CTNNA1 Truncating Variants Define a Moderate-Penetrance Hereditary Diffuse Gastric Cancer Spectrum — Implications for Testing, Surveillance and Risk Reduction

Highlights

– Germline CTNNA1-truncating variants cause loss of αE-catenin through nonsense-mediated mRNA decay (NMD) and are strongly associated with diffuse gastric cancer (DGC) and lobular breast cancer (LBC).

– Truncating variants confer an ≈7-fold increased GC risk versus population controls; risk is lower than for CDH1-truncating carriers (≈38-fold).

– Truncating CTNNA1 variants carry ≈8-fold higher DGC risk than non-truncating CTNNA1 variants; macular dystrophy-patterned 2 associates with non-truncating variants.

– ‘Porto’ simplified referral criteria improved CTNNA1 carrier detection by 9% without reducing performance versus the 2020 HDGC criteria.

Background: clinical context and unmet need

Hereditary diffuse gastric cancer (HDGC) is most often linked to germline CDH1 alterations; however, a subset of families with early-onset or clustered diffuse gastric cancer lacks CDH1 variants. CTNNA1 — which encodes αE-catenin, a core adherens-junction protein interacting with E-cadherin — has emerged as a candidate HDGC gene. Prior data were limited to small series and case reports, leaving uncertainty about variant-type pathogenicity, mechanisms of loss of function, age-specific risks, co-associations such as lobular breast cancer (LBC), and how best to identify carriers for surveillance and prevention.

Study design and methods

This multi-institutional study combined clinical, molecular and population-level data from 1,308 individuals belonging to 351 CTNNA1-variant carrier families and 37,428 non-carrier controls of European and American ancestry, integrating genotype-phenotype analysis with functional assays.

Key elements:

• Genetic classification stratified CTNNA1 variants into truncating versus non-truncating types.
• Multivariable logistic regression estimated genotype-phenotype associations and cancer risks versus non-carrier controls and against published CDH1 risk data.
• Functional validation used CRISPR/Cas9 CTNNA1 knockout in gastric cancer cell lines and CTNNA1-humanized Drosophila models to test the function of truncating versus non-truncating transcripts and to probe the mechanism (nonsense-mediated decay, NMD).
• Clinical utility of testing criteria was evaluated by comparing existing HDGC 2020 guideline performance with a simplified referral algorithm (the ‘Porto’ criteria).

Key findings

Genotype–phenotype relationships and cancer risks

The study presents robust, converging evidence that CTNNA1-truncating variants are the principal disease-causing class. Compared with CTNNA1 non-truncating carriers, truncating carriers had an approximately 8-fold higher risk of diffuse gastric cancer. Relative risks versus the general (non-carrier) population were substantial but lower than those observed for CDH1 truncating variants: CTNNA1-truncating carriers had an approximately 7-fold higher GC risk compared with non-carriers, whereas CDH1-truncating carriers showed a markedly higher (~38-fold) increase. For lobular breast cancer (LBC), CTNNA1-truncating variant carriers also exhibited increased incidence; risk in CTNNA1-truncating carriers was lower than in CDH1 pathogenic/likely pathogenic (P/LP) carriers (≈8-fold lower when directly compared), but nevertheless clinically meaningful and recurrent in several families, including some that would not meet classical HDGC testing criteria.

In practical terms, the data support classifying CTNNA1 as a moderate-penetrance HDGC gene: truncating variants carry materially elevated lifetime risk of DGC and LBC but not to the same degree as CDH1-truncating variants.

Mechanism: nonsense-mediated decay and loss of αE-catenin

Multiple lines of functional evidence indicate that truncating CTNNA1 transcripts are targeted by nonsense-mediated mRNA decay (NMD), leading to reduced αE-catenin expression in gastric tissue. DGCs from truncating variant carriers exhibited loss of αE-catenin protein. In the CTNNA1-null Drosophila ‘humanized’ assays and CRISPR-knockout gastric cell models, truncating transcripts were non-functional while many non-truncating variants retained partial activity. Together these observations support haploinsufficiency via NMD as the dominant pathogenic mechanism for truncating CTNNA1 alleles.

Clinical detection and the ‘Porto’ criteria

The authors derived simplified criteria for CTNNA1 testing (the ‘Porto’ criteria) that increased the detection (pick-up) rate of CTNNA1-carrier families by 9% relative to the 2020 HDGC clinical guidelines, without degrading test performance. This suggests that modest simplification or re-weighting of referral triggers can improve diagnostic yield for CTNNA1 while maintaining specificity in clinic populations.

Non-truncating variants and phenotypic correlations

Non-truncating CTNNA1 variants showed lower association with DGC but were positively associated with an ocular phenotype, macular dystrophy-patterned 2, particularly when localized to the αE-catenin M-fragment. This genotype–phenotype signal underscores that variant-type matters for clinical expectation and counseling.

Expert commentary: interpretation and clinical implications

These findings have direct translational consequences for genetic counseling, surveillance planning and preventive strategies.

First, variant interpretation: the study strengthens the evidence for assigning pathogenicity to truncating CTNNA1 variants in the context of HDGC, documenting both functional loss and epidemiologic disease association. For non-truncating variants, the lower penetrance and distinct non-gastric associations warrant cautious interpretation and, when possible, segregation or functional data to support clinical action.

Second, surveillance and risk-reduction: CTNNA1 truncating carriers should be considered at increased risk for DGC and LBC, but absolute risks appear lower than for CDH1 carriers. This argues for differentiated management: while prophylactic total gastrectomy is standardly recommended for many CDH1-truncating carriers because of very high lifetime DGC risk and difficulties with endoscopic detection, a less uniform approach may be reasonable for CTNNA1-truncating carriers. Shared decision-making is essential, incorporating age, family history (number and ages of affected relatives), variant type, and local expertise with high-quality endoscopic surveillance, ideally using HDGC-focused protocols.

For breast cancer risk, CTNNA1-truncating carriers should be counseled about increased LBC risk and offered an enhanced breast surveillance plan consistent with moderate-penetrance gene management (e.g., individualised MRI plus mammography and consideration of risk-reducing options based on family history and patient preference).

Third, testing strategy: implementation of the Porto criteria could modestly increase detection of pathogenic CTNNA1 variants in families while simplifying referral pathways. Integration of CTNNA1 into multigene panels for hereditary gastric cancer or early-onset diffuse gastric cancer is supported, with explicit guidance on variant-type interpretation.

Limitations and remaining questions

Despite its size and functional integration, the study has limitations to consider. Ascertainment bias is inherent in clinic-based cohorts and may inflate penetrance estimates. Longitudinal follow-up to generate age-specific cumulative risks will be important. The study population is largely of European and American ancestry; risk estimates may not generalize to other populations. Finally, precise age-specific penetrance estimates and the impact of modifying genetic or environmental factors remain open questions.

Practical recommendations for clinicians

• Offer CTNNA1 testing (often as part of a multigene panel) to families with diffuse gastric cancer clustering or early-onset DGC, using the Porto criteria as an efficient alternative to more complex rules.
• Treat truncating CTNNA1 variants as clinically actionable: discuss increased DGC and LBC risks, and provide individualized surveillance (HDGC-expert endoscopy) and breast screening (MRI ± mammography) plans.
• Exercise caution before recommending prophylactic total gastrectomy for CTNNA1 carriers; base decisions on family history, patient values and emerging risk estimates; consider intensive endoscopic surveillance where surgery is deferred.
• Interpret non-truncating CTNNA1 variants conservatively; seek segregation, population frequency and functional data where possible, and monitor for non-gastric phenotypes such as macular dystrophy-patterned 2 when relevant.

Conclusion and future directions

This comprehensive clinical and mechanistic study positions CTNNA1-truncating variants as bona fide contributors to the HDGC spectrum, operating through NMD-mediated loss of αE-catenin and conferring moderate but clinically relevant increases in gastric and lobular breast cancer risk. The results justify incorporation of CTNNA1 into diagnostic panels and support tailored surveillance algorithms differing from those applied to CDH1 carriers. Prospective cohorts, richer ancestry diversity, and age-specific penetrance data will refine risk stratification and guide management choices including the role of prophylactic surgery.

Funding and clinicaltrials.gov

Funding sources and trial registry details are reported in the original publication: Lobo S et al., Gut. 2025. See the cited article for complete acknowledgments and declarations.

References

1. Lobo S, Dias A, Pedro AM, et al. Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls. Gut. 2025 Sep 25:gutjnl-2024-334601. doi:10.1136/gutjnl-2024-334601. Epub ahead of print. PMID: 40998418.

2. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392(6674):402–405.

(For additional guideline details on hereditary diffuse gastric cancer and CDH1 management, clinicians should consult the most recent IGCLC guidance documents and local expert centers.)