WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas

• Published in: Human molecular genetics Vol. 30; no. 24; pp. 2429 - 2440
• Main Authors: Aavikko, Mervi, Kaasinen, Eevi, Andersson, Noora, Pentinmikko, Nalle, Sulo, Päivi, Donner, Iikki, Pihlajamaa, Päivi, Kuosmanen, Anna, Bramante, Simona, Katainen, Riku, Sipilä, Lauri J, Martin, Samantha, Arola, Johanna, Carpén, Olli, Heiskanen, Ilkka, Mecklin, Jukka-Pekka, Taipale, Jussi, Ristimäki, Ari, Lehti, Kaisa, Gucciardo, Erika, Katajisto, Pekka, Schalin-Jäntti, Camilla, Vahteristo, Pia, Aaltonen, Lauri A
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 30.11.2021
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenoma - genetics; Adenoma - pathology; Colorectal Neoplasms - genetics; Humans; Intestinal Mucosa - pathology; Medicin och hälsovetenskap; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - pathology; Wnt2 Protein
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddab206

Abstract Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described. We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas. To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture. We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.