A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase

Abstract

Background & Aims Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced, incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer. Methods We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases. Results Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than 50 y were found to have occult tumors; the tumors were cleared surgically from 91% of these individuals (21/23). Linkage analysis and whole-exome sequencing identified a germline 4 bp deletion in the gene inositol polyphosphate multikinase (IPMK) that truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and 17/35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. Conclusions We found that small intestinal carcinoids can occur as an inherited autosomal dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%–35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early-stage disease. IPMK haplo-insufficiency promotes carcinoid tumorigenesis.

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

“…These syndromes include multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau syndrome (VHL), but also the less common neurofibromatosis type 1 (NF1) syndrome (Larsson et al 1988, Wallace et al 1990, Maher et al 1991. Familial small intestinal NET seem to have a wider spectrum of very rare mutations (Sei et al 2015, Dumanski et al 2017, even if no gene mutation has been mechanistically proven to directly cause this disease.…”

“…SI-NET tend to be multifocal in patients with IPMK mutations. A prospective study conducted on 33 families (Sei et al 2015), revealed a germline 4-bp deletion in the inositol polyphosphate multikinase (IPMK) gene on chromosome 10. This mutation was subsequently detected in all 11 affected individuals of this family but not in the other families, indicating that other genes are responsible for the onset of the disease.…”

“…This mutation was subsequently detected in all 11 affected individuals of this family but not in the other families, indicating that other genes are responsible for the onset of the disease. The IPMK mutation leads to a truncated protein and functional studies demonstrate reduced kinase activity and nuclear localization, which in turn reduces p53 activity and promotes cell survival (Sei et al 2015). Independent studies are needed to validate the IPMK findings.…”

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…Despite substantial efforts no definitive genetic basis for this phenomenon has been described. A recent study used linkage analysis and exome sequencing that revealed IPMK germline mutations in a single family (135). Although experimental investigations seem to indicate a pathogenic effect of the IPMK mutation a validation effort that included 32 additional families did not reveal the presence of any additional mutations (135).…”

The Enigma of Carcinoids

“…In this issue, investigators report on their strategy to identify kindreds with "familial carcinoid" and characterize these kindreds both clinically and genetically. 8 Sei et al 8 at the National Institutes of Health enrolled 33 kindreds with 2 first-degree relatives with small intestinal carcinoid tumors. Affected individuals were diagnosed with disease at an average age of 61 years, and 70% presented with stage IV disease.…”