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Published on: January 17, 2018
Genetic abnormalities of somatostatin receptors in pituitary tumors
A Lania1, G Mantovani, A Spada
1Department of Medical Sciences, University of Milan, Fondazione Ospedale Maggiore IRCCS, Milan, Italy.
Abstract:
Somatostatin exerts antisecretive and antiproliferative effects on different endocrine cells by acting through a family of G protein-coupled receptors that includes five subtypes (SST1-5). Normal human pituitary and pituitary adenomas have been shown to express almost all SST subtypes, with the exception of SST4. Consistent with the observation that octreotide and other somatostatin analogs bind to SST2 and SST5 with high affinity, these genes have been screened for quantitative/qualitative abnormalities in tumors removed from patients with poor responsiveness to somatostatin analogs treatment. Data obtained in GH-secreting adenomas suggested that resistance to octreotide was frequently associated with low expression of SST2 mRNA, although other authors failed to confirm this finding. To date, the only mutational change involving SST2 and SST5 is the Arg to Trp substitution in codon 240 of the SST5 gene that was found in one acromegalic patient resistant to octreotide. Similarly, loss of heterozygosis at SST5 gene locus in pituitary adenomas has been described in individual tumors. In recent years, molecular studies investigated the possible association of gene polymorphisms and susceptibility to diseases and/or resistance to drugs. As far as polymorphic variants of SST genes are concerned, a possible role of SST5 C1004T and T-461C alleles in influencing GH and IGF-I levels in patients with acromegaly has been proposed. Nevertheless, polymorphic variants in SST2 and SST5 genes seem to have a minor, if any, role in determining the different responsiveness to somatostatin analogs in patients with acromegaly.
Insights
Somatostatin receptor (SST) gene variants, particularly in SST2 and SST5, show minimal impact on patient response to somatostatin analogs in acromegaly treatment. Further research is needed to fully understand resistance mechanisms.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Somatostatin (SST) analogs are used to treat endocrine tumors by targeting G protein-coupled receptors (SST1-5).
- Pituitary adenomas express most SST subtypes, with SST2 and SST5 being key targets for drugs like octreotide.
- Understanding genetic factors influencing treatment resistance is crucial for optimizing patient outcomes.
Purpose of the Study:
- To investigate the role of genetic abnormalities and polymorphisms in somatostatin receptor genes (SST2 and SST5) in pituitary adenoma responsiveness to somatostatin analogs.
- To explore potential associations between specific gene variants and treatment resistance in acromegaly.
Main Methods:
- Screening of SST2 and SST5 genes for quantitative/qualitative abnormalities in tumors from patients with poor treatment response.
- Analysis of gene expression (mRNA) and mutations, including loss of heterozygosis.
- Examination of polymorphic variants in SST genes (SST5 C1004T, T-461C) and their correlation with treatment outcomes.
Main Results:
- Low expression of SST2 mRNA was suggested as a factor in octreotide resistance in GH-secreting adenomas, though findings were inconsistent.
- A specific mutation (Arg to Trp at codon 240) in SST5 was identified in one resistant patient.
- Polymorphic variants in SST2 and SST5 genes appear to have a limited role in determining patient responsiveness to somatostatin analogs in acromegaly.
Conclusions:
- Genetic variations in SST2 and SST5, including common polymorphisms, do not significantly explain the variable response to somatostatin analogs in acromegaly.
- While specific mutations or expression levels might play a role in rare cases, broader genetic factors seem less influential than previously hypothesized.
- Further research into other molecular mechanisms is warranted to elucidate somatostatin analog resistance in pituitary adenomas.
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