PILOT PROJECT Pancreatic ductal adenocarcinoma (PDAC) is the fourth most lethal cancer in the USA and is predicted to become the second most deadly cancer in the country by 2030. Blacks display an overall significantly greater age adjusted incidence and mortality rate from PDAC compared to Whites. Recognized risk factors for PDAC while at a higher prevalence in Blacks than Whites, does not account for the increased incidence and mortality from PDAC in Blacks, suggesting a biological explanation for the observed differences. The process of acinar ductal metaplasia (ADM) precedes PDAC precursor lesion formation. Since ADM is the earliest known precursor lesion for PDAC, acinar to ductal transdifferentiation is a key phase in the initiation of pancreatic cancer. We hypothesize that Blacks undergo ADM to a greater degree than Whites and that genetic as well as epigenetic factors account for this disparity.
Specific Aim 1 will investigate the degree of in vitro ADM quantitatively using tissue samples from human pancreata of heathy donors obtained from pancreatic islet procurement centers. Non-islet fractions containing the primary, human pancreatic acini will be cultured and functionality will be demonstrated by inducing ADM in vitro. The duct formation doubling time and fold change in expression of acinar and ductal genes between Black and White donors will determine if ADM is enhanced in Blacks. Expression arrays will be used to identify the top genetic drivers of ADM in Blacks and Whites. Promoter DNA methylation will determine if epigenetic changes are responsible for the change in gene expression between Blacks and Whites.
Specific Aim 2 will perform a genetic association study to identify SNPs in the genetic drivers of ADM using nested, case-control cohorts of PDAC data. Successful completion of this project will establish that racial disparities exist for the ability of pancreatic acini to undergo ADM. We will have also identified a gene expression signature that will characterize the ADM process by race as well as genetic and epigenetic factors that drive ADM in Blacks.
