Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia

Abstract

More information is needed about genetic factors that initiate development of pancreatic intraepithelial neoplasms-the most common precursors of pancreatic ductal adenocarcinoma. We show that more than 99% of the earliest-stage, lowest-grade, pancreatic intraepithelial neoplasm-1 lesions contain mutations in KRAS, p16/CDKN2A, GNAS, or BRAF. These findings could improve our understanding of the development and progression of these premalignant lesions.

Figure 1

(A) An example of a H + E stained PanIN before and after laser capture microdissection. Microdissection was performed at the duct epithelial cell borders to avoid contamination with stromal cells. (B) Scatter-plot graph of actual and predicted concentrations of mutant DNA by pyrosequencing. (C) Prevalence of KRAS codon 12 mutations and concentration of mutations per PanIN by grade of PanIN. KRAS codon 12 mutations were found in more than 92% of PanINs in every group. The average percentage of mutant KRAS alleles within a PanIN increased at each PanIN grade. (D) Representative pyrosequencing traces with mutant sequences highlighted by the arrows. * P<0.05, **P<0.001. a = Concentrations of mutant DNA by pyrosequencing.

Figure 2. Initial mutations of PanIN-1 lesions

The pie chart in the upper portion of the figure is indicates the percentage of mutations in each of the genes tested (KRAS, GNAS, p16, BRAF) identified in PanIN-1 lesions. For PanIN-1 lesions with more than one mutation, we could not determine which gene was mutated first. For example, a few PanIN-1 lesions had both a KRAS mutation and a GNAS mutation so the initial mutation in these PanINs was indicated as arising in either “KRAS or GNAS”. The bottom portion of the figure is a schematic model illustrating the increasing percentage of mutant KRAS cells within PanIN lesions as they progress from a low-grade to a high-grade PanIN and to an invasive ductal adenocarcinoma, based on measurements of the average mutant KRAS concentrations per PanIN. Shaded cells (Present) represent PanIN cells with mutant KRAS, non-shaded cells (absent) represent PanIN cells without mutant KRAS (wild-type). PanIN = pancreatic intraepithelial neoplasia.