title: A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase.
abstract: OBJECTIVE
  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.
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Yoshitatsu
authors: Y
authors: Sei
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Xilin
authors: X
authors: Zhao
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Joanne
authors: J
authors: Forbes
authors: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors: Silke
authors: S
authors: Szymczak
authors: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors: Qing
authors: Q
authors: Li
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Apurva
authors: A
authors: Trivedi
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Mark
authors: M
authors: Voellinger
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Grishma
authors: G
authors: Joy
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Jianying
authors: J
authors: Feng
authors: Nuclear Medicine Division, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors: Millie
authors: M
authors: Whatley
authors: Genomics Core/Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors: MaryPat Sussex
authors: MS
authors: Jones
authors: Genomics Core/Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors: Ursula L
authors: UL
authors: Harper
authors: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Stephen J
authors: SJ
authors: Marx
authors: Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors: Aradhana M
authors: AM
authors: Venkatesan
authors: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors: Settara C
authors: SC
authors: Chandrasekharappa
authors: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors: Mark
authors: M
authors: Raffeld
authors: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors: Martha M
authors: MM
authors: Quezado
authors: Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors: Adeline
authors: A
authors: Louie
authors: Nuclear Medicine Division, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors: Clara C
authors: CC
authors: Chen
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors: Ramona M
authors: RM
authors: Lim
authors: Information Engineering Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland.
authors: Richa
authors: R
authors: Agarwala
authors: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland.
authors: Alejandro A
authors: AA
authors: Schäffer
authors: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors: Marybeth S
authors: MS
authors: Hughes
authors: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors: Joan E
authors: JE
authors: Bailey-Wilson
authors: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address: stevew@mail.nih.gov.
authors: Stephen A
authors: SA
authors: Wank
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002276:Carcinoid Tumor / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005190:Family; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007414:Intestinal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D007813:Laparotomy; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C434257:inositol polyphosphate multikinase
keywords: Familial; Linkage; Screening; Tumor Suppressor Gene