Yoshitatsu Sei1, Xilin Zhao1, Joanne Forbes1, Silke Szymczak2, Qing Li2, Apurva Trivedi1, Mark Voellinger1, Grishma Joy1, Jianying Feng1, Millie Whatley3, MaryPat Sussex Jones4, Ursula L Harper4, Stephen J Marx5, Aradhana M Venkatesan6, Settara C Chandrasekharappa7, Mark Raffeld8, Martha M Quezado8, Adeline Louie6, Clara C Chen3, Ramona M Lim1, Richa Agarwala9, Alejandro A Schäffer10, Marybeth S Hughes11, Joan E Bailey-Wilson2, Stephen A Wank12. 1. Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. 2. Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 3. Nuclear Medicine Division, Clinical Center, National Institutes of Health, Bethesda, Maryland. 4. Genomics Core/Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 5. Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. 6. Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland. 7. Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 8. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 9. Information Engineering Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland. 10. Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland. 11. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 12. Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address: stevew@mail.nih.gov.
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.
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. IPMKhaploinsufficiency promotes carcinoid tumorigenesis.
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