| Title: | Genome-Wide Association Study Identifies 4 Novel Risk Loci for Small Intestinal Neuroendocrine Tumors Including a Missense Mutation in LGR5 |
| Journal: | Gastroenterology |
| Published: | 14 Jul 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37453564/ |
| DOI: | https://doi.org/10.1053/j.gastro.2023.06.031 |
Publication 11628
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Abstract
BACKGROUND & AIMS: Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported.</p>
METHODS: Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls).</p>
RESULTS: We identified 6 genome-wide significant (P < 5 × 10-8) 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 reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10-19) was 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 patients with SI-NETs, 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.</p>
CONCLUSIONS: Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.</p>
25 Authors
- Anil K Giri
- Mervi Aavikko
- Linnea Wartiovaara
- Toni Lemmetyinen
- Juha Karjalainen
- Juha Mehtonen
- Kimmo Palin
- Niko Välimäki
- Max Tamlander
- Riikka Saikkonen
- Auli Karhu
- Ekaterina Morgunova
- Benjamin Sun
- Heiko Runz
- Priit Palta
- Shuang Luo
- Heikki Joensuu
- Tomi P Mäkelä
- Iiro Kostiainen
- Camilla Schalin-Jäntti
- FinnGen
- Aarno Palotie
- Lauri A Aaltonen
- Saara Ollila
- Mark J Daly
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