In the current study, we detected no somatic mutations but found 3 nonsynonymous SNPs—P109S, L48M, and P335L of the SSTR5 gene—in 33 primary pancreatic adenocarcinomas. A case-control analysis revealed that both the P109S variant T allele alone and the L48M variant A allele and smoking were significantly associated with increased pancreatic cancer risk. The P335L CC and P109S CC genotypes were associated with reduced overall survival duration in patients with resectable disease. To our knowledge, this is the first study to demonstrate an association between SSTR5 gene variants and pancreatic cancer.
Studies of SSTR
gene polymorphisms and cancer risk are limited and have been performed mainly in hormone-related cancers. One study showed that SSTR2
gene polymorphisms are significantly but weakly associated with breast cancer risk (14
). Another showed no association between SSTR
gene polymorphisms and prostate cancer risk (13
). Thus, the relationship between SSTR
genetic variants and cancer risk is controversial and may depend on cancer type. In the current study, we found a positive association between SSTR5
genotype and pancreatic cancer risk. Although the functional significance of the SSTR5
P109S variant has not been demonstrated experimentally, it was predicted to be damaging or deleterious using a bioinformatics approach (19
). Considering that SST’s role in inhibiting cell growth and proliferation is mediated via SSTR (8
) and the SSTR5 expression level is decreased in pancreatic cancer tissue (10
), the variant genotypes may result in decreased expression or impaired function, which promotes cell proliferation and cancer development in the pancreas.
The SSTR5 receptor has a high affinity for SST, a multifunctional neuropeptide that is widely distributed throughout the central nervous system and acts in the anterior pituitary gland to inhibit growth hormone secretion (20
). Therefore, SSTR5 negatively regulates IGF-1 levels through the growth hormone (GH)-IGF-1 axis (11
). Circulating IGF-1 in the blood has been correlated with breast and prostate cancer risk (21
) but not with pancreatic cancer risk (22
). However, IGF-1 and IGF-1 receptors are highly expressed in pancreatic cancer cell lines (23
). Notably, the SSTR5
L48M variant allele has been associated with lower circulating IGF-1 and IGFBP3 levels (13
). In the current study, the L48M variant had no significant main effect but had a differential effect on the risk of pancreatic cancer by cigarette smoking status, i.e. the L48M variant was associated with reduced risk among non-smokers but increased risk among smokers. A similar but insignificant interaction between the P109S variant and smoking was also observed. A previous study has observed that smokers had a lower serum IGF1:IGFBP3 molar ratio and IGF1 level than non-smokers among African Americans but not among whites (25
). Thus the increased risk of pancreatic cancer in smokers by L48M variant allele could not be explained by its impact on IGF1 level. We can only speculate that the reduced risk associated with the valiant allele in non-smokers was related to a lower level of IGF1 while the increased risk in smokers could be related to impaired inhibition of cell growth and proliferation conferred by the variant allele. Further investigation is required to confirm these observations and to illustrate the mechanisms underlying such associations. Because of the extremely low frequency of the SNPs’ homozygous variants and the relatively small sample size, the effect of the homozygote on pancreatic cancer could not be assessed in this study.
The SSTR5 P335L SNP has a much higher minor allele frequency than do the P109S and L48M SNPs but little effect on pancreatic cancer risk. Nevertheless, patients with resectable tumors who have the P335L and P109S CC genotypes had significantly shorter overall survival durations than did patients with the common P335L TT/CT and P109S CC genotypes. The underlying mechanism of this association remains unknown. A recent study showed that P335L T allele overexpression in pancreatic cancer cells leads to increased cell proliferation and PDX-1 expression, whereas C allele overexpression enhances the SSTR5 agonist’s inhibitory effect on cell proliferation and insulin secretion (manuscript in preparation). SSTR5’s role in pancreatic cancer development and its complex interactions with PDX1 or IGF-1 and progression require further investigation. The P109S variant CT genotype’s protective effect on patient survival could indicate that its association with pancreatic cancer risk is confounded by a survival bias. However, it was not associated with survival in the most patients with advanced disease.
Overall, we observed weak associations between 3 nonsynonymous SSTR5 gene SNPs and pancreatic cancer risk and survival. Because the minor allele frequencies of 2 of these gene variants (L48M and P109S) were low (≤6%), these observations need to be confirmed in much larger studies. If confirmed, this genetic information will be useful for estimating pancreatic cancer risk and survival.