Details

Autor(en) / Beteiligte

• Sei, Yoshitatsu
• Zhao, Xilin
• Forbes, Joanne
• Szymczak, Silke
• Li, Qing
• Trivedi, Apurva
• Voellinger, Mark
• Joy, Grishma
• Feng, Jianying
• Whatley, Millie
• Jones, MaryPat Sussex
• Harper, Ursula L
• Marx, Stephen J
• Venkatesan, Aradhana M
• Chandrasekharappa, Settara C
• Raffeld, Mark
• Quezado, Martha M
• Louie, Adeline
• Chen, Clara C
• Lim, Ramona M
• Agarwala, Richa
• Schäffer, Alejandro A
• Hughes, Marybeth S
• Bailey-Wilson, Joan E
• Wank, Stephen A

Titel

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

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2015-07, Vol.149 (1), p.67-78

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.