Molecular Analysis of Precursor Lesions in Familial Pancreatic Cancer

Abstract

BackgroundWith less than a 5% survival rate pancreatic adenocarcinoma (PDAC) is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical.Methods and FindingsWe have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses.ConclusionsOur comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive/therapeutic targets for both familial and sporadic pancreatic adenocarcinoma.

Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma

“…They protect epithelial cells from apoptotic death and increase their motility, but also play similar pivotal roles in cancer cells, and are thus involved in the development and progression of various cancer types (32), (33). In PDAC, TFF1 has been reported in both sporadic (34), (35) and familial PanINs (36), and it has been associated with early stages (I and II) of the disease and disease without LN involvement, i.e. stage IIA (37).…”

“…These include pancreatic cancer families (FPC) with at least two affected first-degree relatives and individuals with hereditary syndromes with known underlying gene abnormalities, such as hereditary intestinal polyposis syndrome Peutz-Jeghers (STK11/LKB1), FAMMM, familial atypical multiple mole and melanoma (p16/CDKN2A), and hereditary pancreatitis (PRSS1/SPINK1) (for a recent review see (45)). While we have previously reported deregulation of TFF1 and several REG genes in PanINs from FPC tissues (36), it is now critical to test LYVE1, and the panel as a whole, directly on urines collected from such high-risk individuals. This would best be performed within the framework of already established surveillance programmes (46), in research setting.…”

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

“…Further analysis demonstrated that patients with familial PanIN precursor lesions (27) have an intermediate level of CYR61 ( Figure 3C). Although these assessments at the mRNA level were suggestive, serum protein levels of CYR61 in PDAC patients have not been investigated.…”

“…Patient mRNA microarray expression data were obtained from publically available datasets on NCBI Gene Expression Omnibus (GEO) for GDS4103 and GSE43288 (26,27). The GDS4103 platform was Affymetrix Human Genome U133 Plus 2.0 Array.…”

Intra-tumoral IFN-γ-producing Th22 cells correlate with TNM staging and the worst outcomes in pancreatic cancer

“…One study showed that the expression of both IL-22 and IL-22R1 was elevated in sections of PDAC tissue and predicted poorer patient survival [29]. However, a different group found that IL-22R1 was more poorly expressed in patients with PDAC compared with normal controls [48]. Primary cells and metastases of oral squamous cell carcinomas showed intense staining for IL-22Rα1 [49].…”