Association between somatostatin receptor 5 gene polymorphisms and pancreatic cancer risk and survival

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Cancer (Impact Factor: 4.89). 07/2011; 117(13):2863-72. DOI: 10.1002/cncr.25858
Source: PubMed


Somatostatin (SST) inhibited cell proliferation and negatively regulated the release of growth hormones by means of specific receptors (SSTR). Genetic variation in SSTR had been associated with risk of human cancers but had never been investigated in pancreatic cancer.
In this retrospective study the SSTR5 gene in paired tumor and blood samples from 33 pancreatic adenocarcinoma patients using the Sanger method were sequenced. Three single nucleotide polymorphisms (SNPs) in samples from 863 patients with pancreatic ductal adenocarcinoma and 876 healthy controls using the TaqMan method were analyzed. The associations between gene polymorphisms and pancreatic cancer risk and survival were analyzed by multivariate logistic regression and Cox proportional hazard models, respectively.
No somatic mutations were identified, but 3 nonsynonymous SSTR5 SNPs (P109S, L48M, and P335L) in pancreatic tumors were identified. The SSTR5 P109S variant allele was associated with a 1.62-fold increased risk of pancreatic cancer (95% confidence interval [CI]: 1.08-2.43, P = 0.019). Furthermore, the SSTR5 L48M AC variant and smoking had a joint effect on pancreatic cancer risk (p(interaction) = 0.035). The odds ratios (95% confidence intervals) were 0.58 (0.34-0.97), 1.49 (1.18-1.89), and 2.27 (1.35-3.83) for the variant genotype alone, smoking alone, and both factors, respectively, compared with no factors. Finally, SSTR5 P335L CC and P109S CC combined were associated with lower overall survival durations in patients with resectable disease.
These data suggest that SSTR5 genetic variants play a role in pancreatic cancer development and progression.

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Available from: Donghui Li, Aug 11, 2014
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    • "SSTR5 knockout mice develop islet neoplasia associated with enlarged islets (Wang et al., 2004, 2005a,b). Due to its differential expression, SSTR5 is involved in tumorigenesis and drug responsiveness of a variety of human cancers including pancreatic cancer (Reubi et al., 1988; Li et al., 2011; Zhou et al., 2011a; Kaemmerer et al., 2013), pancreatic endocrine tumors (PETs) (Zhou et al., 2011b, 2012; Kaemmerer et al., 2013), pulmonary neuroendocrine tumors (Tsuta et al., 2012), gastroenteropancreatic neuroendocrine tumors (Kim et al., 2011a; Sclafani et al., 2011), small cell lung cancer (Oddstig et al., 2011), gallbladder cancer (Guo et al., 2013), colon cancer (Wang et al., 2013), endocrine pituitary tumors (Nishioka et al., 2011; Mayr et al., 2013; Chinezu et al., 2014), thyroid cancer (Ocak et al., 2013), corticotroph adenomas (Fleseriu and Petersenn, 2013), prostate cancer (Gu et al., 2010; Mazzucchelli et al., 2011; Lattanzio et al., 2013), and breast cancer (Gu et al., 2010). SSTR5 is also involved in the regulation of angiogenesis (Zatelli et al., 2001) and apoptosis (Qiu et al., 2006; Wang et al., 2013). "
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    ABSTRACT: Somatostatin (SST) is a regulatory peptide and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells. SST's actions are mediated by a family of seven transmembrane domain G protein-coupled receptors that comprise five distinct subtypes (SSTR1-5). SSTR5 is one of the major SSTRs in the islets of Langerhans. Homeodomain-containing transcription factor pancreatic and duodenal homeobox-1 (PDX-1) is essential for pancreatic development, β cell differentiation, maintenance of normal β cell functions in adults and tumorigenesis. Recent studies show that SSTR5 acts as a negative regulator for PDX-1 expression and that SSTR5 mediates somatostatin's inhibitory effect on cell proliferation and insulin expression/excretion through down-regulating PDX-1 expression. SSTR5 exerts its inhibitory effect on PDX-1 expression at both the transcriptional level by down-regulating PDX-1 mRNA and the post-translational level by enhancing PDX-1 ubiquitination. Identification of PDX-1 as a transcriptional target for SSTR5 may help in guiding the choice of therapeutic cancer treatments.
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    ABSTRACT: A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0-5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48-255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Pathologic, cytogenetic, molecular and in silico analysis was undertaken. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.142C>A (p.L48M, rs4988483) in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subjected to extensive morphological, ultrastructural, cytogenetic and molecular studies. The physical proximity of the PKD1 and SSTR5 genes on chromosome 16 suggests a causal relationship between ADPKD and somatotroph adenoma.
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