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Cited by 119Neuroendocrine Tumor Research AdvancesGenetic factors in colorectal cancerCongenital gastrointestinal and neural anomalies

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

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Sei, Yoshitatsu, Zhao, Xilin, Forbes, Joanne, Szymczak, Silke, Li, Qing, Trivedi, Apurva, Voellinger, Mark, Joy, Grishma +17 more·2015·Gastroenterology
DOI 10.1053/j.gastro.2015.04.008PMC PMC4858647
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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 age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 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 haploinsufficiency promotes carcinoid tumorigenesis.

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  • IPMK is implicated in neurodegeneration, cancer, and inflammation.

    “Over two decades, multidisciplinary research has unveiled its far-reaching biological roles and implications in diverse diseases, including neurodegeneration, cancer, and inflammation.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [35]

    The Discussion (page not supplied) links an IPMK mutation to familial small-intestinal carcinoid tumors and describes effects on proliferation and apoptosis, supporting the cancer portion. The passages do not link IPMK to neurodegeneration or inflammation; searches for those terms found no such link in our copy. (LLM, conf=0.88)

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  • IPMK is involved in inflammatory disorders, obesity, Alzheimer's disease, inflammatory bowel disease, and intestinal neuroendocrine tumors.

    “Over the past two decades, research utilizing animal models and human mutation analyses has revealed IPMK’s involvement in a wide array of human diseases, including inflammatory disorders [28,29], obesity [30,31], Alzheimer’s disease [32], inflammatory bowel disease [33,34], and intestinal neuroendocrine tumors [35].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [35]

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Authors
Sei, Y., Zhao, X., Forbes, J., Szymczak, S., Li, Q., Trivedi, A., Voellinger, M., Joy, G., Feng, J., Whatley, M., Jones, M. S., Harper, U. L., Marx, S. J., Venkatesan, A. M., Chandrasekharappa, S. C., Raffeld, M., Quezado, M. M., Louie, A., Chen, C. C., Lim, R. M., Agarwala, R., Schäffer, A. A., Hughes, M. S., Bailey-Wilson, J. E., & Wank, S. A.
Affiliations
National Institutes of Health (US)
Corresponding author
Wank, Stephen A.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2015-07
Volume
149
Issue
1
Pages
67-78
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2015.04.008
PMC
PMC4858647
OpenAlex
W2102079513
Cited by
119
References
5
Citations by year
2026: 10 · 2025: 9 · 2024: 4 · 2023: 12 · 2022: 12 · 2021: 10 · 2020: 18 · 2019: 8 · 2018: 3 · 2017: 14 · 2016: 12 · 2015: 7
FWCI
9.42
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute
  • National Institute of Diabetes and Digestive and Kidney Diseases (ZIADK071010)
  • U.S. National Library of Medicine
Topics
  • Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
Keywords
inositol polyphosphate multikinase, autosomal dominant inheritance, haploinsufficiency, p53 activation, nuclear localization
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Carcinoid Tumor, Family, Female, Humans, Intestinal Neoplasms, Laparotomy, Male, Middle Aged, Pedigree, Prospective Studies, Phosphotransferases (Alcohol Group Acceptor), Germ-Line Mutation, Young Adult

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