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Endocrine Abstracts (2023) 96 OC1 | DOI: 10.1530/endoabs.96.OC1

1University of Exeter, Exeter, United Kingdom; 2Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 3University of Cordoba, Cordoba, Spain; 4Portsmouth Hospitals NHS Trust,
Portsmouth, United Kingdom; 5Kings College London, London, United Kingdom; 6University of Bristol, Bristol, United Kingdom

Neuroendocrine neoplasms (NENs) are a heterogeneous tumour classification including indolent neuroendocrine tumours (NETs), aggressive neuroendocrine carcinomas (NECs). NECs and small cell lung cancer (SCLCs) are poorly differentiated tumours and life expectancy following metastatic diagnosis is less than 1 year. Currently, there are known variants in germline DNA that associate with bronchial and pancreatic NENs, but not intestinal. We conducted an exome-wide association study in the UK Biobank (n=500,000) to test for phenotypic and rare coding variations in germline DNA that associate with NETs, NECs and SCLC. We used histology and ICD10 data from the UK Biobank’s cancer registry linkage to define phenotypes for NET (n=591), NEC (n=328), and SCLC (n=477) and a cohort of cancer-free controls (n=395,914). We used regenie to perform single-variant and rare (<0.1%) variant gene-based tests for cancer-causing germline variants for each of the three NEN phenotypes. We found significant phenotypic associations between baseline BMI and HbA1c with all three NEN phenotypes. SCLC further associated with environmental pollution (OR=1.31 (1.21-1.41) P=2.9e-12) and Townsend deprivation index (OR=1.61 (1.49-1.74) P=4.2e-33). In the single-gene tests, a single variant in the DST gene (6:56482593) associated with SCLC (Beta=6.0 (4.4-7.6), P=4.9e-8). In the gene-based tests, loss-of-function variants in MEN1 (Beta=6.9 (4.9-8.9), P=2.2e-7) associated with NECs. Germline mutations in MEN1 are known to associate with NETs, but this is the first study to show an association with NECs. We also identified a novel variant for SCLC in the DST gene. Further investigation could help understand how NECs and SCLCs develop and progress.

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