1. WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas
- Author
-
Ilkka Heiskanen, Pekka Katajisto, Päivi Pihlajamaa, Pia Vahteristo, Camilla Schalin-Jäntti, Olli Carpén, Lauri A. Aaltonen, Noora Andersson, Lauri J. Sipilä, Jussi Taipale, Riku Katainen, Iikki Donner, Simona Bramante, Päivi Sulo, Nalle Pentinmikko, Kaisa Lehti, Anna Kuosmanen, Erika Gucciardo, Johanna Arola, Mervi Aavikko, Eevi Kaasinen, Jukka-Pekka Mecklin, Samantha Martin, Ari Ristimäki, Medicum, Institute for Molecular Medicine Finland, Department of Medical and Clinical Genetics, ATG - Applied Tumor Genomics, Helsinki Institute of Life Science HiLIFE, HUSLAB, Department of Pathology, Centre of Excellence in Stem Cell Metabolism, Institute of Biotechnology, Organismal and Evolutionary Biology Research Programme, Lauri Antti Aaltonen / Principal Investigator, Doctoral Programme in Biomedicine, HUS Diagnostic Center, Precision Cancer Pathology, Olli Mikael Carpen / Principal Investigator, Research Program in Systems Oncology, HUS Abdominal Center, II kirurgian klinikka, Biosciences, Jussi Taipale / Principal Investigator, Kaisa Irene Lehti / Principal Investigator, Faculty Common Matters (Faculty of Biology and Environmental Sciences), INDIVIDRUG - Individualized Drug Therapy, Faculty of Biological and Environmental Sciences, Clinicum, and Endokrinologian yksikkö
- Subjects
Adenoma ,AcademicSubjects/SCI01140 ,DOMAINS ,adenokarsinooma ,CANCER-RISK ,In situ hybridization ,suolistosyövät ,Adenocarcinoma ,Biology ,Neuroendocrine tumors ,Germline ,Wnt2 Protein ,perinnöllinen alttius ,03 medical and health sciences ,0302 clinical medicine ,WNT2 ,Genetics ,Genetic predisposition ,medicine ,Humans ,Intestinal Mucosa ,MUTATION ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology ,paksusuolisyöpä ,CARCINOID-TUMORS ,0303 health sciences ,perinnölliset taudit ,CYSTIC-FIBROSIS ,General Medicine ,NATIONWIDE ,medicine.disease ,Intestinal epithelium ,3. Good health ,GENOME ,Neuroendocrine Tumors ,Hyperplastic Polyp ,Single cell sequencing ,3121 General medicine, internal medicine and other clinical medicine ,030220 oncology & carcinogenesis ,MAP ,Cancer research ,syöpätaudit ,3111 Biomedicine ,General Article ,geneettiset tekijät ,Colorectal Neoplasms - 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.
- Published
- 2021