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Abstract
PURPOSE:
Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately affect cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of IDO2 in humans is the high prevalence of two inactivating single-nucleotide polymorphisms (SNP), which affords the opportunity to carry out loss-of-function studies directly in humans. In this study, we sought to address whether genetic loss of IDO2 may influence PDAC development and responsiveness to treatment.Experimental Design: Transgenic Ido2 +/+ and Ido2 -/- mice in which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient data sets (N = 200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression, and clinical survival data.

RESULTS:
PDAC development was notably decreased in the Ido2 -/- mice (30% vs. 10%, P < 0.05), with a female predominance similar to the association observed for one of the human SNPs. In patients, the biallelic occurrence of either of the two IDO2-inactivating SNPs was significantly associated with markedly improved disease-free survival in response to adjuvant radiotherapy (P < 0.01), a treatment modality that has been highly debated due to its variable efficacy.

CONCLUSIONS:
The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2 genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy.

Author information

Nevler A1,2,3, Muller AJ2,4,5, Sutanto-Ward E5, DuHadaway JB5, Nagatomo K5, Londin E6, O'Hayer K1, Cozzitorto JA1, Lavu H1,2, Yeo TP1,2, Curtis M6, Villatoro T6, Leiby BE2,7, Mandik-Nayak L5, Winter JM1,2, Yeo CJ1,2, Prendergast GC8,5,6, Brody JR1,2.
1
Departments of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
2
Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
3
The Dr. P. Borenstein Talpiot Medical Leadership Program (2012), ChaimSheba Medical Center, Israel.
4
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania.
5
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
6
Departments of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
7
Division of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania.
8
Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. prendergast@limr.org.