Abstract B30: High expression of PIGR is an independent favorable prognostic factor in pancreatic and periampullary adenocarcinoma

Abstract

Introduction: The polymeric immunoglobulin receptor (PIGR) is a member of the immunoglobulin superfamily and key component of the mucosal immune system that mediates epithelial transcytosis of polymeric immunoglobulins. High PIGR expression has been reported to correlate with a less aggressive tumor phenotype and favorable prognosis in e.g. gastro-esophageal, colon, urinary bladder and ovarian cancer, and with a greater metastatic potential and poor prognosis in hepatitis B-derived hepatocellular carcinoma, PIGR has recently been demonstrated to be up-regulated in pancreatic cancer cells upon exposure to stromal cells in vitro, but its expression and prognostic significance in human pancreatic cancer has not yet been reported. The aim of the present study was therefore to examine the longitudinal expression and prognostic significance of PIGR in a large consecutive series of pancreatic and periampullary adenocarcinoma. Material and Methods: The study cohort encompasses a consecutive series of 175 patients surgically treated by means of pancreaticoduodenectomy for pancreatic and periampullary adenocarcinomas in the University hospitals of Malmö and Lund, Sweden, from January 1, 2001 to December 31, 2011. Tissue microarrays were constructed from all primary tumors (n =175) and paired lymph node metastases from 105 cases. PIGR was expressed in the cytoplasm and both the staining intensity and fraction of positive cells was denoted. For statistical purposes, a multiplier of the fraction and intensity of staining was applied. Mann Whitney U test was applied for analysis of PIGR expression in relation to clinicopathological characteristics. Classification and regression tree analysis was used for selection of prognostic cut-off. The impact of PIGR expression on 5-year overall survival (OS) and hazard ratios (HR) was calculated by adjusted and unadjusted Cox proportional hazards modeling. Results: PIGR expression could be evaluated in 172/175 (98.3%) of the primary tumors and in 96/105 (91.4%) lymph node metastases. High PIGR expression was significantly associated with more well differentiated tumors (p=<0.001), and inversely associated with perineural growth (p=0.016), lymphatic invasion (p=0.010), vascular invasion (p=0.027) and infiltration of the peripancreatic fat (p=0.024). PIGR expression was significantly down regulated in lymph node metastases as compared to primary tumors (p=0.018). High PIGR expression was significantly associated with a prolonged 5-year survival (unadjusted HR 0.21, 95% CI 0.09-0.48, p=<0.001) and this association remained significant after adjustment for T-stage, N-stage, tumor size, tumor grade, perineural growth, invasion in lymphatic vessels, invasion in blood vessels, growth in peripancreatic fat, involved margins, age and sex (HR 0.27, 95% CI 0.12-0.63, p=0.002). Conclusion: The results from this study demonstrate, for the first time, that high PIGR expression is associated with a more favorable tumor phenotype and is an independent marker of improved prognosis in pancreatic and periampullary cancer. The observed down regulation of PIGR expression in lymph node metastases as compared with primary tumors further supports a tumor suppressing role for PIGR in these cancers. These findings are of potential clinical relevance and warrant confirmation in additional patient cohorts. In addition, elucidating the mechanistic basis for the role of PIGR in tumor progression, with particular reference to the interplay of tumor cells and stroma, remains an intriguing challenge for future functional work. Citation Format: Richard Fristedt, Jacob Elebro, Alexander Gaber, Björn Nodin, Mathias Uhlén, Karin Jirström. High expression of PIGR is an independent favorable prognostic factor in pancreatic and periampullary adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B30.

DNA‑methylated gene markers for colorectal cancer in TCGA database

“…For instance, the ectopic expression of transforming growth factor beta induced is associated with enhanced metastasis and extravasation of CRC (19)(20)(21). Polymeric immunoglobulin receptor promotes tumor growth in hepatocellular carcinoma (22), but inhibits pancreatic and periampullary adenocarcinoma development (23). Homeobox (HOX) expression contributes to CRC development: HOXB3, HOXB8 and HOXB9 are significantly upregulated, whereas HOXB2 and HOXB13 are significantly downregulated in carcinoma tissues (24).…”