Project Portugal 2030

Summary

Unlike CDH1 carriers with known risk of early-onset diffuse gastric (DGC) and lobular breast cancer, CTNNA1 risks and cancer spectrum remain unknown. This prevents: 1) CTNNA1-carriers stratification for genetic counselling/downstream clinical management, according to variant-associated causality; 2) guiding surveillance/disease early diagnosis to proven organs at risk; 3) applying cost-effectiveness risk-reduction/prophylactic surgeries directed to carriers at higher risk of CTNNA1-associated disease. Contrary to CDH1, CTNNA1 lacks actionable variant classification guidelines due to 1) scarce clinical/molecular data hindering genotype-phenotype analysis; 2) unclear variant functional consequences and molecular mechanisms; 3) inadequate functional models. Despite CTNNA1-truncating (PTC) variants predisposing to lethal DGC, conventional treatments offer limited efficacy against >75% mortality. Systematic studies on CTNNA1-associated tumors and specific vulnerabilities are lacking, as are robust experimental models for therapy exploration. NAVIGATOR tackles these challenges, backed by preliminary data and the largest dataset of CTNNA1 carriers, comprehensive clinical/molecular data and specialized experimental models. Led by a global HDGC expert, our team collaborates with a broad network of basic and translational researchers, clinicians, healthcare providers, and genetics diagnostics labs in Europe and America. Clinical management of CTNNA1 PTC carriers varies globally. Some recommend prophylactic gastrectomy, as for CDH1, while others view CTNNA1 variants as variants of unknown significance, refusing surveillance or preventive measures. Our preliminary data reveal 14-fold higher DGC risk in CTNNA1 PTC carriers versus NON-PTC carriers, with NON-PTC carriers facing 2.3-fold higher breast cancer risk and Macular Dystrophy Patterned 2. Other cancers occur in both groups. These data underscore clinical management gaps for CTNNA1 carriers and raise the hypothesis that consequences of CTNNA1 impairment are likely not as straightforward as for CDH1 LoF, given aE-Catenin functional pleiotropy and tissue-specificity. IF TRUE, disease-causing CTNNA1 mechanisms are underestimated and current clinical recommendations disregard surveillance of organs at cancer risk and are ignored in the treatment decision process. Lack of consensus delays CTNNA1 testing, leaving carriers undiagnosed until advanced/untreatable cancer develops. Our aims are to: 1) DEFINE CAUSALITY OF CTNNA1 VARIANTS AND ASSOCIATED DISEASE SPECTRUM; and 2) UNDERSTAND FRAGILITIES OF CTNNA1-RELATED CANCERS THAT MAY BE USED FOR TARGETED THERAPY. This will allow delivering proper pre-symptomatic counselling, prioritize surveillance/prophylactic surgery programs to organs at risk, and improve treatment of CTNNA1-deficient DGC. To achieve our goals, we will 1) understand CTNNA1 loss mechanisms using minigene and CRISPR/Cas9 assays in human cells and Drosophila; 2) define variant causality and disease spectrum in >2000 CTNNA1 carriers; 3) identify therapeutic targets through genomics, transcriptomics, synthetic lethality in Drosophila, and drug screening in tumoroids. 4) validate findings in our innovative gastric-tumoroid-on-a-chip model. See Graphical Abstract (AnnexA) for details. This ambitious and multidisciplinary project has enormous potential for clinical translation pushing beyond the current state of art and providing the missing tools to pioneer CTNNA1-specific pathways of care.