18P - The role of CTNNA1 truncating variants in hereditary diffuse gastric cancer (HDGC)

Background

Rare CTNNA1/αE-catenin truncating variants were found in HDGC patients, however, disease spectrum and variant-type causality remains understudied. We aim to explore genotype-phenotype associations and understand the molecular pathways causing CTNNA1-driven diffuse gastric cancer (DGC).

Methods

Using a clinical database of 364 CTNNA1 variant carrier families (1388 individuals), we analyzed genotype–phenotype associations with multivariable logistic regression. Variants functional impact was assessed with in vitro/in vivo models. Transcriptomic profile of 11 DGC and normal stomachs was analyzed.

Results

From 71 European CTNNA1 carrier families, 26 carried truncating variants (21/26 met HDGC criteria). Early onset DGC was significantly more likely to occur in truncating carrier families than in those with missense variants (OR=8.33; 95%CI [3.125-25]; p<0.001). Lobular breast cancer (LBC) followed the same trend in truncating carriers (OR=4.76; 95%CI [0.98-50]; p=0.053), although non significant. In an extended series of 271 families carrying truncating variants, 32 (12%) families fulfilled HDGC criteria, and LBC was more frequent than DGC (20 vs 19 cases). Our CRISPR/Cas9 edited gastric cancer cell line bearing a CTNNA1 truncating showed complete CTNNA1/αE-catenin loss. Nonsense Mediated mRNA Decay (NMD) blockade increased CTNNA1 mRNA expression ∼13-fold, recovering to wild-type (WT) levels. In our Drosophila α-cat knockout (KO), organ development/lethality was rescued with overexpression of human WT/missense αE-catenin, but not with a truncated αE-catenin. DGC transcriptomic analysis from carriers’ revealed 67 upregulated genes in tumors vs normal, including HIF1α and PIK3R3, two known cancer therapy targets and candidates for drug repurposing in CTNNA1-driven DGC.

Conclusions

DGC is 8-fold more likely to occur in carriers of truncating than missense variants, and data on LBC is still scarce. We highlight NMD as a prime mechanism for CTNNA1 truncated transcripts degradation and created an in vivo model to assess variants functional impact. CTNNA1-associated DGC overexpress a set of molecules worth exploring as therapy targets.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

C. Oliveira.

Funding

Portuguese Foundation for Science and Technology (funded S. Lobo PhD scholarship 2020.05773.BD and the LEGOH Project PTDC/BTM-TEC/6706/2020). ERN-GENTURIS (No. 739547).

Disclosure

J. Herrera-Mullar, R. Karam: Financial Interests, Personal, Full or part-time Employment, NA: Ambrygenetics. P.R. Benusiglio: Financial Interests, Institutional, Financially compensated role, NA: AstraZeneca, BMS, Merck pharmaceuticals. All other authors have declared no conflicts of interest.