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Different patterns of 11q allelic losses in digestive endocrine tumors
Tiziana D'adda1, Silvia Pizzi, Cinzia Azzoni
1Department of Pathology and Laboratory Medicine, Section of Pathological Anatomy, University of Parma, Parma, Italy.
Abstract:
Most foregut digestive endocrine neoplasms may be associated with the multiple endocrine type 1 (MEN-1) syndrome. In contrast, midgut/hindgut carcinoids never show such association. To investigate the pathogenetic involvement of the MEN-1 gene and of putative additional oncosuppressor gene(s) distal to it, a comparative analysis of loss of heterozygosity (LOH) at chromosome 11q13 to 11qter was performed in 27 foregut (pancreatic endocrine tumors [PETs]), 23 midgut (ileal and appendiceal), and 3 hindgut (rectal) endocrine tumors. LOH at the MEN-1 gene locus at 11q13 was observed in 52% of the 23 sporadic and in all 4 MEN-1-associated PETs and was found to consistently and continuously span to the most distal marker investigated at 11qter. In contrast, only occasional, discontinuous, and mostly interstitial LOH for 11q markers was observed in ileal (midgut) carcinoids, whereas no LOH was found in all appendiceal (midgut) and rectal (hindgut) carcinoids. The consistent extension of LOH from the MEN-1 region to 11qter in sporadic PETs suggests a mechanism of gene inactivation via chromosomal breakage and complete loss of chromosome 11q; furthermore, these results expand beyond the 11q13 region the search for additional oncosuppressor gene(s) potentially involved in the genesis of these neoplasms. The low frequency, limited extension, and discontinuous distribution of 11q deletions in midgut/hindgut carcinoids suggest that MEN-1 gene is not involved in the pathogenesis of these tumors.
Insights
Loss of heterozygosity (LOH) at chromosome 11q13 to 11qter was analyzed in digestive endocrine tumors. MEN-1 gene involvement was confirmed in foregut tumors, but not midgut/hindgut carcinoids.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Foregut digestive endocrine neoplasms are often linked to multiple endocrine type 1 (MEN-1) syndrome.
- Midgut/hindgut carcinoids do not typically associate with MEN-1 syndrome.
- The role of the MEN-1 gene and other tumor suppressor genes in digestive endocrine tumors requires further investigation.
Purpose of the Study:
- To compare loss of heterozygosity (LOH) patterns at chromosome 11q13 to 11qter in foregut, midgut, and hindgut endocrine tumors.
- To investigate the pathogenetic involvement of the MEN-1 gene and potential additional oncosuppressor genes.
Main Methods:
- Comparative analysis of LOH at chromosome 11q13 to 11qter.
- Study included 27 foregut (pancreatic endocrine tumors [PETs]), 23 midgut (ileal and appendiceal), and 3 hindgut (rectal) endocrine tumors.
- Analysis distinguished between MEN-1-associated and sporadic tumors.
Main Results:
- LOH at the MEN-1 locus (11q13) was observed in 52% of sporadic PETs and 100% of MEN-1-associated PETs, consistently spanning to 11qter.
- Midgut carcinoids showed occasional, discontinuous LOH for 11q markers.
- Appendiceal and rectal carcinoids exhibited no LOH for 11q markers, suggesting MEN-1 gene is not involved in their pathogenesis.
Conclusions:
- Consistent LOH in sporadic PETs suggests gene inactivation via chromosomal breakage and complete chromosome 11q loss.
- The findings support the search for additional oncosuppressor genes beyond 11q13 in the genesis of foregut neoplasms.
- The MEN-1 gene is unlikely to be involved in the pathogenesis of midgut/hindgut carcinoids due to low-frequency, discontinuous LOH.