Endocrine Abstracts

JOINT1043

Pituitary neuroendocrine tumours (PitNETs) have a prevalence of 75.7/100,000 within the Maltese population. These tumours present a wide range of clinical behaviours, from hormone overproduction to local effects secondary to compression of adjacent structures, making them a significant public health concern. Despite their prevalence, the genetic factors contributing to sporadic PitNETs, which account for 95% of all cases, remain poorly understood. The primary aim of this study was to identify genetic variants associated with PitNETs in Maltese patients using germline whole exome sequencing, thereby contributing to the global understanding of the genetic aetiology of these tumours. The study cohort consisted of 44 Maltese patients diagnosed with PitNETs, selected based on comprehensive clinical evaluations and atypical phenotypic presentation. Germline DNA was extracted from blood samples, and whole exome sequencing was performed. Bioinformatic analysis was conducted using an in-house pipeline, incorporating variant calling, annotation, and filtering through a curated 75-gene panel associated with PitNET tumorigenesis, which was constructed using a PRISMA systematic review. Identified variants underwent functional prediction and pathogenicity assessment through in silico tools and structural modelling to predict the impact of missense variants on protein function. The study identified significant variants in five genes: SDHA, CABLES1, CDK8, CDH23, and NGDN. These genetic alterations were correlated with clinical data, revealing potential genotype-phenotype associations that could inform personalized treatment strategies. Each variant was validated through Sanger sequencing. This research provides novel insights into the genetic basis of PitNETs in the Maltese population and highlights unique characterisation of Maltese genetics and the importance of considering ethnic-specific genetic profiles in disease research. The findings underscore the potential for genetic screening in the clinical management of PitNETs. Future work will focus on supporting these findings through functional assays, and exploring multi-omic approaches to further elucidate the molecular mechanisms thus improving diagnostic and therapeutic strategies.