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The −409 C/T Genotype of PRSS1 Protects Against Pancreatic Cancer in the Han Chinese Population

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Abstract

Background and Aims

The high mortality rate of pancreatic cancer is a bottleneck for further treatment with long-term efficacy. Thus, it is urgent to identify new methods to accurately predict the early onset of pancreatic cancer. We hypothesized that the different genotypes of cationic trypsinogen (PRSS1) gene could confer susceptibility and/or resistance to pancreatic cancer in the Han Chinese population.

Methods

The genotypes of PRSS1 were determined in 154 patients with pancreatic cancer and in a control group of 520 healthy individuals of Han Chinese descent. Clinical information was obtained, single-nucleotide polymorphisms (SNPs) of the PRSS1 gene were analyzed by direct sequencing, and the distribution of the genotypes were tested for Hardy–Weinberg equilibrium. Odds ratios and 95% confidence intervals were calculated by logistic regression analysis to estimate the associations between the different genotypes or haplotypes and the risk of pancreatic cancer.

Results

Three SNPs (−409 C/T, −204 A/C, and c.486 C/T) were identified. A case-control analysis revealed a 0.118-fold (95% CI: 0.037–0.653), 0.842-fold (95% CI: 0.177–4.010), and 0.750-fold (95% CI: 0.519–1.085) change in risk of develo** pancreatic cancer for individuals harboring these SNPs, respectively. The individuals with the −409 C/T genotype tended to have a reduced risk compared to those who carried the −409 T/T genotype. A protective effect was observed for the C−409–A−204–C486 haplotype compared to the T−409–A−204–T486 haplotype (OR = 0.115, 95% CI: 0.016–0.849) or compared to the T−409–A−204–C486 haplotype (OR = 0.090, 95% CI: 0.012–0.667). Serum levels of trypsin in patients with the −409 C/T genotype were only one-fourth that of those with the −409 T/T genotype and only one-third that of the healthy controls.

Conclusions

The −409 C/T genotype of PRSS1 was reveled to be a protective factor against pancreatic cancer in the Han Chinese population.

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References

  1. Tersmette AC, Petersen GM, Offerhaus GJ, et al. Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res. 2001;7:738–744.

    PubMed  CAS  Google Scholar 

  2. Eberle MA, Pfutzer R, Pogue-Geile KL, et al. A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32–34. Am J Hum Genet. 2002;70:1044–1048.

    Article  PubMed  CAS  Google Scholar 

  3. van der Heijden MS, Yeo CJ, Hruban RH, Kern SE. Fanconianemia gene mutations in young-onset pancreatic cancer. Cancer Res. 2003;63:2585–2588.

    PubMed  Google Scholar 

  4. Cox B, Waisfisz Q, Die-Smulders C, et al. Biallelic inactivation of BRCA2 in fanconianemia. Science. 2002;297:606–609.

    Article  PubMed  Google Scholar 

  5. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res. 2002;62:3789–3793.

    PubMed  CAS  Google Scholar 

  6. Jemal A, Siegel R, Ward E, et al. Cancer statistics 2007. CA Cancer J Clin. 2007;57:43–66.

    Article  PubMed  Google Scholar 

  7. Zogopoulos G, Rothenmund H, Eppel A, et al. The P239S palladin variant does not account for a significant fraction of hereditary or early onset pancreas cancer. Hum Genet. 2007;121:635–637.

    Article  PubMed  Google Scholar 

  8. Rulyak SJ, Lowenfels AB, Maisonneuve P, Brentnall TA. Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindred’s. Gastroenterology. 2003;124:1292–1299.

    Article  PubMed  Google Scholar 

  9. Ikeda O, Egami H, Ishiko T, Ishikawa S, et al. Signal of proteinase-activated receptor-2 contributes to highly malignant potential of human pancreatic cancer by up-regulation of interleukin-8 release. Int J Oncol. 2006;28:939–946.

    PubMed  CAS  Google Scholar 

  10. Rebours V, Boutron-Ruault MC, Schnee M, et al. Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series. Am J Gastroenterol. 2008;103:111–119.

    PubMed  Google Scholar 

  11. Hengstler JG, Bauer A, Wolf HK, et al. Mutation analysis of the cationic trypsinogen gene in patients with pancreatic cancer. Anticancer Res. 2000;20:2967–2974.

    PubMed  CAS  Google Scholar 

  12. Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol. 2002;10:153–169.

    Article  PubMed  Google Scholar 

  13. Chen JM, Férec C. Chronic pancreatitis: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2009;10:63–87.

    Article  PubMed  CAS  Google Scholar 

  14. Liu QC, Gao F, Ou QS, et al. Novel mutation and polymorphism of PRSS1 gene in the Chinese patients with hereditary pancreatitis and chronic pancreatitis. Chin Med J. 2008;121:108–111.

    Article  PubMed  CAS  Google Scholar 

  15. Jemal A, Siegel R, Ward E, et al. Cancer statistics 2008. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  16. Szmola R, Sahin-Tóth M. Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations. J Med Genet. 2010;47:348–350.

    Article  PubMed  CAS  Google Scholar 

  17. Rebours V, Lévy P, Mosnier JF, et al. Pathology analysis reveals that dysplastic pancreatic ductal lesions are frequent in patients with hereditary pancreatitis. Clin Gastroenterol Hepatol. 2010;8:206–212.

    Article  PubMed  Google Scholar 

  18. Chen JM, Le Mar’echal C, Lucas D, et al. Loss-of-function mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis. Mol Genet Metab. 2003;79:67–70.

    Article  PubMed  CAS  Google Scholar 

  19. Witt H, Sahin-Toth M, Landt O, et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet. 2006;38:668–673.

    Article  PubMed  CAS  Google Scholar 

  20. Jiao L, Bondy ML, Hassan MM, et al. Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer. Cancer. 2007;109:840–848.

    Article  PubMed  CAS  Google Scholar 

  21. Ducroc R, Bontemps C, Marazova K, et al. Trypsin is produced by and activates protease-activated receptor-2 in human cancer colon cells: evidence for new autocrine loop. Life Sci. 2002;270:1359–1367.

    Article  Google Scholar 

  22. Shimamoto R, Sawada T, Uchima Y, et al. A role for protease-activated receptor-2 in pancreatic cancer cell proliferation. Int J Oncol. 2004;24:1401–1406.

    PubMed  CAS  Google Scholar 

  23. Lowenfels AB, Maisonneuve P, Whitcomb DC, et al. Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. JAMA. 2001;286:169–170.

    Article  PubMed  CAS  Google Scholar 

  24. Rulyak SJ, Lowenfels AB, Maisonneuve P, Brentnall TA. Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindred’s. Gastroenterology. 2003;124:1292–1299.

    Article  PubMed  Google Scholar 

  25. Huxley R, Ansary-Moghaddam A, Berrington DG, et al. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92:2076–2083.

    Article  PubMed  CAS  Google Scholar 

  26. Chari ST, Leibson CL, Rabe KG, et al. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology. 2005;129:504–511.

    PubMed  Google Scholar 

  27. Liu QC, Zhuang ZH, Zeng K, et al. Prevalence of pancreatic diabetes in patients carrying mutations or polymorphisms of the PRSS1 gene in the Han population. Diabetes Technol Ther. 2009;11:799–804.

    Article  PubMed  CAS  Google Scholar 

  28. Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol. 2004;2:252–261.

    Article  PubMed  CAS  Google Scholar 

  29. Lowenfels AB, Maisonneuve P, Whitcomb DC, et al. Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. J Am Med Assoc. 2001;286:169–170.

    Article  CAS  Google Scholar 

  30. Dale V, Paula G, Eithne C, John N. Genetics and prevention of pancreatic cancer. Cancer Control. 2004;11:6–14.

    Google Scholar 

  31. Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med. 2010;61:413–424.

    Article  PubMed  CAS  Google Scholar 

  32. Rebours V, Boutron-Ruault MC, Schnee M, et al. Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series. Am J Gastroenterol. 2008;103:111–119.

    PubMed  Google Scholar 

  33. Berndt C, Haubold K, Wenger F, et al. k-ras mutations in stools and tissue samples from patients with malignant and nonmalignant pancreatic diseases. Clin Chem. 1998;44:2103–2107.

    PubMed  CAS  Google Scholar 

  34. Tang Z, Geng G, Huang Q, et al. Prognostic significance of tissue factor pathway inhibitor-2 in pancreatic carcinoma and its effect on tumor invasion and metastasis. Med Oncol. 2010;27:867–875.

    Article  PubMed  CAS  Google Scholar 

  35. Caruso R, Pallone F, Fina D, et al. Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor trans-activation and proliferation. Am J Pathol. 2006;169:268–278.

    Article  PubMed  CAS  Google Scholar 

  36. Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev. 2004;84:579–621.

    Article  PubMed  CAS  Google Scholar 

  37. Grocock CJ, Rebours V, Delhaye MN, et al. The variable phenotype of the p. A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. Gut. 2010;59:357–363.

    Article  PubMed  CAS  Google Scholar 

  38. Dong X, Jiao L, Li Y, et al. Significant Associations of mismatch repair gene polymorphisms with clinical outcome of pancreatic cancer. J Clin Oncol. 2009;27:1592–1599.

    Article  PubMed  CAS  Google Scholar 

  39. Pickering BM, Willis AE. The implications of structured 5′ untranslated regions on translation and disease. Semin Cell Dev Biol. 2005;16:39–47.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Financial support from the Project Foundation of Fujian Provincial Education (JA10143), National High Technology Investigation Project Foundation of China (2008AA02Z433), National Natural Science Foundation of China (20975021, 20805006), and the Major Program Foundation of Fujian Medical University (09ZD013) is greatly acknowledged.

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Correspondence to **nhua Lin.

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Liu, Q., Lin, X., Liu, J. et al. The −409 C/T Genotype of PRSS1 Protects Against Pancreatic Cancer in the Han Chinese Population. Dig Dis Sci 57, 573–579 (2012). https://doi.org/10.1007/s10620-011-1893-6

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  • DOI: https://doi.org/10.1007/s10620-011-1893-6

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