Abstract:
The hamartomatous polyposis syndromes are a heterogeneous group of rare syndromes showing autosomal dominant inheritance and characterized by the onset of gastrointestinal hamartomatous polyps and increased cancer risk. Among them there are the Peutz-Jeghers syndrome, juvenile polyposis, and PTEN-related hamartomatous tumor syndrome.
The aim of this work was to identify new genes involved in the pathogenesis of the diseases, new relationships between molecular pathways involved, and new alternative therapeutic targets useful for disease management.
To realize this aim, we planned the following research stages:
• NGS analysis of a specific gene panel in 20 subjects with clinical suspicion of familial hamartomatous polyposis.
• Investigation of the STK11 and PTEN genes/protein expression, in subjects carrier of SDHB and SDHD genes variants;
• Investigation of the SDH inhibition effect on the STK11 gene expression.
Using this method, we identified 6 subjects carrying a pathogenetic variant of the STK11 gene, 1 carrier of a VUS of the STK11 gene, 1 carrier of a VUS in the SDHB gene and 2 carriers of a VUS in the SDHD gene. It was therefore observed that the presence of the SDHD gene variants is associated with downregulation of the STK11 and PTEN tumor suppressor genes. Furthermore, we in vitro demonstrated downregulation of STK11 protein due to SDH inhibition.
In conclusion, a previously undescribed regulation between the SDH enzyme and STK11/LKB1 and PTEN genes emerges, which contribute to shed light on the pathogenesis of hamartomatous polyposis and opens new insight into the standardization of a targeted therapy for the management of affected patients.
Audience Take Away Notes:
The data presented will be useful to the audience investigating the molecular basis of solid tumors. Genes, such as STK11, PTEN and SDH, are involved in the onset of colon cancer, but also of other types of cancer
The identification of a crosstalk between the genes coding for SDH and the STK11 and PTEN genes will be useful to clarify the effects of alterations in SDH genes and to improve the known on the molecular basis of hereditary and sporadic tumors
In our opinion these results will be useful for the identification of new therapeutic targets
The workflow used in this study could represent a study model for other types of autosomal dominant diseases
