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CTNNA1, a New HDGC Gene: Inactivating Mechanisms and Driven Phenotypes

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Hereditary Gastric and Breast Cancer Syndrome

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Abstract

This chapter focuses on CTNNA1, the second gene to be acknowledged as a hereditary diffuse gastric cancer (HDGC) predisposing gene. CTNNA1 loss of function was first found in a family meeting HDGC criteria in 2013. CTNNA1 loss of function germline variants affect a smaller fraction of HDGC families, as compared to CDH1 variants. CTNNA1 missense germline variants predispose specifically to macular dystrophy patterned 2, an autosomal dominant eye disorder.

Throughout this book chapter, we will deepen the knowledge on CTNNA1 and αE-catenin protein and their involvement in HDGC, we will review CTNNA1 germline variants distribution and association with disease phenotypes, and describe CTNNA1-related mechanisms underlying tumor formation and development in sporadic cancer. In particular, we will address predisposition related to CTNNA1 germline pathogenic variants and development of diffuse gastric cancer, CTNNA1 germline likely pathogenic variants and development of breast cancer of unknown histotype; data available on CTNNA1 germline variants and lobular breast cancer; predisposition related to CTNNA1 germline missense variants, classified as variants of unknown significance for HDGC, and development of macular dystrophy patterned 2; the importance of αE-catenin to connect and stabilize the adherens junction complex and the actin cytoskeleton; the multiple interactions of αE-catenin with different proteins and regulation of several signaling pathways; and the role of αE-catenin dysregulation in different types of sporadic cancer.

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Authors and Affiliations

  1. i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Silvana Lobo, Paulo S. Pereira & Carla Oliveira

  2. IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal

    Silvana Lobo & Carla Oliveira

  3. International Doctoral Programme in Molecular and Cellular Biotechnology Applied to Health Sciences (BiotechHealth) from Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

    Silvana Lobo

  4. IBMC – Instituto de Biologia Molecular e Celular, Porto, Portugal

    Paulo S. Pereira

  5. Unité fonctionnelle d’Oncogénétique clinique, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris, France

    Patrick R. Benusiglio

  6. Chirurgie générale et digestive, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France

    Patrick R. Benusiglio

  7. FMUP – Faculty of Medicine of the University of Porto, Porto, Portugal

    Carla Oliveira

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  1. Silvana Lobo
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  1. European Institute of Oncology, University of Milan, Milan, Italy

    Giovanni Corso

  2. European Institute of Oncology, University of Milan, Milan, Italy

    Paolo Veronesi

  3. University of Siena, Siena, Italy

    Franco Roviello

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Lobo, S., Pereira, P.S., Benusiglio, P.R., Oliveira, C. (2023). CTNNA1, a New HDGC Gene: Inactivating Mechanisms and Driven Phenotypes. In: Corso, G., Veronesi, P., Roviello, F. (eds) Hereditary Gastric and Breast Cancer Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-031-21317-5_5

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