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• W4384157642 abstract "Background and aims Small intestinal neuroendocrine tumor (SI-NET) is a rare disease whose incidence has increased over the last 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here, we report the results of the largest genome-wide association study (GWAS) of SI-NETs performed to date with 405 cases and 614,666 controls. Methods We used samples from 307 SI-NET patients and 287,137 controls in the FinnGen study for the identification of SI-NET risk-associated genetic variants. We also metanalysed the results with summary statistics from the UK Biobank (n=98 SI-NET cases and n=327,529 controls). Results We identified 6 genome-wide significant (p<5x10-8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been previously reported. Interestingly, the top hit (rs200138614, p=1.80x10-19) is a missense variant (p.Cys712Phe) in the LGR5 gene, a bona fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 SI-NET patients, as well as in the UK Biobank exome sequence data (n=92 cases and n=392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling. Conclusion Our study is the largest GWAS study to date on SI-NETs and reports 4 new associated GWAS loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells." @default.
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• W4384157642 date "2023-10-01" @default.
• W4384157642 modified "2023-10-14" @default.
• W4384157642 title "Genome-Wide Association Study Identifies 4 Novel Risk Loci for Small Intestinal Neuroendocrine Tumors Including a Missense Mutation in LGR5" @default.
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• W4384157642 doi "https://doi.org/10.1053/j.gastro.2023.06.031" @default.
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