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

Mervi Aavikko,Noora Andersson,Ari Ristimäki,Anna Kuosmanen,Johanna Arola,Ilkka Heiskanen,Erika Gucciardo,Päivi Sulo,Simona Bramante,Olli Carpén,Kaisa Lehti,Riku Katainen,Nalle Pentinmikko,Pekka Katajisto,Iikki Donner,Samantha Martin,Pia Vahteristo,Jussi Taipale,Päivi Pihlajamaa,Eevi Kaasinen,Camilla Schalin‐Jäntti ,Jukka‐Pekka Mecklin ,Lauri J Sipilä ,Lauri A Aaltonen

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.

Highlights

Intestinal cancer syndromes, such as Lynch syndrome, familial adenomatous polyposis, juvenile polyposis syndrome and PeutzJeghers syndrome are associated with elevated relative risk of small and large intestinal adenocarcinomas
small intestinal neuroendocrine tumors (SI-NETs) may develop in individuals with menin 1 (MEN1), ret proto-oncogene (RET) and neurofibromin 1 (NF1) germline mutations, and in more recent studies, inositol polyphosphate multikinase (IPMK) and mutY DNA glycosylase (MUTYH) have been suggested as predisposition genes [5,6]
SI-NETs have been reported to cluster in families [1,2,3,4], and occasionally manifest in individuals with Mendelian disorders, such as Multiple endocrine neoplasms (MEN1) and neurofibromatosis 1 (NF1)

Summary

Introduction

Intestinal cancer syndromes, such as Lynch syndrome, familial adenomatous polyposis, juvenile polyposis syndrome and PeutzJeghers syndrome are associated with elevated relative risk of small and large intestinal adenocarcinomas. An increasing amount of research has described the familial occurrence of small intestinal neuroendocrine tumors (SI-NETs) [1,2,3,4]. Mendelian conditions bearing a high risk to both intestinal adenocarcinomas and SI-NETs have not been described. Studies on the three-dimensional genome organization have demonstrated that mammalian chromosomes partition into self-interacting domains, known as topologically associating domains (TADs) [7,8]. Genomic regions in these interact with each other more frequently than with the surrounding regions, and genes within TADs have been shown to be often co-regulated [7,8]. Disruption of a TAD border may result in aberrant genomic interactions, disturbed gene regulation and disease [9]

Methods

Results

Conclusion