (3.4%, 64/1860). a-MDM2 was more common in males (P = .01). Compared to MDM2 not amplified (na), a-MDM2 GI tumors showed lower mut rates in TP53 (23 vs 69%), KRAS (15 vs 44%), APC (5 vs 41%), and PIK3CA (4 vs 12%), whereas ATM mut were higher (9.5 vs 4%) (Q < .001). Copy number alterations (CNA) were significantly higher in a-MDM2 vs na, including CDK4, ERBB3, HMGA2, LGR5, NACA and WIF1 (Q < .001). Main results according to tumor type are summarized in the table. MDM2 amplification had an inverse relationship with TMB (Q = .04) and MSI-H/dMMR (Q = .03). No association was found with PDL1 levels and CPS score. A total of 785 genes were significantly differentially expressed based on MDM2 levels, with an increase in FGF signaling related pathways in MDM2 overexpressing tumors (Q < .05). Table: 1952P
| BC | Esophageal | Gastric | Small Bowel | |||||||||
| a-MDM2 % | na % | Q-value | a-MDM2 % | na % | Q-value | a-MDM2 % | na % | Q-value | a-MDM2 % | na % | Q-value | |
| NGS TP53 | 16 | 44 | 0.002 | 41 | 89 | < 0.0001 | 9 | 57 | < 0.0001 | 8 | 60 | < 0.0001 |
| CNA CDK4 | 19 | 0.2 | < 0.0001 | 21 | 0.2 | < 0.0001 | 6 | 0.1 | 0.02 | 11 | 0.3 | 0.02 |
| CNA ERBB3 | 3 | 0 | 0.05 | 6 | 0.1 | 0.01 | 2 | 0 | 0.4 | 4 | 0.2 | 0.8 |
| CNA GNAS | 6 | 0.2 | 0.005 | 8 | 0.7 | 0.03 | 0 | 0.3 | 1 | 37 | 0.5 | < 0.0001 |
| CNA HMGA2 | 42 | 0.3 | < 0.0001 | 35 | 0.5 | < 0.0001 | 27 | 0.2 | < 0.0001 | 52 | 0.3 | < 0.0001 |
| CNA LGR5 | 31 | 0.1 | 0.01 | 25 | 0.1 | < 0.0001 | 6 | 0.1 | 0.01 | 18 | 0 | < 0.0001 |
| CNA NACA | 5 | 0.1 | < 0.0001 | 6 | 0 | 0.002 | 2 | 0 | 0.4 | 0 | 0.2 | 1 |
| CNA WIF1 | 36 | 0.1 | < 0.0001 | 27 | 0.4 | < 0.0001 | 18 | 0.1 | < 0.0001 | 38 | 0.2 | < 0.0001 |
Conclusions
This is the most extensive profiling study to investigate a-MDM2 GI tumors. Our data show distinct molecular patterns of a-MDM2 GI cancers involving WNT pathway genes, upregulation of FGF signaling and inverse association with TMB and MSI which may explain the resistance mechanisms to ICI.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Cancer Institute grant number P30CA014089, the Gloria Borges WunderGlo Foundation-The Wunder Project, the Dhont Family Foundation, the San Pedro Peninsula Cancer Guild, the Daniel Butler Research Fund, the Call to Cure Research Fund and the Fong Research Project.
Disclosure
F. Battaglin, R.M. Goldberg, A. Seeber: Travel/Accommodation/Expenses: Caris Life Sciences. J. Xiu, Y. Baca: Full/Part-time employment: Caris Life Sciences. A.F. Shields: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Caris Life Sciences. I. Astaturov: Advisory/Consultancy: Caris Life Sciences. J.L. Marshall: Honoraria (self), Advisory/Consultancy, Full/Part-time employment: Caris Life Sciences. W.M. Korn: Leadership role, Full/Part-time employment: Caris Life Sciences. H.J. Lenz: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: GlaxoSmithKline; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Isofol Medical. All other authors have declared no conflicts of interest.