The Screening For Pancreatic Cancer In Asymptomatic Community Populations Using The High Risk Scoring Model And The Preliminary Study Of SNP Applications In High Risk Populition

Pancreatic cancer(PC) is one of the gastroenterological malignant tumors with occult clinical manifestation,rapid progress and dismal prognosis.It is generally diagnosed at an advanced stage that the minority of patients who are able to undergo a complete resection.The difficulty in identifying patients in the early disease process leads to the poor survival,so that the impact of screening is greatest in high-risk population to reduce the mortality of pancreatic cancer.The detection of early pancreatic cancer will require screening of asymptomatic patients for the disease. Currently,individuals with genetic syndromes such as hereditary pancreatitis, Peutz-Jeghers syndrome and hereditary non-polyposis colorectal cancer are being screened,and achieving exciting advances.However such patients account for less than 5%～10%of all pancreatic cancer.Screening the general population for pancreatic cancer is unlikely to be cost effective or practical.Absence of high risk population restricts our ability to screen for sporadic pancreatic cancer,so an entirely different approach is required to establish for asymptomatic community individuals.Wang et al. found that multivariate-adjusted odds ratio(95%confidence interval) for 5,10-Methylenetetrahydrofolate reductase(MTHFR)-677CT and 677TT were 2.17 (1.26-3.85) and 3.53(1.85-6.84) times compared with 677CC respectively.It suggested that individuals with MTHFR -677 CT and TT genotype might contribute to inter-individual variability in susceptibility to pancreatic cancer and might be the high risk individuals of pancreatic cancer.It is an important way to screen the asymptomatic high risk population of sporadic pancreatic cancer through comprehensively assessing the environmental and genetic factors.Many studies indicated that patients with diabetes mellitus(DM) had an 1.0～8.0 times higher probability than the general population of subsequently being diagnosed with pancreatic cancer.It was reported that diabetes was new-onset in 0.31%patients with pancreatic cancer per year.It is still a challenge to make clear that DM is an aetiological factor or a consequence for PC in Chinese population.A strategy that relies on high-risk scoring model along with susceptibility gene of PC might capture early diagnosis of PC in a population-based cohort. This study combined the high-risk scoring model firstly constructed by PUMCH with gene polymorphisms in asymptomatic community population for the earlier diagnosis of PC.Strategies of the study:1.To explore the relationship between gene polymorphism of cytotoxic T lymphocyte associated antigen-4(CTLA-4) rs231775,rs5742909 and CD86 rs1129055, rs9831894 and the susceptibility of PC in Chinese Han population.2.To assess the application value of the high-risk scoring model for PC and the application feasibility of combining gene polymorphisms with the scoring model in asymptomatic community population.3.To establish a prospective cohort of DM associated with pancreatic cancer.Part 1.Association of cellular immune gene polymorphisms with hereditary susceptibility to pancreatic cancerMethods:We genotyped CTLA-4 rs231775,rs5742909 and CD86 rs1129055,rs9831894 in 138 patients with PC along with 278 age/sex matched healthy individuals. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and polymerase chain reaction-sequence specific primer(PCR-SSP).Results:1.The rs231775 polymorphisms of the CTLA-4 gene are associated with an increased risk of pancreatic cancer in Chinese Han population.Multivariate-adjusted odds ratio (ORs;95%confidence interval) for AG-AA genotype of rs231775 compared with GG were 1.93(1.24-3.01,P=0.0032).2.The rs9831894 polymorphisms of the CD86 gene are associated with an increased risk of pancreatic cancer in Chinese Han population.Multivariate-adjusted odds ratio (ORs;95%confidence interval) for CC genotype of rs9831894 compared with AA-AC were 2.27(1.03-4.98,P=0.042).3.Analysis of haplotypes shows that individuals who carried CD86 gene rs1129055 G-rs9831894 C type alleles are higher risk for PC compared with those who carried rs1129055A-rs9831894A type alleles(OR=1.59,95%CI=1.01-2.50,P=0.048).Summary:These results suggest that polymorphisms of the CTLA-4 and CD86 gene are associated with an increased risk of PC,which may be the important factors for individual genetic susceptibility to PC in Chinese Han population.Part 2.The screening for pancreatic cancer in asymptomatic community population using the high risk scoring model and the preliminary study of SNP applicationsMethods:A questionnaire of high risk scoring model which was established by a hospital-based case-control study was filled to the residents of 86 communities in Daqing who were older than 55 years old.These individuals whose score were higher than 45 by computer were defined as the high-risk asymptomatic community population for PC and were followed up every year to assess the application value of the high-risk scoring model for PC.We genotyped CTLA-4 rs231775 by PCR-RFLP for 25 high risk individuals whose CA19-9≥37U/ml and compared them with PC and control group.Results:1.We screened 29550 people and determined 1173(3.9%) high risk individuals.The average score of the high risk population was significantly higher than that of the other populations(65.3±17.8 vs 8.7±8.7,P<0.0001).2.We found two patients with advanced PC and one patient with early PC in high risk population during the two years follow-up.We also found four patients with other gastroenterological cancers among the high risk population.3.The distribution of rs231775 polymorphisms of the CTLA-4 gene are no statistical difference among the high risk population,PC and control group.Summary:This high risk scoring model can identify 3.9%enrolled people as high risk populations.Part 3.The establishment of prospective cohort for understanding the relationship of diabetes mellitus with pancreatic cancerMethods:We enrolled the patients with diabetes mellitus(DM) who had been registered in all the 86 communities of the Daqing Oilfield General Hospital in 2009. the patients with new-onset DM would be enrolled into the cohort momentarily.and followed up at regular intervals.Results:2217 patients with DM were enrolled in this study.The diagnostic median age is 52.7 years old.The mean course of disease is 85.8±55.20 months.There are 273 new-onset DM(12.3%) in this group.6602 first-degree relatives with mdian age of 55.9 years old were included in this group.Summary:We established a prospective cohort of DM with reliable information, scientific design and easily followed-up.This cohort is helpful for the understanding the relationship of DM with pancreatic cancer..Conclusions:1.These results suggested that polymorphisms of the CTLA-4 and CD86 gene were associated with an increased risk of PC,which may be the important factors for individual genetic susceptibility to PC in Chinese Han population.2.Preliminarily identifying the application value of the high risk scoring model for PC in asymptomatic Community population.3.We have established a prospective cohort of DM associated with pancreatic cancer for future study.