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Familial small-intestine carcinoids: Chromosomal alterations and germline inositol polyphosphate multikinase
Louis de Mestier1, Eric Pasmant2, Clémence Fleury3
1Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims, France.
Background:
Familial small-intestine neuroendocrine tumors (SI-NETs) are an exceptional inherited entity. Underlying predisposing mechanisms are unelucidated, but inositol polyphosphate multikinase (IPMK) gene alterations might promote their tumorigenesis.
Methods:
A retrospective-prospective nationwide cohort was constituted, by including patients with proven SI-NETs and at least one relative with the same disease. We performed constitutional and somatic IPMK sequencing, and somatic DNA comparative genomic hybridization (CGH).
Results:
We included 17 patients from 8 families, who were characterized by high prevalence (57%) of multiple SI-NETs, and high frequency of distant metastases (82%) and carcinoid syndrome (65%). No IPMK mutation was found in constitutional or tumor DNA. CGH array revealed recurrent chromosome-18 deletions but no alteration in the IPMK region.
Conclusion:
We report here the first European series of patients with familial SI-NETs. Predisposing mechanisms may not involve the IPMK-encoding sequence or chromosomal region and might not differ from those of sporadic SI-NETs.
Insights
Familial small-intestine neuroendocrine tumors (SI-NETs) are rare inherited conditions. This study found no evidence that IPMK gene mutations predispose individuals to familial SI-NETs, suggesting other mechanisms may be involved.
Area of Science:
- Oncology
- Genetics
- Gastroenterology
Background:
- Familial small-intestine neuroendocrine tumors (SI-NETs) represent an uncommon inherited cancer predisposition.
- The underlying genetic mechanisms driving familial SI-NETs remain largely unknown.
- Alterations in the inositol polyphosphate multikinase (IPMK) gene were hypothesized to play a role in SI-NET tumorigenesis.
Purpose of the Study:
- To investigate the role of IPMK gene alterations in the development of familial SI-NETs.
- To characterize the clinical features of familial SI-NETs in a European cohort.
- To explore potential genetic predisposing mechanisms for inherited SI-NETs.
Main Methods:
- A nationwide cohort of 17 patients from 8 families with confirmed SI-NETs and a family history was analyzed.
- Constitutional and tumor DNA underwent sequencing for IPMK alterations.
- Somatic DNA comparative genomic hybridization (CGH) was performed to detect chromosomal abnormalities.
Main Results:
- No mutations in the IPMK gene were identified in either constitutional or tumor DNA from the studied patients.
- Comparative genomic hybridization revealed recurrent deletions on chromosome 18, but not within the IPMK gene region.
- The cohort exhibited a high prevalence of multiple SI-NETs (57%), distant metastases (82%), and carcinoid syndrome (65%).
Conclusions:
- This study presents the first European cohort of patients with familial SI-NETs.
- The findings suggest that IPMK gene sequence alterations or the specific chromosomal region are unlikely to be the primary predisposing factors for familial SI-NETs.
- The underlying genetic mechanisms for familial SI-NETs may be similar to those observed in sporadic cases.
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